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Jiang SM, Li XJ, Wang ZL, Chen ZW, Liu ZL, Li Q, Chen XL. Role of autophagy in rejection after solid organ transplantation: A systematic review of the literature. World J Transplant 2025; 15:103163. [DOI: 10.5500/wjt.v15.i3.103163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 04/18/2025] Open
Abstract
Organ transplantation has long been recognized as an effective treatment for end-stage organ failure, metabolic diseases, and malignant tumors. However, graft rejection caused by major histocompatibility complex mismatch remains a significant challenge. While modern immunosuppressants have made significant strides in reducing the incidence and risk of rejection, they have not been able to eliminate it completely. The intricate mechanisms underlying transplant rejection have been the subject of intense investigation by transplant immunologists. Among these factors, autophagy has emerged as a key player. Autophagy is an evolutionarily conserved mechanism in eukaryotic cells that mediates autophagocytosis and cellular protection. This process is regulated by autophagy-related genes and their encoded protein families, which maintain the material and energetic balance within cells. Additionally, autophagy has been reported to play crucial roles in the development, maturation, differentiation, and responses of immune cells. In the complex immune environment following transplantation, the role and mechanisms of autophagy are gradually being revealed. In this review, we aim to explore the current understanding of the role of autophagy in solid organ rejection after transplantation. Furthermore, we delve into the therapeutic advancements achieved by targeting autophagy involved in the rejection process.
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Affiliation(s)
- Shu-Min Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Xue-Jiao Li
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Zi-Lin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Wei Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Long Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Xiao-Long Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
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Sethapati VR, Narula N, Yunce M. Expanding Horizons: Single-Center Insights on Extracorporeal Photopheresis (ECP) in Non-Lung Solid Organ Transplantation. J Clin Apher 2025; 40:e70028. [PMID: 40375496 DOI: 10.1002/jca.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/14/2025] [Accepted: 04/08/2025] [Indexed: 05/18/2025]
Abstract
Transplantation remains the best option for patients with advanced-stage organ failure. In some patients, despite aggressive medical management with immunosuppressants, refractory/recurrent rejection occurs. This single-center retrospective study aims to analyze the role of ECP as an add-on therapy to treat acute cellular rejection (ACR) and/or antibody-mediated rejection (AMR) in non-lung organ transplantation. We identified five non-lung solid organ transplant (SOT) recipients refractory to standard anti-rejection interventions that received ECP therapy in the last 5 years: one liver transplant, two heart transplants, and two small bowel transplants. Baseline demographics, time to ECP initiation, clinical assessment, and biopsy results were analyzed. They received at least 6 months of ECP for biopsy-proven ACR and/or AMR. Graft function was assessed clinically after 6 months by biopsy and/or clinical functional assessment. Graft function improved in all five patients after 6 months of ECP therapy based on clinical functional evaluation and by biopsy in some patients. No complications or adverse events were reported. This study supports the potential for ECP as an adjunctive therapy in non-lung organ transplant recipients who are refractory to standard therapies and present with ACR and/or AMR. ECP has immunomodulating effect with minimal procedural risk. Prospective studies are warranted to confirm the beneficial effects of ECP in the setting of ACR and AMR post organ transplantation.
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Affiliation(s)
- V Rakesh Sethapati
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Naureen Narula
- Department of Cardiothoracic Surgery, University of Kentucky Healthcare, Lexington, Kentucky, USA
| | - Muharrem Yunce
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
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Land WG, Linkermann A. Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 1: their emergence from injuries to the donor organ. FRONTIERS IN TRANSPLANTATION 2025; 4:1571516. [PMID: 40343197 PMCID: PMC12060192 DOI: 10.3389/frtra.2025.1571516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025]
Abstract
This Part 1 of a bipartite review commences with a succinct exposition of innate alloimmunity in light of the danger/injury hypothesis in Immunology. The model posits that an alloimmune response, along with the presentation of alloantigens, is driven by DAMPs released from various forms of regulated cell death (RCD) induced by any severe injury to the donor or the donor organ, respectively. To provide a strong foundation for this review, which examines RCD and DAMPs as biomarkers and therapeutic targets in normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) to improve outcomes in organ transplantation, key insights are presented on the nature, classification, and functions of DAMPs, as well as the signaling mechanisms of RCD pathways, including ferroptosis, necroptosis, pyroptosis, and NETosis. Subsequently, a comprehensive discussion is provided on major periods of injuries to the donor or donor organs that are associated with the induction of RCD and DAMPs and precede the onset of the innate alloimmune response in recipients. These periods of injury to donor organs include conditions associated with donation after brain death (DBD) and donation after circulatory death (DCD). Particular emphasis in this discussion is placed on the different origins of RCD-associated DAMPs in DBD and DCD and the different routes they use within the circulatory system to reach potential allografts. The review ends by addressing another particularly critical period of injury to donor organs: their postischemic reperfusion following implantation into the recipient-a decisive factor in determining transplantation outcome. Here, the discussion focuses on mechanisms of ischemia-induced oxidative injury that causes RCD and generates DAMPs, which initiate a robust innate alloimmune response.
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Affiliation(s)
- Walter G. Land
- German Academy for Transplantation Medicine, Munich, Germany
- Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, Strasbourg, France
- Department of Integrated Medical Sciences, Medical Science Faculty, State University of Rio De Janeiro, Cabo Frio, Brazil
| | - Andreas Linkermann
- Department of Medicine V, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
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Cheng Y, Zhang J, Mu W, Ye S, Cheng J, Zhu L, Wang G, Cao Y, Li D, Hu G, Huang L, Wang J, Zhou J. Dasatinib-resistant universal CAR-T cells proliferate in the presence of host immune cells and exhibit antitumor activity. Mol Ther 2025; 33:1535-1551. [PMID: 39935177 PMCID: PMC11997472 DOI: 10.1016/j.ymthe.2025.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 12/01/2024] [Accepted: 02/06/2025] [Indexed: 02/13/2025] Open
Abstract
The universal chimeric antigen receptor T cell (UCAR-T) immunotherapy derived from healthy donors holds great promise in pan-cancer treatment. However, UCAR-T cell therapy faces a challenge in the rapid elimination of allogeneic cells by the host immune system. To address this, we introduced a T316I mutation in the leukocyte-specific protein tyrosine kinase (LCK) locus in CAR-T cells using the cytosine base editor (CBE) system. Concurrently, we disrupted endogenous T cell receptor alpha chain (TRAC) and beta-2 microglobulin (B2M) with the CRISPR-Cas9 system, along with dasatinib to overcome host immune rejection, an Src family kinase (SFK) inhibitor. The resulting LCK mutated UCAR-T (KM UCAR-T) cells exhibited normal phenotypes in activation, proliferation, differentiation, and tumor cytotoxicity in vitro. Moreover, KM UCAR-T cells demonstrated sustained expansion in mixed lymphocyte reactions (MLR) when incubated with T cells or peripheral blood mononuclear cells (PBMCs) from HLA-mismatched donors upon dasatinib treatment. Additionally, we illustrated that KM UCAR-T cells displayed antitumor activity in a xenograft murine model and verified the expansion and cytotoxicity of KM UCAR-T over traditional UCAR-T in the presence of allogeneic PBMCs when treated with dasatinib in vivo. These findings offer a novel strategy for UCAR-T cells to resist host immune rejection and achieve sustained expansion.
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Affiliation(s)
- Yuhang Cheng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Jiayuan Zhang
- Nanjing IASO Biotherapeutics Co., Ltd., Nanjing, Jiangsu 210000, China
| | - Wei Mu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Shanwei Ye
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Jiali Cheng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Li Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Gaoxiang Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Yang Cao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Dengju Li
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
| | - Guang Hu
- Nanjing IASO Biotherapeutics Co., Ltd., Nanjing, Jiangsu 210000, China.
| | - Liang Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China.
| | - Jue Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China.
| | - Jianfeng Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, Hubei 430030, China
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Gomes KT, Prasad PR, Sandhu JS, Kumar A, Kumar NAN, Shridhar NB, Bisht B, Paul MK. Decellularization techniques: unveiling the blueprint for tracheal tissue engineering. Front Bioeng Biotechnol 2025; 13:1518905. [PMID: 40092377 PMCID: PMC11906413 DOI: 10.3389/fbioe.2025.1518905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/03/2025] [Indexed: 03/19/2025] Open
Abstract
Certain congenital or acquired diseases and defects such as tracheo-oesophageal fistula, tracheomalacia, tracheal stenosis, airway ischemia, infections, and tumours can cause damage to the trachea. Treatments available do not offer any permanent solutions. Moreover, long-segment defects in the trachea have no available surgical treatments. Tissue engineering has gained popularity in current regenerative medicine as a promising approach to bridge this gap. Among the various tissue engineering techniques, decellularization is a widely used approach that removes the cellular and nuclear contents from the tissue while preserving the native extracellular matrix components. The decellularized scaffolds exhibit significantly lower immunogenicity and retain the essential biomechanical and proangiogenic properties of native tissue, creating a foundation for trachea regeneration. The present review provides an overview of trachea decellularization advancements, exploring how recellularization approaches can be optimized by using various stem cells and tissue-specific cells to restore the scaffold's structure and function. We examine critical factors such as mechanical properties, revascularization, and immunogenicity involved in the transplantation of tissue-engineered grafts.
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Affiliation(s)
- Keisha T Gomes
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Palla Ranga Prasad
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Jagnoor Singh Sandhu
- Central Animal Research Facility, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
- Center for Animal Research, Ethics and Training (CARET), Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Ashwini Kumar
- Department of Forensic Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Naveena A N Kumar
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - N B Shridhar
- Department of Pharmacology and Toxicology, Obscure Disease Research Center, Veterinary College Campus, Shivamogga, Karnataka, India
| | - Bharti Bisht
- Department of Microbiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Manash K Paul
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, United States
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Belardi R, Pacifici F, Baldetti M, Velocci S, Minieri M, Pieri M, Campione E, Della-Morte D, Tisone G, Anselmo A, Novelli G, Bernardini S, Terrinoni A. Trends in Precision Medicine and Pharmacogenetics as an Adjuvant in Establishing a Correct Immunosuppressive Therapy for Kidney Transplant: An Up-to-Date Historical Overview. Int J Mol Sci 2025; 26:1960. [PMID: 40076585 PMCID: PMC11900248 DOI: 10.3390/ijms26051960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host's immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes.
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Affiliation(s)
- Riccardo Belardi
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Francesca Pacifici
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, 00166 Rome, Italy; (F.P.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ-on-Chip Applications (ICLOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Matteo Baldetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Silvia Velocci
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Marilena Minieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Massimo Pieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Elena Campione
- Dermatology Unit, Policlinico Tor Vergata, System Medicine Department, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - David Della-Morte
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, 00166 Rome, Italy; (F.P.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ-on-Chip Applications (ICLOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Department of Neurology, Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Giuseppe Tisone
- Department of Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (G.T.)
| | - Alessandro Anselmo
- Department of Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (G.T.)
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Alessandro Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
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Li B, Wang Y, Owens CR, Banaee T, Chu CT, Jabbari K, Lee AD, Khatter NJ, Palestine AG, Su AJA, Huang CA, Washington KM. Immune responses in rodent whole eye transplantation: elucidation and preliminary investigations into rejection diagnosis and monitoring. Front Immunol 2025; 16:1475055. [PMID: 39944695 PMCID: PMC11814173 DOI: 10.3389/fimmu.2025.1475055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 01/06/2025] [Indexed: 02/16/2025] Open
Abstract
Background Whole Eye Transplantation (WET) offers potential for vision restoration but is hindered by the complex challenge of immune rejection. Understanding and closely monitoring these immunological responses is crucial for advancing WET. This study delves into the timeline and nature of immune responses in a rodent model of WET without immunosuppression, aiming to elucidate a detailed picture of the immune landscape post-transplantation and establish innovative diagnostic and monitoring methods. Methods We employed a multi-faceted approach to analyze immune responses post-WET, including assessments of gross changes in corneal transparency, thickness, and skin condition. Histopathological examinations of both ocular and surrounding skin tissues provided insights into cellular changes, complemented by ocular RT-qPCR for molecular analysis. Serological analysis was employed to quantify cytokines, chemokines, and donor-specific antibodies, aiming to identify potential biomarkers correlating with WET rejection and to validate the presence of antibody-mediated rejection. These methodologies collectively contribute to the development of non-invasive diagnostic and monitoring strategies for WET. Results Our study revealed a rapid and acute immune response following WET, characterized by an early innate immune response dominated by complement involvement, and infiltration of neutrophils and monocytes by post-operative day (POD) 2. This was succeeded by an acute T-cell-mediated immune reaction, predominantly involving T helper 1 (Th1) cells and cytotoxic T lymphocytes (CTLs). The presence of donor specific antibody (DSA) and indications of pyroptosis in the early phases of rejection were observed. Notably, the early elevation of serum CXCL10 by POD4, coupled with ocular CD3+ cell infiltration, emerged as a potential early biomarker for WET rejection. Additionally, corneal transparency grading proved effective as a non-invasive monitoring tool. Conclusion This study offers a first-time comprehensive exploration of immune responses in WET, unveiling rapid and complex rejection mechanisms. The identification of early biomarkers and the development of non-invasive monitoring techniques significantly advance our understanding of WET rejection. Additionally, these findings establish an essential baseline for future research in this evolving field.
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Affiliation(s)
- Bing Li
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Yong Wang
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Charles R. Owens
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Touka Banaee
- Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, United States
| | - Charleen T. Chu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Kayvon Jabbari
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Anna D. Lee
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Neil J. Khatter
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Alan G. Palestine
- Sue Anschutz-Rogers Eye Center, Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - An-Jey A. Su
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Christene A. Huang
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kia M. Washington
- Division of Plastic Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Uehara R, Takeda S, Oku D, Sasaki R, Murakami M, Shiba H, Katakura F, Moritomo T. Establishment of a novel clonal GFP-expressing transgenic ginbuna crucian carp. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 162:105290. [PMID: 39571925 DOI: 10.1016/j.dci.2024.105290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 11/14/2024] [Accepted: 11/18/2024] [Indexed: 11/27/2024]
Abstract
The clonal triploid ginbuna crucian carp Carassius auratus langsdorfii, a naturally occurring gynogenetic fish, is suitable for cell transplantation studies to reveal the roles of stem cells and immune cells. To ensure long-term traceability of donor cells within recipient fish, we have established a transgenic ginbuna line that expresses green fluorescent protein (GFP). The Xenopus laevis ef1a promoter was introduced for regulating GFP expression. Tol2 transposon-based transgenesis to ginbuna embryos resulted in producing a putative founder fish (F0) in a mosaic fluorescent fashion; the frequency of germline transmission was 14.9%. All embryos of GFP-positive offspring (F1)-derived F2 generation expressed GFP widely across the body. The result of Southern blot analysis showed that the transgene was present on a single DNA fragment of equivalent size among F1 and F2 individuals tested, indicating that the transgene was stably transmitted without translocation. Analysis of the fluorescence intensity of organs obtained from F1 and F2 juveniles using fluorescence microscope showed that eyes, brain, skeletal muscle, heart and gonad exhibited a strong GFP fluorescence while gill, spleen and intestine gave a weak signal; no fluorescence was observed in erythrocytes. Flow cytometric analyses of peripheral leukocytes from F1 and F2 adult fish revealed all cell populations expressed GFP. Scale grafts from the transgenic fish to the wild-type fish exhibited persistent engraftment. Together, our transgenic line can be a powerful tool for studying cellular dynamics by cell transplantation and provide a solid basis for further immunological research advances in teleost.
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Affiliation(s)
- Ren Uehara
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan
| | - Shinji Takeda
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan
| | - Daichi Oku
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan
| | - Ryo Sasaki
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan
| | - Masaru Murakami
- Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara, Kanagawa, 252-5201, Japan
| | - Hajime Shiba
- Department of Bioscience, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan
| | - Fumihiko Katakura
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan.
| | - Tadaaki Moritomo
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan
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Meng F, Fu Y, Xie H, Wang H. Nanoparticle-assisted Targeting Delivery Technologies for Preventing Organ Rejection. Transplantation 2024; 108:2174-2185. [PMID: 38597913 DOI: 10.1097/tp.0000000000005025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.
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Affiliation(s)
- Fanchao Meng
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, People's Republic of China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yang Fu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Haiyang Xie
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Hangxiang Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, People's Republic of China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
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10
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Zhang HL, Qiu XX, Liao XH. Dermal Papilla Cells: From Basic Research to Translational Applications. BIOLOGY 2024; 13:842. [PMID: 39452150 PMCID: PMC11504027 DOI: 10.3390/biology13100842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/13/2024] [Accepted: 10/18/2024] [Indexed: 10/26/2024]
Abstract
As an appendage of the skin, hair protects against ultraviolet radiation and mechanical damage and regulates body temperature. It also reflects an individual's health status and serves as an important method of expressing personality. Hair loss and graying are significant psychosocial burdens for many people. Hair is produced from hair follicles, which are exclusively controlled by the dermal papilla (DP) at their base. The dermal papilla cells (DPCs) comprise a cluster of specialized mesenchymal cells that induce the formation of hair follicles during early embryonic development through interaction with epithelial precursor cells. They continue to regulate the growth cycle, color, size, and type of hair after the hair follicle matures by secreting various factors. DPCs possess stem cell characteristics and can be cultured and expanded in vitro. DPCs express numerous stemness-related factors, enabling them to be reprogrammed into induced pluripotent stem cells (iPSCs) using only two, or even one, Yamanaka factor. DPCs are an important source of skin-derived precursors (SKPs). When combined with epithelial stem cells, they can reconstitute skin and hair follicles, participating in the regeneration of the dermis, including the DP and dermal sheath. When implanted between the epidermis and dermis, DPCs can induce the formation of new hair follicles on hairless skin. Subcutaneous injection of DPCs and their exosomes can promote hair growth. This review summarizes the in vivo functions of the DP; highlights the potential of DPCs in cell therapy, particularly for the treatment of hair loss; and discusses the challenges and recent advances in the field, from basic research to translational applications.
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Affiliation(s)
- He-Li Zhang
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China;
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
| | - Xi-Xi Qiu
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
| | - Xin-Hua Liao
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
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11
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Naaz A, Turnquist HR, Gorantla VS, Little SR. Drug delivery strategies for local immunomodulation in transplantation: Bridging the translational gap. Adv Drug Deliv Rev 2024; 213:115429. [PMID: 39142608 DOI: 10.1016/j.addr.2024.115429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 08/07/2024] [Accepted: 08/11/2024] [Indexed: 08/16/2024]
Abstract
Drug delivery strategies for local immunomodulation hold tremendous promise compared to current clinical gold-standard systemic immunosuppression as they could improve the benefit to risk ratio of life-saving or life-enhancing transplants. Such strategies have facilitated prolonged graft survival in animal models at lower drug doses while minimizing off-target effects. Despite the promising outcomes in preclinical animal studies, progression of these strategies to clinical trials has faced challenges. A comprehensive understanding of the translational barriers is a critical first step towards clinical validation of effective immunomodulatory drug delivery protocols proven for safety and tolerability in pre-clinical animal models. This review overviews the current state-of-the-art in local immunomodulatory strategies for transplantation and outlines the key challenges hindering their clinical translation.
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Affiliation(s)
- Afsana Naaz
- Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, PA 15261, United States; Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, 15213, United States.
| | - Heth R Turnquist
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, 15213, United States; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, United States; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15213, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, United States.
| | - Vijay S Gorantla
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, United States; Departments of Surgery, Ophthalmology and Bioengineering, Wake Forest School of Medicine, Wake Forest Institute of Regenerative Medicine, Winston Salem, NC, 27101, United States.
| | - Steven R Little
- Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, PA 15261, United States; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, United States; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15213, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, United States; Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15213, United States; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, United States.
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12
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Kanazawa R, Goto R, Harada T, Ota T, Kobayashi N, Shibuya K, Ganchiku Y, Watanabe M, Zaitsu M, Kawamura N, Shimamura T, Taketomi A. Early graft-infiltrating lymphocytes are not associated with graft rejection in a mouse model of skin transplantation. Scand J Immunol 2024; 100:e13397. [PMID: 39080853 DOI: 10.1111/sji.13397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 06/13/2024] [Accepted: 06/24/2024] [Indexed: 11/05/2024]
Abstract
Graft-infiltrating lymphocytes (GILs) play an important role in promoting rejection after organ transplantation. We recently reported that GILs that accumulated up to 3 days post-transplantation did not promote rejection, whereas GILs present 3-5 days post-transplantation promoted rejection in a mouse heart transplantation model. However, the immunological behaviour of GILs in murine skin transplantation remains unclear. GILs were isolated on days 3, 5 or 7 post-transplantation from C57BL/6 (B6) allogeneic skin grafts transplanted onto BALB/c mice. BALB/c Rag2-/- γc-/- mice (BRGs) underwent B6 skin graft transplantation 10 weeks after adoptive transfer of day 3, 5, or 7 GILs. BRGs reconstituted with day 5 or 7 GILs completely rejected B6 grafts. However, when B6 grafts harvested from recipient BALB/c mice on day 5 or 7 were re-transplanted into BRGs, half of the re-transplanted day 5 grafts established long-term survival, although all re-transplanted day 7 grafts were rejected. BRGs reconstituted with day 3 GILs did not reject B6 grafts. Consistently, re-transplantation using day 3 skin grafts resulted in no rejection. Administration of anti-CD25 antibodies did not prevent the phenomenon observed for the day 3 skin grafts. Furthermore, BRGs reconstituted with splenocytes from naïve BALB/c mice immediately rejected the naïve B6 skin grafts and the re-transplanted day 3 B6 grafts, suggesting that day 3 GILs were unable to induce allograft rejection during the rejection process. In conclusion, the immunological role of GILs depends on the time since transplantation. Day 3 GILs had neither protective nor alloreactive effects in the skin transplant model.
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Affiliation(s)
- Ryo Kanazawa
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Ryoichi Goto
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Takuya Harada
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Takuji Ota
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Kazuaki Shibuya
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Yoshikazu Ganchiku
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Masaaki Watanabe
- Department of Transplant Surgery, Hokkaido University, Sapporo, Japan
| | - Masaaki Zaitsu
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
| | - Norio Kawamura
- Department of Transplant Surgery, Hokkaido University, Sapporo, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery 1, Hokkaido University, Sapporo, Japan
- Department of Transplant Surgery, Hokkaido University, Sapporo, Japan
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13
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Bhattacharya T, Kumari M, Kaur K, Kaity S, Arumugam S, Ravichandiran V, Roy S. Decellularized extracellular matrix-based bioengineered 3D breast cancer scaffolds for personalized therapy and drug screening. J Mater Chem B 2024; 12:8843-8867. [PMID: 39162395 DOI: 10.1039/d4tb00680a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/21/2024]
Abstract
Breast cancer (BC) is the second deadliest cancer after lung cancer. Similar to all cancers, it is also driven by a 3D microenvironment. The extracellular matrix (ECM) is an essential component of the 3D tumor micro-environment, wherein it functions as a scaffold for cells and provides metabolic support. BC is characterized by alterations in the ECM. Various studies have attempted to mimic BC-specific ECMs using artificial materials, such as Matrigel. Nevertheless, research has proven that naturally derived decellularized extracellular matrices (dECMs) are superior in providing the essential in vivo-like cues needed to mimic a cancer-like environment. Developing in vitro 3-D BC models is not straightforward and requires extensive analysis of the data established by researchers. For the benefit of researchers, in this review, we have tried to highlight all developmental studies that have been conducted by various scientists so far. The analysis of the conclusions drawn from these studies is also discussed. The advantages and drawbacks of the decellularization methods employed for generating BC scaffolds will be covered, and the review will shed light on how dECM scaffolds help develop a BC environment. The later stages of the article will also focus on immunogenicity issues arising from decellularization and the origin of the tissue. Finally, this review will also discuss the biofabrication of matrices, which is the core part of the bioengineering process.
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Affiliation(s)
- Teeshyo Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
| | - Mamta Kumari
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Kulwinder Kaur
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine a Health Sciences, Dublin, Ireland
- Tissue Engineering Research Group, Department of Anatomy & Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Santanu Kaity
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Somasundaram Arumugam
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
| | - Velayutham Ravichandiran
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
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14
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Tu AB, Krishna G, Smith KR, Lewis JS. Harnessing Immunomodulatory Polymers for Treatment of Autoimmunity, Allergy, and Transplant Rejection. Annu Rev Biomed Eng 2024; 26:415-440. [PMID: 38959388 DOI: 10.1146/annurev-bioeng-110122-014306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection.
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Affiliation(s)
- Allen B Tu
- Department of Biomedical Engineering, University of California, Davis, California, USA
| | - Gaddam Krishna
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA;
| | - Kevin R Smith
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA;
| | - Jamal S Lewis
- Department of Biomedical Engineering, University of California, Davis, California, USA
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA;
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15
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Huang D, Shen H, Xie F, Hu D, Jin Q, Hu Y, Zhong T. Role of mesenchymal stem cell-derived exosomes in the regeneration of different tissues. J Biol Eng 2024; 18:36. [PMID: 38845032 PMCID: PMC11155050 DOI: 10.1186/s13036-024-00431-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/10/2024] [Indexed: 06/10/2024] Open
Abstract
Exosomes are nanovesicles with multiple components used in several applications. Mesenchymal stem cells (MSCs) are well known for their great potential in clinical applications. MSC-derived exosomes (MSC-Exos) have been shown to mediate tissue regeneration in various diseases, including neurological, autoimmune, and inflammatory diseases, cancer, ischemic heart disease, lung injury, and liver fibrosis. They can modulate the immune response by interacting with immune effector cells in the presence of anti-inflammatory compounds and are involved in intercellular communication through various types of cargo. This review summarizes the MSC-Exos-mediated tissue regeneration in various diseases, including neurological, cardiovascular, liver, kidney, articular cartilage, and oral tissue applications. In addition, we discuss the challenges and prospects of MSC-Exos in tissue regeneration.
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Affiliation(s)
- Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Haibin Shen
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Fangfang Xie
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Die Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qing Jin
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yuexin Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
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16
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Udomkarnjananun S, Schagen MR, Hesselink DA. A review of landmark studies on maintenance immunosuppressive regimens in kidney transplantation. ASIAN BIOMED 2024; 18:92-108. [PMID: 39175954 PMCID: PMC11338012 DOI: 10.2478/abm-2024-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Immunosuppressive medications play a pivotal role in kidney transplantation, and the calcineurin inhibitors (CNIs), including cyclosporine A (CsA) and tacrolimus (TAC), are considered as the backbone of maintenance immunosuppressive regimens. Since the introduction of CNIs in kidney transplantation, the incidence of acute rejection has decreased, and allograft survival has improved significantly. However, CNI nephrotoxicity has been a major concern, believed to heavily impact long-term allograft survival and function. To address this concern, several CNI-sparing regimens were developed and studied in randomized, controlled, clinical trials, aiming to reduce CNI exposure and preserve long-term allograft function. However, more recent information has revealed that CNI nephrotoxicity is not the primary cause of late allograft failure, and its histopathology is neither specific nor pathognomonic. In this review, we discuss the historical development of maintenance immunosuppressive regimens in kidney transplantation, covering the early era of transplantation, the CNI-sparing era, and the current era where the alloimmune response, rather than CNI nephrotoxicity, appears to be the major contributor to late allograft failure. Our goal is to provide a chronological overview of the development of maintenance immunosuppressive regimens and summarize the most recent information for clinicians caring for kidney transplant recipients (KTRs).
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Affiliation(s)
- Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok10330, Thailand
- Excellence Center for Solid Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok10330, Thailand
- Renal Immunology and Transplantation Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok10330, Thailand
| | - Maaike R. Schagen
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam3000, The Netherlands
| | - Dennis A. Hesselink
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam3000, The Netherlands
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17
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Augusto JF, Benden C, Diekmann F, Zuckermann A. The value of extracorporeal photopheresis as an immunosuppression-modifying approach in solid organ transplantation: a potential solution to an unmet medical need. Front Immunol 2024; 15:1371554. [PMID: 38846942 PMCID: PMC11154098 DOI: 10.3389/fimmu.2024.1371554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/07/2024] [Indexed: 06/09/2024] Open
Abstract
Allograft rejection is a critical issue following solid organ transplantation (SOT). Immunosuppressive therapies are crucial in reducing risk of rejection yet are accompanied by several significant side effects, including infection, malignancy, cardiovascular diseases, and nephrotoxicity. There is a current unmet medical need with a lack of effective minimization strategies for these side effects. Extracorporeal photopheresis (ECP) has shown potential as an immunosuppression (IS)-modifying technique in several SOT types, with improvements seen in acute and recurrent rejection, allograft survival, and associated side effects, and could fulfil this unmet need. Through a review of the available literature detailing key areas in which ECP may benefit patients, this review highlights the IS-modifying potential of ECP in the four most common SOT procedures (heart, lung, kidney, and liver transplantation) and highlights existing gaps in data. Current evidence supports the use of ECP for IS modification following SOT, however there is a need for further high-quality research, in particular randomized control trials, in this area.
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Affiliation(s)
- Jean-François Augusto
- Department of Nephrology-Dialysis-Transplantation, University Hospital of Angers, Angers, France
| | | | - Fritz Diekmann
- Renal Transplantation Unit, Department of Nephrology and Kidney Transplantation, Hospital Clinic, Barcelona, Spain
| | - Andreas Zuckermann
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
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18
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Zhang L, Arenas Hoyos I, Helmer A, Banz Y, Zubler C, Lese I, Hirsiger S, Constantinescu M, Rieben R, Gultom M, Olariu R. Transcriptome profiling of immune rejection mechanisms in a porcine vascularized composite allotransplantation model. Front Immunol 2024; 15:1390163. [PMID: 38840906 PMCID: PMC11151749 DOI: 10.3389/fimmu.2024.1390163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/06/2024] [Indexed: 06/07/2024] Open
Abstract
Background Vascularized composite allotransplantation (VCA) offers the potential for a biological, functional reconstruction in individuals with limb loss or facial disfigurement. Yet, it faces substantial challenges due to heightened immune rejection rates compared to solid organ transplants. A deep understanding of the genetic and immunological drivers of VCA rejection is essential to improve VCA outcomes. Methods Heterotopic porcine hindlimb VCA models were established and followed until reaching the endpoint. Skin and muscle samples were obtained from VCA transplant recipient pigs for histological assessments and RNA sequencing analysis. The rejection groups included recipients with moderate pathological rejection, treated locally with tacrolimus encapsulated in triglycerol-monostearate gel (TGMS-TAC), as well as recipients with severe end-stage rejection presenting evident necrosis. Healthy donor tissue served as controls. Bioinformatics analysis, immunofluorescence, and electron microscopy were utilized to examine gene expression patterns and the expression of immune response markers. Results Our comprehensive analyses encompassed differentially expressed genes, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways, spanning various composite tissues including skin and muscle, in comparison to the healthy control group. The analysis revealed a consistency and reproducibility in alignment with the pathological rejection grading. Genes and pathways associated with innate immunity, notably pattern recognition receptors (PRRs), damage-associated molecular patterns (DAMPs), and antigen processing and presentation pathways, exhibited upregulation in the VCA rejection groups compared to the healthy controls. Our investigation identified significant shifts in gene expression related to cytokines, chemokines, complement pathways, and diverse immune cell types, with CD8 T cells and macrophages notably enriched in the VCA rejection tissues. Mechanisms of cell death, such as apoptosis, necroptosis and ferroptosis were observed and coexisted in rejected tissues. Conclusion Our study provides insights into the genetic profile of tissue rejection in the porcine VCA model. We comprehensively analyze the molecular landscape of immune rejection mechanisms, from innate immunity activation to critical stages such as antigen recognition, cytotoxic rejection, and cell death. This research advances our understanding of graft rejection mechanisms and offers potential for improving diagnostic and therapeutic strategies to enhance the long-term success of VCA.
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Affiliation(s)
- Lei Zhang
- Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Switzerland
- Department for BioMedical Research, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Isabel Arenas Hoyos
- Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Switzerland
| | - Anja Helmer
- Department for BioMedical Research, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Yara Banz
- Institute of Pathology, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Cédric Zubler
- Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Switzerland
| | - Ioana Lese
- Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Switzerland
- Department for BioMedical Research, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Stefanie Hirsiger
- Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Switzerland
| | - Mihai Constantinescu
- Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Switzerland
| | - Robert Rieben
- Department for BioMedical Research, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Mitra Gultom
- Department for BioMedical Research, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Radu Olariu
- Department of Plastic and Hand Surgery, Inselspital University Hospital Bern, Bern, Switzerland
- Department for BioMedical Research, Faculty of Medicine, University of Bern, Bern, Switzerland
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Wang R, Peng X, Yuan Y, Shi B, Liu Y, Ni H, Guo W, Yang Q, Liu P, Wang J, Su Z, Yu S, Liu D, Zhang J, Xia J, Liu X, Li H, Yang Z, Peng Z. Dynamic immune recovery process after liver transplantation revealed by single-cell multi-omics analysis. Innovation (N Y) 2024; 5:100599. [PMID: 38510071 PMCID: PMC10952083 DOI: 10.1016/j.xinn.2024.100599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 02/27/2024] [Indexed: 03/22/2024] Open
Abstract
Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation (LT) is critical for precise clinical management strategies. Here, we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) collected from LT patients (with and without acute cellular rejection [ACR]) at 13 time points. Validation was performed in two independent cohorts with additional LT patients and healthy controls. Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition, expression programs, and interactions along this process. The intensity of the immune response differs between the ACR and non-ACR patients. Notably, the newly identified inflamed NK cells, CD14+RNASE2+ monocytes, and FOS-expressing monocytes emerged as predictive indicators of ACR. This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery, providing a four-phase framework that aids the clinical management of LT patients.
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Affiliation(s)
- Rui Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Xiao Peng
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Yixin Yuan
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Baojie Shi
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Yuan Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Hengxiao Ni
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Qiwei Yang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Pingguo Liu
- Department of Hepatobiliary & Pancreatic Surgery, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Jie Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Zhaojie Su
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Shengnan Yu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Dehua Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Jinyan Zhang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Junjie Xia
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Hao Li
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Zhengfeng Yang
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Zhihai Peng
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361102, China
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20
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Ortega JA, Soares de Aguiar GP, Chandravanshi P, Levy N, Engel E, Álvarez Z. Exploring the properties and potential of the neural extracellular matrix for next-generation regenerative therapies. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1962. [PMID: 38723788 DOI: 10.1002/wnan.1962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 04/05/2024] [Accepted: 04/09/2024] [Indexed: 05/24/2024]
Abstract
The extracellular matrix (ECM) is a dynamic and complex network of proteins and molecules that surrounds cells and tissues in the nervous system and orchestrates a myriad of biological functions. This review carefully examines the diverse interactions between cells and the ECM, as well as the transformative chemical and physical changes that the ECM undergoes during neural development, aging, and disease. These transformations play a pivotal role in shaping tissue morphogenesis and neural activity, thereby influencing the functionality of the central nervous system (CNS). In our comprehensive review, we describe the diverse behaviors of the CNS ECM in different physiological and pathological scenarios and explore the unique properties that make ECM-based strategies attractive for CNS repair and regeneration. Addressing the challenges of scalability, variability, and integration with host tissues, we review how advanced natural, synthetic, and combinatorial matrix approaches enhance biocompatibility, mechanical properties, and functional recovery. Overall, this review highlights the potential of decellularized ECM as a powerful tool for CNS modeling and regenerative purposes and sets the stage for future research in this exciting field. This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants.
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Affiliation(s)
- J Alberto Ortega
- Department of Pathology and Experimental Therapeutics, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet del Llobregat, Spain
| | - Gisele P Soares de Aguiar
- Department of Pathology and Experimental Therapeutics, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet del Llobregat, Spain
| | - Palash Chandravanshi
- Biomaterials for Neural Regeneration Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Natacha Levy
- Biomaterials for Neural Regeneration Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Elisabeth Engel
- IMEM-BRT Group, Department of Materials Science and Engineering, EEBE, Technical University of Catalonia (UPC), Barcelona, Spain
- Biomaterials for Regenerative Therapies Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain
| | - Zaida Álvarez
- Biomaterials for Neural Regeneration Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois, USA
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21
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Matarneh AS, Salameh O, Sardar S, Karasinski A, Channapragada T, Abdulbasit M, Washburn E, Ghahramani N. A rare case of non-lupus full house nephropathy in a transplanted kidney, case report. Clin Case Rep 2024; 12:e8886. [PMID: 38707603 PMCID: PMC11066189 DOI: 10.1002/ccr3.8886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 05/07/2024] Open
Abstract
Key Clinical Message Non-lupus full house nephropathy is a rare entity that is still poorly understood. It can complicate post-transplant kidneys and result in a de novo process. Treatment is difficult but can be possibly achieved with optimization of immune suppression. Abstract Non-lupus full house nephropathy is a rare entity with an unclear incidence. It describes the kidney biopsy findings of positive deposits for IgG, IgA, IgM, C3, and C1q on immunofluorescence in the absence of the classical diagnostic features of systemic lupus nephritis. This disease entity is becoming more recognized but further studies are still needed to evaluate the incidence, etiologies, and management of this condition. Transplant glomerulopathy is a major cause for renal graft loss. It can present with a wide variety of manifestations; it can cause AKI, CKD, or glomerular inflammations through an immune complex or autoimmune-mediated damage.
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Affiliation(s)
- Ahmad Samir Matarneh
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Omar Salameh
- Department of Internal MedicinePenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Sundus Sardar
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Amanda Karasinski
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Theja Channapragada
- Department of Internal MedicinePenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Muhammad Abdulbasit
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Erik Washburn
- Department of PathologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Nasrollah Ghahramani
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
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22
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Ding M, Gao T, Song Y, Yi L, Li W, Deng C, Zhou W, Xie M, Zhang L. Nanoparticle-based T cell immunoimaging and immunomodulatory for diagnosing and treating transplant rejection. Heliyon 2024; 10:e24203. [PMID: 38312645 PMCID: PMC10835187 DOI: 10.1016/j.heliyon.2024.e24203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 02/06/2024] Open
Abstract
T cells serve a pivotal role in the rejection of transplants, both by directly attacking the graft and by recruiting other immune cells, which intensifies the rejection process. Therefore, monitoring T cells becomes crucial for early detection of transplant rejection, while targeted drug delivery specifically to T cells can significantly enhance the effectiveness of rejection therapy. However, regulating the activity of T cells within transplanted organs is challenging, and the prolonged use of immunosuppressive drugs is associated with notable side effects and complications. Functionalized nanoparticles offer a potential solution by targeting T cells within transplants or lymph nodes, thereby reducing the off-target effects and improving the long-term survival of the graft. In this review, we will provide an overview of recent advancements in T cell-targeted imaging molecular probes for diagnosing transplant rejection and the progress of T cell-regulating nanomedicines for treating transplant rejection. Additionally, we will discuss future directions and the challenges in clinical translation.
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Affiliation(s)
- Mengdan Ding
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Tang Gao
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yishu Song
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Luyang Yi
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Wenqu Li
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Cheng Deng
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Wuqi Zhou
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mingxing Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Li Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
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23
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Lonez C, Breman E. Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met? Cells 2024; 13:146. [PMID: 38247837 PMCID: PMC10814647 DOI: 10.3390/cells13020146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 01/23/2024] Open
Abstract
This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this therapy to other malignancies and broader patient populations. However, several limitations remain, including those associated with the time-consuming and highly personalized manufacturing of autologous CAR-Ts. Technologies to establish "off-the-shelf" allogeneic CAR-Ts with low alloreactivity are currently being developed, with a strong focus on gene-editing technologies. Although these technologies have many advantages, they have also strong limitations, including double-strand breaks in the DNA with multiple associated safety risks as well as the lack of modulation. As an alternative, non-gene-editing technologies provide an interesting approach to support the development of allogeneic CAR-Ts in the future, with possibilities of fine-tuning gene expression and easy development. Here, we will review the different ways allogeneic CAR-Ts can be manufactured and discuss which technologies are currently used. The biggest hurdles for successful therapy of allogeneic CAR-Ts will be summarized, and finally, an overview of the current clinical evidence for allogeneic CAR-Ts in comparison to its autologous counterpart will be given.
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24
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Tiwari A, Mukherjee S. Role of Complement-dependent Cytotoxicity Crossmatch and HLA Typing in Solid Organ Transplant. Rev Recent Clin Trials 2024; 19:34-52. [PMID: 38155466 DOI: 10.2174/0115748871266738231218145616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/10/2023] [Accepted: 11/10/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND Solid organ transplantation is a life-saving medical operation that has progressed greatly because of developments in diagnostic tools and histocompatibility tests. Crossmatching for complement-dependent cytotoxicity (CDC) and human leukocyte antigen (HLA) typing are two important methods for checking graft compatibility and reducing the risk of graft rejection. HLA typing and CDC crossmatching are critical in kidney, heart, lung, liver, pancreas, intestine, and multi-organ transplantation. METHODS A systematic literature search was conducted on the internet, using PubMed, Scopus, and Google Scholar databases, to identify peer-reviewed publications about solid organ transplants, HLA typing, and CDC crossmatching. CONCLUSION Recent advances in HLA typing have allowed for high-resolution evaluation, epitope matching, and personalized therapy methods. Genomic profiling, next-generation sequencing, and artificial intelligence have improved HLA typing precision, resulting in better patient outcomes. Artificial intelligence (AI) driven virtual crossmatching and predictive algorithms have eliminated the requirement for physical crossmatching in the context of CDC crossmatching, boosting organ allocation and transplant efficiency. This review elaborates on the importance of HLA typing and CDC crossmatching in solid organ transplantation.
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Affiliation(s)
- Arpit Tiwari
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
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25
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Nielsen WH, Gustafsson F, Olsen PS, Hansen PB, Rossing K, Lilleør NB, Møller-Sørensen PH, Møller CH. Short-term outcomes after heart transplantation using donor hearts preserved with ex vivo perfusion. SCAND CARDIOVASC J 2023; 57:2267804. [PMID: 37822186 DOI: 10.1080/14017431.2023.2267804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 10/01/2023] [Indexed: 10/13/2023]
Abstract
The standard Conventional Cold Storage (CCS) during heart transplantation procurement is associated with time-dependent ischemic injury to the graft, which is a significant independent risk factor for post-transplant early morbidity and mortality - especially when cold ischemic time exceeds four hours. Since 2018, Rigshospitalet (Copenhagen, Denmark) has been utilising ex vivo perfusion (Organ Care System, OCS) in selected cases. The objective of this study was to compare the short-term clinical outcomes of patients transplanted with OCS compared to CCS. Methods: This retrospective single-centre study was based on consecutive patients undergoing a heart transplant between January 2018 and April 2021. Patients were selected for the OCS group when the cold ischemic time was expected to exceed four hours. The primary outcome measure was six-month event-free survival. Results: In total, 48 patients were included in the study; nine were transplanted with an OCS heart. The two groups had no significant differences in baseline characteristics. Six-month event-free survival was 77.8% [95% CI: 54.9-100%] in the OCS group and 79.5% [95% CI: 67.8-93.2%] in the CCS group (p = 0.91). While the OCS group had a median out-of-body time that was 183 min longer (p < 0.0001), the cold ischemic time was reduced by 51 min (p = 0.007). Conclusion: In a Scandinavian setting, our data confirms that utilising OCS in heart procurement allows for a longer out-of-body time and a reduced cold ischemic time without negatively affecting safety or early post-transplant outcomes.
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Affiliation(s)
- William Herrik Nielsen
- Department of Cardiothoracic Surgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Peter Skov Olsen
- Department of Cardiothoracic Surgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Peter Bo Hansen
- Department of Cardiothoracic Anesthesiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Kasper Rossing
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Nikolaj Bang Lilleør
- Department of Cardiothoracic Surgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Peter Hasse Møller-Sørensen
- Department of Cardiothoracic Anesthesiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Christian Holdflod Møller
- Department of Cardiothoracic Surgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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26
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Evangelista-Leite D, Carreira ACO, Nishiyama MY, Gilpin SE, Miglino MA. The molecular mechanisms of extracellular matrix-derived hydrogel therapy in idiopathic pulmonary fibrosis models. Biomaterials 2023; 302:122338. [PMID: 37820517 DOI: 10.1016/j.biomaterials.2023.122338] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 08/20/2023] [Accepted: 09/23/2023] [Indexed: 10/13/2023]
Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a progressively debilitating lung condition characterized by oxidative stress, cell phenotype shifts, and excessive extracellular matrix (ECM) deposition. Recent studies have shown promising results using decellularized ECM-derived hydrogels produced through pepsin digestion in various lung injury models and even a human clinical trial for myocardial infarction. This study aimed to characterize the composition of ECM-derived hydrogels, assess their potential to prevent fibrosis in bleomycin-induced IPF models, and unravel their underlying molecular mechanisms of action. Porcine lungs were decellularized and pepsin-digested for 48 h. The hydrogel production process, including visualization of protein molecular weight distribution and hydrogel gelation, was characterized. Peptidomics analysis of ECM-derived hydrogel contained peptides from 224 proteins. Probable bioactive and cell-penetrating peptides, including collagen IV, laminin beta 2, and actin alpha 1, were identified. ECM-derived hydrogel treatment was administered as an early intervention to prevent fibrosis advancement in rat models of bleomycin-induced pulmonary fibrosis. ECM-derived hydrogel concentrations of 1 mg/mL and 2 mg/mL showed subtle but noticeable effects on reducing lung inflammation, oxidative damage, and protein markers related to fibrosis (e.g., alpha-smooth muscle actin, collagen I). Moreover, distinct changes were observed in macroscopic appearance, alveolar structure, collagen deposition, and protein expression between lungs that received ECM-derived hydrogel and control fibrotic lungs. Proteomic analyses revealed significant protein and gene expression changes related to cellular processes, pathways, and components involved in tissue remodeling, inflammation, and cytoskeleton regulation. RNA sequencing highlighted differentially expressed genes associated with various cellular processes, such as tissue remodeling, hormone secretion, cell chemotaxis, and cytoskeleton engagement. This study suggests that ECM-derived hydrogel treatment influence pathways associated with tissue repair, inflammation regulation, cytoskeleton reorganization, and cellular response to injury, potentially offering therapeutic benefits in preventing or mitigating lung fibrosis.
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Affiliation(s)
- Daniele Evangelista-Leite
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, 05508-010, Brazil; School of Medical Sciences, State University of Campinas, Campinas, São Paulo, 13083-970, Brazil.
| | - Ana C O Carreira
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, 05508-010, Brazil; NUCEL (Cell and Molecular Therapy Center), School of Medicine, University of São Paulo, São Paulo, 05360-130, Brazil; Center for Human and Natural Sciences, Federal University of ABC, Santo André, São Paulo, 09210-580, Brazil.
| | - Milton Y Nishiyama
- Laboratory of Applied Toxinology, Butantan Institute, São Paulo, 05503-900, Brazil.
| | - Sarah E Gilpin
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, 05508-010, Brazil.
| | - Maria A Miglino
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, 05508-010, Brazil.
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27
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Abinti M, Favi E, Alfieri CM, Zanoni F, Armelloni S, Ferraresso M, Cantaluppi V, Castellano G. Update on current and potential application of extracellular vesicles in kidney transplantation. Am J Transplant 2023; 23:1673-1693. [PMID: 37517555 DOI: 10.1016/j.ajt.2023.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023]
Abstract
Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy.
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Affiliation(s)
- Matteo Abinti
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Evaldo Favi
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Carlo Maria Alfieri
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Francesca Zanoni
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Silvia Armelloni
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mariano Ferraresso
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplant Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), "Maggiore della Carita" University Hospital, Novara, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
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Cheshire C, Messer S, Martinez L, Vokshi I, Ali J, Cernic S, Page A, Andal R, Berman M, Kaul P, Osman M, Rafiq M, Goddard M, Tweed K, Jenkins D, Tsui S, Large S, Kydd A, Lewis C, Parameshwar J, Pettit S, Bhagra S. Graft function and incidence of cardiac allograft vasculopathy in donation after circulatory-determined death heart transplant recipients. Am J Transplant 2023; 23:1570-1579. [PMID: 37442277 DOI: 10.1016/j.ajt.2023.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 07/02/2023] [Accepted: 07/05/2023] [Indexed: 07/15/2023]
Abstract
Experience in donation after circulatory-determined death (DCD) heart transplantation (HTx) is expanding. There is limited information on the functional outcomes of DCD HTx recipients. We sought to evaluate functional outcomes in our cohort of DCD recipients. We performed a single-center, retrospective, observational cohort study comparing outcomes in consecutive DCD and donation after brain death (DBD) HTx recipients between 2015 and 2019. Primary outcome was allograft function by echocardiography at 12 and 24 months. Secondary outcomes included incidence of cardiac allograft vasculopathy, treated rejection, renal function, and survival. Seventy-seven DCD and 153 DBD recipients were included. There was no difference in left ventricular ejection fraction at 12 months (59% vs 59%, P = .57) and 24 months (58% vs 58%, P = .87). There was no significant difference in right ventricular function at 12 and 24 months. Unadjusted survival between DCD and DBD recipients at 5 years (85.7% DCD and 81% DBD recipients; P = .45) was similar. There were no significant differences in incidence of cardiac allograft vasculopathy (odds ratio 1.59, P = .21, 95% confidence interval 0.77-3.3) or treated rejection (odds ratio 0.60, P = .12, 95% confidence interval 0.32-1.15) between DBD and DCD recipients. Post-transplant renal function was similar at 1 and 2 years. In conclusion, cardiac allografts from DCD donors perform similarly to a contemporary population of DBD allografts in the medium term.
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Affiliation(s)
- Caitlin Cheshire
- Department of Cardiology, Alfred Health, Melbourne, Australia; Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Simon Messer
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Luis Martinez
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Ismail Vokshi
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Jason Ali
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Sendi Cernic
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Aravinda Page
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Ryan Andal
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Marius Berman
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Pradeep Kaul
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Mohamed Osman
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Muhammad Rafiq
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Martin Goddard
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Katharine Tweed
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - David Jenkins
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Steven Tsui
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Stephen Large
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Anna Kydd
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Clive Lewis
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Jayan Parameshwar
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Stephen Pettit
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
| | - Sai Bhagra
- Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
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Zvyagina AI, Minaychev VV, Kobyakova MI, Lomovskaya YV, Senotov AS, Pyatina KV, Akatov VS, Fadeev RS, Fadeeva IS. Soft Biomimetic Approach for the Development of Calcinosis-Resistant Glutaraldehyde-Fixed Biomaterials for Cardiovascular Surgery. Biomimetics (Basel) 2023; 8:357. [PMID: 37622962 PMCID: PMC10452421 DOI: 10.3390/biomimetics8040357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/01/2023] [Accepted: 08/06/2023] [Indexed: 08/26/2023] Open
Abstract
Pathological aseptic calcification is the most common form of structural valvular degeneration (SVD), leading to premature failure of heart valve bioprostheses (BHVs). The processing methods used to obtain GA-fixed pericardium-based biomaterials determine the hemodynamic characteristics and durability of BHVs. This article presents a comparative study of the effects of several processing methods on the degree of damage to the ECM of GA-fixed pericardium-based biomaterials as well as on their biostability, biocompatibility, and resistance to calcification. Based on the assumption that preservation of the native ECM structure will enable the creation of calcinosis-resistant materials, this study provides a soft biomimetic approach for the manufacture of GA-fixed biomaterials using gentle decellularization and washing methods. It has been shown that the use of soft methods for preimplantation processing of materials, ensuring maximum preservation of the intactness of the pericardial ECM, radically increases the resistance of biomaterials to calcification. These obtained data are of interest for the development of new calcinosis-resistant biomaterials for the manufacture of BHVs.
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Affiliation(s)
- Alyona I. Zvyagina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
| | - Vladislav V. Minaychev
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
| | - Margarita I. Kobyakova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
| | - Yana V. Lomovskaya
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
| | - Anatoliy S. Senotov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
| | - Kira V. Pyatina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
- Pushchino State Institute of Natural Science, 142290 Pushchino, Russia
| | - Vladimir S. Akatov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
- Pushchino State Institute of Natural Science, 142290 Pushchino, Russia
| | - Roman S. Fadeev
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
- Pushchino State Institute of Natural Science, 142290 Pushchino, Russia
| | - Irina S. Fadeeva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia (V.S.A.); (R.S.F.)
- Pushchino State Institute of Natural Science, 142290 Pushchino, Russia
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30
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Chandrasekar NR, Cajigas H. Covid-19, HLA, and race common link: A novel hypothesis. Transpl Immunol 2023; 79:101859. [PMID: 37230393 PMCID: PMC10234414 DOI: 10.1016/j.trim.2023.101859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 05/01/2023] [Accepted: 05/20/2023] [Indexed: 05/27/2023]
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) accountable for the coronavirus disease 2019 (Covid-19) prompted a catastrophic pandemic striking millions of people with diverse presentations, from asymptomatic to severe, potentially lethal disease requiring unprecedented levels of specialized care and extraordinary resources that have overwhelmed healthcare systems around the world. In this detailed communication we postulating a novel hypothesis, based on the viral replication and transplantation immunology. This based on reviewing published journal articles and text book chapters to account for variable mortality and degrees of morbidity among various race and origins. Homo sapiens evolution over millions of years, for that the matter the origin of any biologic form of life form initiated by microorganisms. The entire body of a human has several millions of bacterial and viral genomes incorporated over millions of years. Perhaps the answer or a clue lies how compatible a foreign genomic sequence fits into three billion copies of human genome.
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Affiliation(s)
- N R Chandrasekar
- Harvard Medical School Teaching Hospitals; IQ Medical Devices, United States of America.
| | - Helen Cajigas
- Pathology, Cytopathology & Laboratory Medicine, Harvard Medical School-affiliated Institutions, Pearl Consulting Services, United States of America
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31
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Novacescu D, Latcu SC, Bardan R, Daminescu L, Cumpanas AA. Contemporary Biomarkers for Renal Transplantation: A Narrative Overview. J Pers Med 2023; 13:1216. [PMID: 37623466 PMCID: PMC10456039 DOI: 10.3390/jpm13081216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/18/2023] [Accepted: 07/28/2023] [Indexed: 08/26/2023] Open
Abstract
Renal transplantation (RT) is the preferred treatment for end-stage renal disease. However, clinical challenges persist, i.e., early detection of graft dysfunction, timely identification of rejection episodes, personalization of immunosuppressive therapy, and prediction of long-term graft survival. Biomarkers have emerged as valuable tools to address these challenges and revolutionize RT patient care. Our review synthesizes the existing scientific literature to highlight promising biomarkers, their biological characteristics, and their potential roles in enhancing clinical decision-making and patient outcomes. Emerging non-invasive biomarkers seemingly provide valuable insights into the immunopathology of nephron injury and allograft rejection. Moreover, we analyzed biomarkers with intra-nephron specificities, i.e., glomerular vs. tubular (proximal vs. distal), which can localize an injury in different nephron areas. Additionally, this paper provides a comprehensive analysis of the potential clinical applications of biomarkers in the prediction, detection, differential diagnosis and assessment of post-RT non-surgical allograft complications. Lastly, we focus on the pursuit of immune tolerance biomarkers, which aims to reclassify transplant recipients based on immune risk thresholds, guide personalized immunosuppression strategies, and ultimately identify patients for whom immunosuppression may safely be reduced. Further research, validation, standardization, and prospective studies are necessary to fully harness the clinical utility of RT biomarkers and guide the development of targeted therapies.
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Affiliation(s)
- Dorin Novacescu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Razvan Bardan
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Liviu Daminescu
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
| | - Alin Adrian Cumpanas
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
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32
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Cao ZR, Zheng WX, Jiang YX, Chai H, Gong JH, Zhao MJ, Yan P, Liu YY, Liu XY, Huang ZT, Yang H, Peng DD, Zong KZ, Wu ZJ. miR-449a ameliorates acute rejection after liver transplantation via targeting procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 in macrophages. Am J Transplant 2023; 23:336-352. [PMID: 36695693 DOI: 10.1016/j.ajt.2022.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 01/13/2023]
Abstract
Acute rejection (AR) is an important factor that leads to poor prognosis after liver transplantation (LT). Macrophage M1-polarization is an important mechanism in AR development. MicroRNAs play vital roles in disease regulation; however, their effects on macrophages and AR remain unclear. In this study, rat models of AR were established following LT, and macrophages and peripheral blood mononuclear cells were isolated from rats and humans, respectively. We found miR-449a expression to be significantly reduced in macrophages and peripheral blood mononuclear cells. Overexpression of miR-449a not only inhibited the M1-polarization of macrophages in vitro but also improved the AR of transplant in vivo. The mechanism involved inhibiting the noncanonical nuclear factor-kappaB (NF-κB) pathway. We identified procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 (PLOD1) as a target gene of miR-449a, which could reverse miR-449a's inhibition of macrophage M1-polarization, amelioration of AR, and inhibition of the NF-κB pathway. Overall, miR-449a inhibited the NF-κB pathway in macrophages through PLOD1 and also inhibited the M1-polarization of macrophages, thus attenuating AR after LT. In conclusion, miR-449a and PLOD1 may be new targets for the prevention and mitigation of AR.
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Affiliation(s)
- Zhen-Rui Cao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Wei-Xiong Zheng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Yu-Xin Jiang
- Department of Dermatology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Hao Chai
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Jun-Hua Gong
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Min-Jie Zhao
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Ping Yan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Yan-Yao Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Xiao-Ya Liu
- Department of Oncology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Zuo-Tian Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Hang Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Da-Di Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Ke-Zhen Zong
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Zhong-Jun Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
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33
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Kasravi M, Ahmadi A, Babajani A, Mazloomnejad R, Hatamnejad MR, Shariatzadeh S, Bahrami S, Niknejad H. Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine. Biomater Res 2023; 27:10. [PMID: 36759929 PMCID: PMC9912640 DOI: 10.1186/s40824-023-00348-z] [Citation(s) in RCA: 100] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Tissue-engineered decellularized extracellular matrix (ECM) scaffolds hold great potential to address the donor shortage as well as immunologic rejection attributed to cells in conventional tissue/organ transplantation. Decellularization, as the key process in manufacturing ECM scaffolds, removes immunogen cell materials and significantly alleviates the immunogenicity and biocompatibility of derived scaffolds. However, the application of these bioscaffolds still confronts major immunologic challenges. This review discusses the interplay between damage-associated molecular patterns (DAMPs) and antigens as the main inducers of innate and adaptive immunity to aid in manufacturing biocompatible grafts with desirable immunogenicity. It also appraises the impact of various decellularization methodologies (i.e., apoptosis-assisted techniques) on provoking immune responses that participate in rejecting allogenic and xenogeneic decellularized scaffolds. In addition, the key research findings regarding the contribution of ECM alterations, cytotoxicity issues, graft sourcing, and implantation site to the immunogenicity of decellularized tissues/organs are comprehensively considered. Finally, it discusses practical solutions to overcome immunogenicity, including antigen masking by crosslinking, sterilization optimization, and antigen removal techniques such as selective antigen removal and sequential antigen solubilization.
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Affiliation(s)
- Mohammadreza Kasravi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Ahmadi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
| | - Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
| | - Radman Mazloomnejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
| | - Mohammad Reza Hatamnejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavash Shariatzadeh
- Department of Surgery, University of California Los Angeles, Los Angeles, California, USA
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran.
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34
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Supplemental mineral ions for bone regeneration and osteoporosis treatment. ENGINEERED REGENERATION 2023. [DOI: 10.1016/j.engreg.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
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35
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Immunopathological insights into villitis of unknown etiology on the basis of transplant immunology. Placenta 2023; 131:49-57. [PMID: 36473393 DOI: 10.1016/j.placenta.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 11/15/2022] [Indexed: 11/27/2022]
Abstract
Villitis of unknown etiology (VUE) is an inflammatory disease characterized by the infiltration of maternal CD8 +T cells into the placental villi. Although the pathogenesis of VUE is still debated, dysregulation of the immune system appears to be an important factor in the development of the disease. Interaction of maternal T cells with the fetal antigens seems to be the trigger for the VUE onset. In this context, graft vs host disease (GVHD) and allographic rejection seem to share similarities in the VUE immunopathological mechanism, especially those related to immunoregulation. In this review, we compared the immunological characteristics of VUE with allograft rejection, and GVHD favoring a better knowledge of VUE pathogenesis that may contribute to VUE therapeutics strategies in the future.
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36
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van der Elst G, Varol H, Hermans M, Baan CC, Duong-van Huyen JP, Hesselink DA, Kramann R, Rabant M, Reinders MEJ, von der Thüsen JH, van den Bosch TPP, Clahsen-van Groningen MC. The mast cell: A Janus in kidney transplants. Front Immunol 2023; 14:1122409. [PMID: 36891297 PMCID: PMC9986315 DOI: 10.3389/fimmu.2023.1122409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.
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Affiliation(s)
- G van der Elst
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - H Varol
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M Hermans
- Department of Internal Medicine, Division of Allergy and Clinical Immunology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - C C Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | | | - D A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - R Kramann
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.,Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - M Rabant
- Department of Pathology, Necker Hospital, APHP, Paris, France
| | - M E J Reinders
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - J H von der Thüsen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - T P P van den Bosch
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M C Clahsen-van Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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Zhi Y, Li M, Lv G. Into the multi-omics era: Progress of T cells profiling in the context of solid organ transplantation. Front Immunol 2023; 14:1058296. [PMID: 36798139 PMCID: PMC9927650 DOI: 10.3389/fimmu.2023.1058296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/20/2023] [Indexed: 02/04/2023] Open
Abstract
T cells are the common type of lymphocyte to mediate allograft rejection, remaining long-term allograft survival impeditive. However, the heterogeneity of T cells, in terms of differentiation and activation status, the effector function, and highly diverse T cell receptors (TCRs) have thus precluded us from tracking these T cells and thereby comprehending their fate in recipients due to the limitations of traditional detection approaches. Recently, with the widespread development of single-cell techniques, the identification and characterization of T cells have been performed at single-cell resolution, which has contributed to a deeper comprehension of T cell heterogeneity by relevant detections in a single cell - such as gene expression, DNA methylation, chromatin accessibility, surface proteins, and TCR. Although these approaches can provide valuable insights into an individual cell independently, a comprehensive understanding can be obtained when applied joint analysis. Multi-omics techniques have been implemented in characterizing T cells in health and disease, including transplantation. This review focuses on the thesis, challenges, and advances in these technologies and highlights their application to the study of alloreactive T cells to improve the understanding of T cell heterogeneity in solid organ transplantation.
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Affiliation(s)
- Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
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Lei T, Chen L, Wang K, Du S, Gonelle-Gispert C, Wang Y, Buhler LH. Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps. Front Immunol 2022; 13:1031185. [PMID: 36561750 PMCID: PMC9766364 DOI: 10.3389/fimmu.2022.1031185] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Xenotransplantation has the potential to solve the shortfall of human organ donors. Genetically modified pigs have been considered as potential animal donors for human xenotransplantation and have been widely used in preclinical research. The genetic modifications aim to prevent the major species-specific barriers, which include humoral and cellular immune responses, and physiological incompatibilities such as complement and coagulation dysfunctions. Genetically modified pigs can be created by deleting several pig genes related to the synthesis of various pig specific antigens or by inserting human complement- and coagulation-regulatory transgenes. Finally, in order to reduce the risk of infection, genes related to porcine endogenous retroviruses can be knocked down. In this review, we focus on genetically modified pigs and comprehensively summarize the immunological mechanism of xenograft rejection and recent progress in preclinical and clinical studies. Overall, both genetically engineered pig-based xenografts and technological breakthroughs in the biomedical field provide a promising foundation for pig-to-human xenotransplantation in the future.
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Affiliation(s)
- Tiantian Lei
- Department of Pharmacy, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, Chongqing, China
| | - Lin Chen
- Department of Pharmacy, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, Chongqing, China
| | - Kejing Wang
- Department of Pharmacy, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, Chongqing, China
| | - Suya Du
- Department of Clinical Pharmacy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Sichuan, China
| | | | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Leo H. Buhler
- Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
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Paul PK, Das R, Drow T, Nylen EA, de Souza AH, Wang Z, Wood MW, Davis DB, Bjorling DE, Galipeau J. Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression. Am J Transplant 2022; 22:2571-2585. [PMID: 35897156 PMCID: PMC9804298 DOI: 10.1111/ajt.17162] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 06/19/2022] [Accepted: 07/19/2022] [Indexed: 01/25/2023]
Abstract
Allogeneic islet transplantation is a promising experimental therapy for poorly controlled diabetes. Despite pharmacological immunosuppression, long-term islet engraftment remains elusive. Here, we designed a synthetic fusion transgene coupling PD-L1 and indoleamine dioxygenase [hereafter PIDO] whose constitutive expression prevents immune destruction of genetically engineered islet allograft transplanted in immunocompetent mice. PIDO expressing murine islets maintain robust dynamic insulin secretion in vitro and when transplanted in allogeneic hyperglycemic murine recipients reverse pre-existing streptozotocin-induced and autoimmune diabetes in the absence of pharmacological immunosuppression for more than 50 and 8 weeks, respectively, and is dependent on host CD4 competence. Additionally, PIDO expression in allografts preserves endocrine functional viability of islets and promotes a localized tolerogenic milieu characterized by the suppression of host CD8 T cell and phagocyte recruitment and accumulation of FOXP3+ Tregs. Furthermore, in the canine model of xenogeneic islet transplantation, muscle implanted PIDO-expressing porcine islets displayed physiological glucose-responsive insulin secretion competency in euglycemic recipient for up to 20 weeks. In conclusion, the PIDO transgenic technology enables host CD4+ T cell-modulated immune evasiveness and long-term functional viability of islet allo- and xenografts in immune-competent recipients without the need for pharmacological immune suppression and would allow for improved outcomes for tissue transplantation.
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Affiliation(s)
- Pradyut K Paul
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Rahul Das
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Travis Drow
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Emily A Nylen
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Arnaldo Henrique de Souza
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Zunyi Wang
- Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Michael W Wood
- Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Dawn B Davis
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.,William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA
| | - Dale E Bjorling
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jacques Galipeau
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
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40
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Muacevic A, Adler JR. Classic and Current Opinions in Human Organ and Tissue Transplantation. Cureus 2022; 14:e30982. [PMID: 36337306 PMCID: PMC9624478 DOI: 10.7759/cureus.30982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2022] [Indexed: 11/30/2022] Open
Abstract
Graft tolerance is a pathophysiological condition heavily reliant on the dynamic interaction of the innate and adaptive immune systems. Genetic polymorphism determines immune responses to tissue/organ transplantation, and intricate humoral and cell-mediated mechanisms control these responses. In transplantation, the clinician's goal is to achieve a delicate equilibrium between the allogeneic immune response, undesired effects of the immunosuppressive drugs, and the existing morbidities that are potentially life-threatening. Transplant immunopathology involves sensitization, effector, and apoptosis phases which recruit and engages immunological cells like natural killer cells, lymphocytes, neutrophils, and monocytes. Similarly, these cells are involved in the transfer of normal or genetically engineered T cells. Advances in tissue transplantation would involve a profound knowledge of the molecular mechanisms that underpin the respective immunopathology involved and the design of precision medicines that are safe and effective.
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41
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Immune response associated with ischemia and reperfusion injury during organ transplantation. Inflamm Res 2022; 71:1463-1476. [PMID: 36282292 PMCID: PMC9653341 DOI: 10.1007/s00011-022-01651-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 12/03/2022] Open
Abstract
Background Ischemia and reperfusion injury (IRI) is an ineluctable immune-related pathophysiological process during organ transplantation, which not only causes a shortage of donor organs, but also has long-term and short-term negative consequences on patients. Severe IRI-induced cell death leads to the release of endogenous substances, which bind specifically to receptors on immune cells to initiate an immune response. Although innate and adaptive immunity have been discovered to play essential roles in IRI in the context of organ transplantation, the pathway and precise involvement of the immune response at various stages has not yet to be elucidated. Methods We combined “IRI” and “organ transplantation” with keywords, respectively such as immune cells, danger signal molecules, macrophages, neutrophils, natural killer cells, complement cascade, T cells or B cells in PubMed and the Web of Science to search for relevant literatures. Conclusion Comprehension of the immune mechanisms involved in organ transplantation is promising for the treatment of IRI, this review summarizes the similarities and differences in both innate and adaptive immunity and advancements in the immune response associated with IRI during diverse organ transplantation.
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42
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Nowak PG, Stencel A. How many ways can you die? Multiple biological deaths as a consequence of the multiple concepts of an organism. THEORETICAL MEDICINE AND BIOETHICS 2022; 43:127-154. [PMID: 35859085 PMCID: PMC9477939 DOI: 10.1007/s11017-022-09583-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/03/2022] [Indexed: 05/13/2023]
Abstract
According to the mainstream position in the bioethical definition of death debate, death is to be equated with the cessation of an organism. Given such a perspective, some bioethicists uphold the position that brain-dead patients are dead, while others claim that they are alive. Regardless of the specific opinion on the status of brain-dead patients, the mere bioethical concept of death, according to many bioethicists, has the merit of being unanimous and univocal, as well as grounded in biology. In the present article, we challenge such a thesis. We provide evidence that theoretical biology operates with a plurality of equally valid organismic concepts, which imply different conclusions regarding the organismal status of a brain-dead patient. Moreover, the theoretical biology concepts of an organism are very distant from the view on an organism that appears by way of bioethicists theorizing on death. We conclude that if death is to be understood as the cessation of an organism, there is no single correct answer to the question of whether a brain-dead patient is alive or dead.
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Affiliation(s)
- Piotr Grzegorz Nowak
- Institute of Philosophy, Jagiellonian University, Grodzka 52, 31-044 Kraków, Poland
| | - Adrian Stencel
- Institute of Philosophy, Jagiellonian University, Grodzka 52, 31-044 Kraków, Poland
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43
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Huang J, Han Q, Cai M, Zhu J, Li L, Yu L, Wang Z, Fan G, Zhu Y, Lu J, Zhou G. Effect of Angiogenesis in Bone Tissue Engineering. Ann Biomed Eng 2022; 50:898-913. [PMID: 35525871 DOI: 10.1007/s10439-022-02970-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 04/17/2022] [Indexed: 12/20/2022]
Abstract
The reconstruction of large skeletal defects is still a tricky challenge in orthopedics. The newly formed bone tissue migrates sluggishly from the periphery to the center of the scaffold due to the restrictions of exchange of oxygen and nutrition impotent cells osteogenic differentiation. Angiogenesis plays an important role in bone reconstruction and more and more studies on angiogenesis in bone tissue engineering had been published. Promising advances of angiogenesis in bone tissue engineering by scaffold designs, angiogenic factor delivery, in vivo prevascularization and in vitro prevascularization are discussed in detail. Among all the angiogenesis mode, angiogenic factor delivery is the common methods of angiogenesis in bone tissue engineering and possible research directions in the future.
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Affiliation(s)
- Jianhao Huang
- Department of Orthopedics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, People's Republic of China
| | - Qixiu Han
- Department of Orthopedics, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, People's Republic of China
| | - Meng Cai
- Department of Orthopedics, Jinling Hospital, School of Medicine, Southeast University, Nanjing, 210002, People's Republic of China
| | - Jie Zhu
- Department of Orthopedics, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, People's Republic of China
| | - Lan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Lingfeng Yu
- Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, People's Republic of China
| | - Zhen Wang
- Department of Orthopedics, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, People's Republic of China
| | - Gentao Fan
- Department of Orthopedics, Nanjing Jinling Hospital, 305 Zhongshan East Road, Nanjing, 210002, People's Republic of China
| | - Yan Zhu
- Department of Orthopedics, Nanjing Jinling Hospital, 305 Zhongshan East Road, Nanjing, 210002, People's Republic of China
| | - Jingwei Lu
- Department of Orthopedics, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, People's Republic of China. .,Department of Orthopedics, Nanjing Jinling Hospital, 305 Zhongshan East Road, Nanjing, 210002, People's Republic of China.
| | - Guangxin Zhou
- Department of Orthopedics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, People's Republic of China. .,Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, People's Republic of China. .,Department of Orthopedics, Nanjing Jinling Hospital, 305 Zhongshan East Road, Nanjing, 210002, People's Republic of China. .,The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China.
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44
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Novel Soluble Mediators of Innate Immune System Activation in Solid Allograft Rejection. Transplantation 2022; 106:500-509. [PMID: 34049364 DOI: 10.1097/tp.0000000000003834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
During the past years, solid allograft rejection has been considered the consequence of either cellular- or antibody-mediated reaction both being part of the adaptive immune response, whereas the role of innate immunity has been mostly considered less relevant. Recently, a large body of evidence suggested that the innate immune response and its soluble mediators may play a more important role during solid allograft rejection than originally thought. This review will highlight the role of novel soluble mediators that are involved in the activation of innate immunity during alloimmune response and solid allograft rejection. We will also discuss emerging strategies to alleviate the aforementioned events. Hence, novel, feasible, and safe clinical therapies are needed to prevent allograft loss in solid organ transplantation. Fully understanding the role of soluble mediators of innate immune system activation may help to mitigate solid allograft rejection and improve transplanted recipients' outcomes.
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45
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Turkey ovarian tissue transplantation: effects of surgical technique on graft attachment and immunological status of the grafts, 6 days post-surgery. Poult Sci 2022; 101:101648. [PMID: 35093770 PMCID: PMC8808259 DOI: 10.1016/j.psj.2021.101648] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/22/2021] [Indexed: 11/20/2022] Open
Abstract
Biobanked poultry ovaries can be revived via transplantation into a recipient female, which upon maturity will produce donor-derived progeny. Previously, a large portion of these recipients also produced recipient-derived progeny, making them gonadal chimeras. These were potentially created when portions of the recipient's ovary were inadvertently left behind. Completely removing the recipient ovary would solve this problem; however, leaving a portion of the recipient's ovary may have inadvertently increased the transplant attachment rate by providing a damaged area for attachment. To test this hypothesis in the turkey, we removed various portions (33–100%) of recipient ovarian tissue and determined the transplant attachment rate. Furthermore, the use of the abdominal air sac membrane as an additional anchoring point was tested. The overall attachment rate of transplants was 91% (27/30), while the average size of the transplants was 4.2 ± 0.6 mm2, 6 d postsurgery. There was no difference (P > 0.05) in the attachment rates, or transplant size between groups with varying amounts of recipent tissue removed, or by using the abdominal air sac membrane as an anchor. Finally, the immunological status of the grafts were evaluated by analyzing the presences of CD3 and MUM-1 (T and B cell markers). This showed that all transplants were infiltrated by large numbers of T and B cells. Shown by a high (P ≤ 0.001) percentage of CD3-positive immunostained cytoplasmic area (49.78 ± 3.90%) in transplants compared to remnant recipient tissue (0.30 ± 0.10%), as well as a high (P ≤ 0.001) percentage of MUM-1-positive immunostained nuclear area (9.85 ± 1.95%) in transplants over remnant recipient tissues (0.39 ± 0.12%). From this study we would recommend removing the entire recipient ovary, and not covering the transplants with the abdominal air sac membrane, to prevent gonadal chimeras. The high levels of lymphocytes within the grafts indicate possible tissue rejection, which could be overcome via immunosuppression with or without histocompatibility matching between donors and recipients.
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Williams L, Bagley J, Iacomini J. The role of IL-6 in hyperlipidemia-induced accelerated rejection. Am J Transplant 2022; 22:427-437. [PMID: 34551194 PMCID: PMC8813896 DOI: 10.1111/ajt.16852] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/16/2021] [Accepted: 09/10/2021] [Indexed: 02/03/2023]
Abstract
Hyperlipidemia induces accelerated rejection of cardiac allografts and resistance to tolerance induction using costimulatory molecule blockade in mice due in part to anti-donor Th17 responses and reduced regulatory T cell function. Accelerated rejection in hyperlipidemic mice is also associated with increased serum levels of IL-6. Here, we examined the role of IL-6 in hyperlipidemia-induced accelerated rejection and resistance to tolerance. Genetic ablation of IL-6 prevented hyperlipidemia-induced accelerated cardiac allograft rejection. Using Th17-lineage fate tracking mice, we observed that IL-6 is required to promote the development of anti-donor Th17 lineage cells independently of antigen challenge. In contrast, the frequency of alloreactive T cells producing IL-2 or IFN-γ remained increased in hyperlipidemic IL-6-deficient mice. Ablation of IL-6 overcame hyperlipidemia-induced changes in Tregs, but was not sufficient to overcome resistance to costimulatory molecule blockade induced tolerance. We suggest that accelerated rejection in hyperlipidemic mice results from IL-6 driven anti-donor Th17 responses. While alterations in Tregs were overcome by ablation of IL-6, the reversal of hyperlipidemia-induced changes in Tregs was not sufficient to overcome increased Th1-type anti-donor T cell responses, suggesting that hyperlipidemia induced IL-6-independent effects on recipient immunity prevent tolerance induction.
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Affiliation(s)
- Linus Williams
- Tufts University School of Medicine, and the Graduate School of Biomedical Sciences, Boston, MA, USA.,Department of Immunology, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA.,Immunology Graduate Program, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA
| | - Jessamyn Bagley
- Tufts University School of Medicine, and the Graduate School of Biomedical Sciences, Boston, MA, USA.,Department of Immunology, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA
| | - John Iacomini
- Tufts University School of Medicine, and the Graduate School of Biomedical Sciences, Boston, MA, USA.,Department of Immunology, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA.,Immunology Graduate Program, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA
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Seiler LK, Phung NL, Nikolin C, Immenschuh S, Erck C, Kaufeld J, Haller H, Falk CS, Jonczyk R, Lindner P, Thoms S, Siegl J, Mayer G, Feederle R, Blume CA. An Antibody-Aptamer-Hybrid Lateral Flow Assay for Detection of CXCL9 in Antibody-Mediated Rejection after Kidney Transplantation. Diagnostics (Basel) 2022; 12:diagnostics12020308. [PMID: 35204399 PMCID: PMC8871475 DOI: 10.3390/diagnostics12020308] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
Chronic antibody-mediated rejection (AMR) is a key limiting factor for the clinical outcome of a kidney transplantation (Ktx), where early diagnosis and therapeutic intervention is needed. This study describes the identification of the biomarker CXC-motif chemokine ligand (CXCL) 9 as an indicator for AMR and presents a new aptamer-antibody-hybrid lateral flow assay (hybrid-LFA) for detection in urine. Biomarker evaluation included two independent cohorts of kidney transplant recipients (KTRs) from a protocol biopsy program and used subgroup comparisons according to BANFF-classifications. Plasma, urine and biopsy lysate samples were analyzed with a Luminex-based multiplex assay. The CXCL9-specific hybrid-LFA was developed based upon a specific rat antibody immobilized on a nitrocellulose-membrane and the coupling of a CXCL9-binding aptamer to gold nanoparticles. LFA performance was assessed according to receiver operating characteristic (ROC) analysis. Among 15 high-scored biomarkers according to a neural network analysis, significantly higher levels of CXCL9 were found in plasma and urine and biopsy lysates of KTRs with biopsy-proven AMR. The newly developed hybrid-LFA reached a sensitivity and specificity of 71% and an AUC of 0.79 for CXCL9. This point-of-care-test (POCT) improves early diagnosis-making in AMR after Ktx, especially in KTRs with undetermined status of donor-specific HLA-antibodies.
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Affiliation(s)
- Lisa K. Seiler
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Ngoc Linh Phung
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Christoph Nikolin
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany; (C.N.); (S.I.)
| | - Stephan Immenschuh
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany; (C.N.); (S.I.)
| | - Christian Erck
- Helmholtz Centre for Infection Research, Cellular Proteome Research Group, 38124 Braunschweig, Germany;
| | - Jessica Kaufeld
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (J.K.); (H.H.)
| | - Hermann Haller
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (J.K.); (H.H.)
| | - Christine S. Falk
- Institute for Transplant Immunology, Hannover Medical School, 30625 Hannover, Germany;
| | - Rebecca Jonczyk
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Patrick Lindner
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Stefanie Thoms
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Julia Siegl
- Chemical Biology & Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53121 Bonn, Germany; (J.S.); (G.M.)
- Center of Aptamer Research & Development (CARD), University of Bonn, 53121 Bonn, Germany
| | - Günter Mayer
- Chemical Biology & Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53121 Bonn, Germany; (J.S.); (G.M.)
- Center of Aptamer Research & Development (CARD), University of Bonn, 53121 Bonn, Germany
| | - Regina Feederle
- Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz-Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
| | - Cornelia A. Blume
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
- Correspondence:
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48
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Rodriguez ER, Santos-Martins C, Tan CD. Pathology of cardiac transplantation. Cardiovasc Pathol 2022. [DOI: 10.1016/b978-0-12-822224-9.00023-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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49
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Farrokhi A, Rahavi M, Jo S, Jalili R, Lim CJ, Ghahsary A, Reid GSD. Inflammatory Immune Responses Trigger Rejection of Allogeneic Fibroblasts Transplanted into Mouse Skin. Cell Transplant 2022; 31:9636897221113803. [PMID: 35912954 PMCID: PMC9340901 DOI: 10.1177/09636897221113803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Fibroblasts, or their homolog stromal cells, are present in most tissues and play an essential role in tissue homeostasis and regeneration. As a result, fibroblast-based strategies have been widely employed in tissue engineering. However, while considered to have immunosuppressive properties, the survival and functionality of allogeneic fibroblasts after transplantation remain controversial. Here, we evaluated innate and adaptive immune responses against allogeneic fibroblasts following intradermal injection into different immune-deficient mouse strains. While allogeneic fibroblasts were rejected 1 week after transplantation in immunocompetent mice, rejection did not occur in immunodeficient γ chain–deficient NOD-SCID (NSG) mice. T-cell- and B-cell-deficient RAG1 knockout mice showed greater loss of fibroblasts by day 5 after transplantation compared with NSG mice (P ≤ 0.05) but prolonged persistence compared with wild-type recipient (P ≤ 0.005). Loss of fibroblasts correlated with the expression of proinflammatory chemokine genes and infiltration of myeloid cells in the transplantation site. Depletion of macrophages and neutrophils delayed rejection, revealing the role of innate immune cells in an early elimination of fibroblasts that is followed by T-cell-mediated rejection in the second week. These findings indicate that the application of allogeneic fibroblasts in tissue engineering products requires further improvements to overcome cell rejection by innate and adaptive immune cells.
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Affiliation(s)
- Ali Farrokhi
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada
| | - MohammadReza Rahavi
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Sumin Jo
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Reza Jalili
- Burn & Wound Healing Research Group, Division of Plastic Surgery, Department of Surgery and International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, BC, Canada
| | - C. James Lim
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada
| | - Aziz Ghahsary
- Burn & Wound Healing Research Group, Division of Plastic Surgery, Department of Surgery and International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, BC, Canada
| | - Gregor S. D. Reid
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada
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50
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Bhat DK, Olkhanud PB, Gangaplara A, Seifuddin F, Pirooznia M, Biancotto A, Fantoni G, Pittman C, Francis B, Dagur PK, Saxena A, McCoy JP, Pfeiffer RM, Fitzhugh CD. Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease. Front Immunol 2021; 12:757279. [PMID: 34917079 PMCID: PMC8669726 DOI: 10.3389/fimmu.2021.757279] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/11/2021] [Indexed: 12/24/2022] Open
Abstract
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a widely available curative option for patients with sickle cell disease (SCD). Our original non-myeloablative haplo-HSCT trial employing post-transplant (PT) cyclophosphamide had a low incidence of GVHD but had high rejection rates. Here, we aimed to evaluate immune reconstitution following haplo-HSCT and identify cytokines and cells associated with graft rejection/engraftment. 50 cytokines and 10 immune cell subsets were screened using multiplex-ELISA and flow cytometry, respectively, at baseline and PT-Days 30, 60, 100, and 180. We observed the most significant differences in cytokine levels between the engrafted and rejected groups at PT-Day 60, corresponding with clinical findings of secondary graft rejection. Of the 44 cytokines evaluated, plasma concentrations of 19 cytokines were different between the two groups at PT-Day 60. Factor analysis suggested two independent factors. The first factor (IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, and TGFb1 contributed significantly) was strongly associated with engraftment with OR = 2.7 (95%CI of 1.4 to 5.4), whereas the second factor (GROa and IL-18 contributed significantly) was not significantly associated with engraftment. Sufficient donor myeloid chimerism (DMC) is critical for the success of HSCT; here, we evaluated immune cells among high (H) DMC (DMC≥20%) and low (L) DMC (DMC<20%) groups along with engrafted and rejected groups. We found that early myeloid-derived suppressor cell (eMDSC) frequencies were elevated in engrafted patients and patients with HDMC at PT-Day 30 (P< 0.04 & P< 0.003, respectively). 9 of 20 patients were evaluated for the source of eMDSCs. The HDMC group had high mixed chimeric eMDSCs as compared to the LDMC group (P< 0.00001). We found a positive correlation between the frequencies of eMDSCs and Tregs at PT-Day 100 (r=0.72, P <0.0007); eMDSCs at BSL and Tregs at PT-Day 100 (r=0.63, P <0.004). Of 10 immune regulatory cells and 50 cytokines, we observed mixed chimeric eMDSCs and IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, TGFb1 as potential hits which could serve as prognostic markers in predicting allograft outcome towards engraftment following haploidentical HSCT employing post-transplant cyclophosphamide. The current findings need to be replicated and further explored in a larger cohort.
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Affiliation(s)
- Deepali K Bhat
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Purevdorj B Olkhanud
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Arunakumar Gangaplara
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Fayaz Seifuddin
- Bioinformatics and Computational Biology Core Facility, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Mehdi Pirooznia
- Bioinformatics and Computational Biology Core Facility, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Angélique Biancotto
- Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Giovanna Fantoni
- Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Corinne Pittman
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Berline Francis
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Pradeep K Dagur
- Flow Cytometry Core, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda MD, United States
| | - Ankit Saxena
- Flow Cytometry Core, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda MD, United States
| | - J Philip McCoy
- Flow Cytometry Core, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda MD, United States
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Courtney D Fitzhugh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
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