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Zhang J, Zhan H, Song Z, Liu S. Immune reactions following intestinal transplantation: Mechanisms and prevention. Asian J Surg 2024; 47:3819-3826. [PMID: 38431471 DOI: 10.1016/j.asjsur.2024.02.097] [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: 07/07/2023] [Accepted: 02/16/2024] [Indexed: 03/05/2024] Open
Abstract
For patients with intestinal failure, small bowel transplantation remains one of the most effective treatments despite continuous advancements in parenteral nutrition techniques. Long-term use of parenteral nutrition can result in serious complications that lead to metabolic dysfunction and organ failure. However, the small intestine is a highly immunogenic organ with a large amount of mucosa-associated lymphoid tissue and histocompatibility antigens; therefore, the small intestine is highly susceptible to severe immune rejection. This article discusses the mechanisms underlying immune rejection after small bowel transplantation and presents various options for prevention and treatment. Our findings offer new insights into the development of small bowel transplantation.
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Affiliation(s)
- Junhao Zhang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hanxiang Zhan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zifang Song
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
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Wang Y, Tao X, Jin P. Clinical Features and Prognostic Predictors in Patients with Renal Transplant Complicated by SARS-CoV-2 Infection, a Retrospective Single-Center Study. Infect Drug Resist 2024; 17:1999-2007. [PMID: 38800582 PMCID: PMC11122271 DOI: 10.2147/idr.s465805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 05/16/2024] [Indexed: 05/29/2024] Open
Abstract
Background This study examines the clinical outcomes and prognostic factors of COVID-19 in renal transplant recipients. Given their immunosuppressed status, these patients are at higher risk of severe complications from COVID-19. The study aims to provide healthcare professionals with critical insights for diagnosing and managing this vulnerable population. Patients and methods This retrospective cohort study included adult renal transplant recipients diagnosed with COVID-19. Data on demographics, medical history, laboratory results, and patient outcomes were analyzed to identify clinical characteristics and prognostic factors. Results This study included 115 renal transplant recipients with COVID-19, predominantly male, with a mortality rate of 10.4% (12 deaths). The overall vaccination rate was 20%. Univariate analysis showed significant differences between survivors and non-survivors in initial serum creatinine levels, and percentages of neutrophils, monocytes, and lymphocytes, along with CRP levels on day 3. Additionally, CRP levels, hemoglobin, and platelet counts on day 7 also differed significantly. Multivariate analysis identified CRP levels on days 3 and 7, day 7 hemoglobin and platelet counts, and concurrent bacterial infections as independent risk factors for mortality. Conclusion Elevated CRP levels, renal impairment, and bacterial co-infections play a significant role in the outcomes of COVID-19 in kidney transplant recipients. This study highlights the importance of monitoring these factors for early identification and management of high-risk patients.
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Affiliation(s)
- Yinfeng Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China
| | - Xiaogen Tao
- Department of Intensive Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China
| | - Peng Jin
- Department of Intensive Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China
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Shi QS, Jiang X, Li M, Fang J, Fu Z, Zhu S, Wu C, Meng Q, Jie T, Askar M. Microvascular activation and exocytosis after exposure to the serum from mismatched recipients by using donor microvascular cultures. Transpl Immunol 2024; 82:101963. [PMID: 38013122 DOI: 10.1016/j.trim.2023.101963] [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: 07/26/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Microvascular injury resulting from activation and exocytosis are early signs of tissue damage caused by allografting. However, humoral anti-graft reactions are not easily detectable in transplant biopsies. The aim of this study was to establish a bioassay to recapitulate this process in a prospective approach. METHODS The study was executed by using our previously established protocol to isolate and freeze the donors' microvascular endothelial cells (MVEC) at the transplantation (34 living-related donors and 26 cadaver donors); and to collect sera from the recipients before the transplantation, one-, three- and six-months after transplantation. The activation and exocytosis of the MVEC were determined by incubating the donors' cultures with the recipients' sera. We determined if there was any endothelial activation by quantifying the releases of monocyte chemotactic protein-1 (MCP-1) and interleukin 8 (IL-8) in supernatants and the expressions of membrane intercellular adhesion molecule-1 (CD54) and intercellular adhesion molecule-1 (CD106) by flow cytometry. Endothelial exocytosis was determined by quantifying soluble E-selectin (CD62E) and cytoplasmic von Willebrand Factor (vWF) in supernatants. Endothelial activation or exocytosis was considered positive when the fold change (≧1.5) of post-transplantation to pre-transplantation was reached. We also monitored serum PRA and cytokines using Luminex multiple-plex and cytometric bead-based assay respectively. RESULTS We found 41.2% recipients (14 out of 34, ranging from 1.5 to 5.2 folds, p < 0.05) exhibited positive MVEC activation in the first month after transplantation as determined by IL-8 levels; 26.5% recipients (9 out of 34, ranging from 1.5 to 11.8 folds, p < 0.05) by MCP-1 levels. In the group of three months post-transplantation, 70.6% patients were positive (12 out of 17, ranging from 1.8 to 87.1 folds, p < 0.05) by IL-8 increased levels; 24% recipients (4 out of 17, ranging from 1.8 to 50.5 folds, p < 0.05) measured by MCP-1 levels. However, these changes disappeared six months after transplantation. Flow cytometric data showed that a time-dependent of CD54+ and CD106+ expressions existed over the course of six months. Most CD54+ and CD106+ cells were CD31- (platelet-endothelial cell adhesion molecule-1), though CD31+/CD106+ (37.5%, 3 out of 8) and CD31+/CD106+ (25%. 2 out of 8) were seen. When comparing donor MVEC activation to their recipient's proinflammatory cytokine levels or PRA status, we could not draw a conclusion regarding the connections between them. The sera collected from recipients at either one- or three-months after allografting did not significantly induce the release of either soluble CD62E or vWF (p > 0.05), indicating exocytosis was not significantly involved in the acute phase of allografting. CONCLUSIONS This bioassay enables us to detect the activation and exocytosis of donor MVEC elicited by respective sera from mismatched kidney recipients.
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Affiliation(s)
- Qiang Sebastian Shi
- Minnie & Max T. Voelcker Laboratory, Tianjin International Joint Academy of Bio-medicine, S1515 Room, 220 Dongting Road, TEDA, Tianjin, China; Minnie & Max T. Voelcker Laboratory (Suzhou), 1304 Room No. 1 Building, 399 Xiarong Street, Wujiang District, Suzhou, China.
| | - Xin Jiang
- Department of Organ Transplantation, The Fifth Medical College of Henan University of Chinese Medicine, 33 Huanghe Road, Zhengzhou, Henan Province, China.
| | - Ming Li
- Department of Organ Transplantation, The Fifth Medical College of Henan University of Chinese Medicine, 33 Huanghe Road, Zhengzhou, Henan Province, China
| | - Jun Fang
- Department of Organ Transplantation, The Fifth Medical College of Henan University of Chinese Medicine, 33 Huanghe Road, Zhengzhou, Henan Province, China
| | - Zhiqiang Fu
- The Eco-City Hospital of Tianjin Fifth Central Hospital, 3333 He-Chang Road, Eco-City, Tianjin 300367, China
| | - Shengyi Zhu
- Minnie & Max T. Voelcker Laboratory (Suzhou), 1304 Room No. 1 Building, 399 Xiarong Street, Wujiang District, Suzhou, China.
| | - Chengyu Wu
- Transplant Immunology Laboratory, Central Texas Baylor Scott & White Health, 2401 South 31st Street, Temple, TX 76508, USA.
| | - Qianghe Meng
- Department of Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
| | - Tun Jie
- Transplant Immunology Laboratory, Central Texas Baylor Scott & White Health, 2401 South 31st Street, Temple, TX 76508, USA.
| | - Medhat Askar
- Transplant Immunology, Baylor University Medical Center, 3500 Gaston Ave, 4th Floor of the Y Wing, RM# L-0470, Dallas, TX 75246, USA.
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Schmalkuche K, Rother T, Besli S, Schwinzer R, Blasczyk R, Petersen B, Figueiredo C. Human PD-L1 overexpression decreases xenogeneic human T-cell immune responses towards porcine kidneys. Front Immunol 2024; 15:1279050. [PMID: 38352884 PMCID: PMC10861674 DOI: 10.3389/fimmu.2024.1279050] [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: 08/17/2023] [Accepted: 01/11/2024] [Indexed: 02/16/2024] Open
Abstract
Xenotransplantation offers a promising alternative to circumvent the lack of donated human organs available for transplantation. Different attempts to improve the survival of xenografts led to the generation of transgenic pigs expressing various combinations of human protective genes or knocked out for specific antigens. Currently, testing the efficiency of porcine organs carrying different genetic modifications in preventing xenogeneic immune responses completely relies on in vitro assays, humanized mouse models, or non-human primate transplantation models. However, these tests are often associated with major concerns due to reproducibility and generation of insufficient data as well as they raise ethical, logistical, and economic issues. In this study, we investigated the feasibility of specifically assessing the strength of human T-cell responses towards the kidneys of wild-type (WT) or transgenic pigs overexpressing human programmed death-1 ligand 1 (hPD-L1) during ex vivo kidney perfusion (EVKP). Human T cells were shown to adhere to the endothelium and transmigrate into WT and hPD-L1 kidneys. However, transcript levels of TNF-a and IFN-y as well as cytotoxic molecules such as granzyme B and perforin secreted by human T cells were significantly decreased in the tissue of hPD-L1 kidneys in comparison to WT kidneys. These results were confirmed via in vitro assays using renal endothelial cells (ECs) isolated from WT and hPD-L1 transgenic pigs. Both CD4+ and CD8+ T cells showed significantly lower proliferation rates after exposure to hPD-L1 porcine renal ECs in comparison to WT ECs. In addition, the secretion of pro-inflammatory cytokines was significantly reduced in cultures using hPD-L1 ECs in comparison to WT ECs. Remarkably, hPD-L1 EC survival was significantly increased in cytotoxic assays. This study demonstrates the feasibility of evaluating the human response of specific immune subsets such as human T cells towards the whole xenograft during EVKP. This may represent a robust strategy to assess the potency of different genetic modifications to prevent xenogeneic immune responses and thereby predict the risk of immune rejection of new genetically engineered xenografts.
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Affiliation(s)
- Katharina Schmalkuche
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Hannover, Germany
| | - Tamina Rother
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Sevval Besli
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Reinhard Schwinzer
- Transregional Collaborative Research Centre 127, Hannover Medical School, Hannover, Germany
- Transplantation Laboratory, Clinic for General, Visceral and Transplantation-Surgery, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Björn Petersen
- Transregional Collaborative Research Centre 127, Hannover Medical School, Hannover, Germany
- Department of Biotechnology, Institute of Farm Animal Genetics, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Neustadt am Rübenberge, Germany
| | - Constanca Figueiredo
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Hannover, Germany
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Villalba-López F, García-Bernal D, Mateo SV, Vidal-Correoso D, Jover-Aguilar M, Alconchel F, Martínez-Alarcón L, López-López V, Ríos-Zambudio A, Cascales P, Pons JA, Ramírez P, Pelegrín P, Baroja-Mazo A. Endothelial cell activation mediated by cold ischemia-released mitochondria is partially inhibited by defibrotide and impacts on early allograft function following liver transplantation. Biomed Pharmacother 2023; 167:115529. [PMID: 37729732 DOI: 10.1016/j.biopha.2023.115529] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/29/2023] [Accepted: 09/15/2023] [Indexed: 09/22/2023] Open
Abstract
DAMPs (danger-associated molecular patterns) are self-molecules of the organism that appear after damage. The endothelium plays several roles in organ rejection, such as presenting alloantigens to T cells and contributing to the development of inflammation and thrombosis. This study aimed to assess whether DAMPs present in the organ preservation solution (OPS) after cold ischemic storage (CIS) contribute to exacerbating the endothelial response to an inflammatory challenge and whether defibrotide treatment could counteract this effect. The activation of cultured human umbilical vein endothelial cells (HUVECs) was analyzed after challenging with end-ischemic OPS (eiOPS) obtained after CIS. Additionally, transwell assays were performed to study the ability of eiOPS to attract lymphocytes across the endothelium. The study revealed that eiOPS upregulated the expression of MCP-1 and IL-6 in HUVECs. Moreover, eiOPS increased the membrane expression of ICAM-1and HLA-DR, which facilitated leukocyte migration toward a chemokine gradient. Furthermore, eiOPS demonstrated its chemoattractant ability. This activation was mediated by free mitochondria. Defibrotide was found to partially inhibit the eiOPS-mediated activation. Moreover, the eiOPS-mediated activation of endothelial cells (ECs) correlated with early allograft dysfunction in liver transplant patients. Our finding provide support for the hypothesis that mitochondria released during cold ischemia could trigger EC activation, leading to complications in graft outcomes. Therefore, the analysis and quantification of free mitochondria in the eiOPS samples obtained after CIS could provide a predictive value for monitoring the progression of transplantation. Moreover, defibrotide emerges as a promising therapeutic agent to mitigate the damage induced by ischemia in donated organs.
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Affiliation(s)
- Francisco Villalba-López
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain
| | - David García-Bernal
- Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain; Hematopoietic Transplant and Cell Therapy Group, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain.
| | - Sandra V Mateo
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain
| | - Daniel Vidal-Correoso
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain
| | - Marta Jover-Aguilar
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain
| | - Felipe Alconchel
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Laura Martínez-Alarcón
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain
| | - Víctor López-López
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Antonio Ríos-Zambudio
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Pedro Cascales
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - José A Pons
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; Hepatology and Liver Transplant Unit, University Clinical Hospital Virgen de la Arrixaca, 30120 Murcia, Spain
| | - Pablo Ramírez
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Pablo Pelegrín
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain
| | - Alberto Baroja-Mazo
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain.
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Mironov AA, Savin MA, Zaitseva AV, Dimov ID, Sesorova IS. Mechanisms of Formation of Antibodies against Blood Group Antigens That Do Not Exist in the Body. Int J Mol Sci 2023; 24:15044. [PMID: 37894724 PMCID: PMC10606600 DOI: 10.3390/ijms242015044] [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: 09/02/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
The system of the four different human blood groups is based on the oligosaccharide antigens A or B, which are located on the surface of blood cells and other cells including endothelial cells, attached to the membrane proteins or lipids. After transfusion, the presence of these antigens on the apical surface of endothelial cells could induce an immunological reaction against the host. The final oligosaccharide sequence of AgA consists of Gal-GlcNAc-Gal (GalNAc)-Fuc. AgB contains Gal-GlcNAc-Gal (Gal)-Fuc. These antigens are synthesised in the Golgi complex (GC) using unique Golgi glycosylation enzymes (GGEs). People with AgA also synthesise antibodies against AgB (group A [II]). People with AgB synthesise antibodies against AgA (group B [III]). People expressing AgA together with AgB (group AB [IV]) do not have these antibodies, while people who do not express these antigens (group O [0; I]) synthesise antibodies against both antigens. Consequently, the antibodies are synthesised against antigens that apparently do not exist in the body. Here, we compared the prediction power of the main hypotheses explaining the formation of these antibodies, namely, the concept of natural antibodies, the gut bacteria-derived antibody hypothesis, and the antibodies formed as a result of glycosylation mistakes or de-sialylation of polysaccharide chains. We assume that when the GC is overloaded with lipids, other less specialised GGEs could make mistakes and synthesise the antigens of these blood groups. Alternatively, under these conditions, the chylomicrons formed in the enterocytes may, under this overload, linger in the post-Golgi compartment, which is temporarily connected to the endosomes. These compartments contain neuraminidases that can cleave off sialic acid, unmasking these blood antigens located below the acid and inducing the production of antibodies.
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Affiliation(s)
- Alexander A. Mironov
- Department of Cell Biology, IFOM ETS—The AIRC Institute of Molecular Oncology, Via Adamello, 16, 20139 Milan, Italy
| | - Maksim A. Savin
- The Department for Welding Production and Technology of Constructional Materials, Perm National Research Polytechnic University, Komsomolsky Prospekt, 29, 614990 Perm, Russia;
| | - Anna V. Zaitseva
- Department of Anatomy, Saint Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Ivan D. Dimov
- Department of Cell Biology, IFOM ETS—The AIRC Institute of Molecular Oncology, Via Adamello, 16, 20139 Milan, Italy
| | - Irina S. Sesorova
- Department of Anatomy, Ivanovo State Medical Academy, 153012 Ivanovo, Russia
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Lee HJ, Shin K, Kim IY, Choi BH, Kim H. Association between anti-endothelial antigen antibodies and allograft rejection in kidney transplantation. J Clin Lab Anal 2023; 37:e24961. [PMID: 37694947 PMCID: PMC10561590 DOI: 10.1002/jcla.24961] [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: 06/02/2022] [Revised: 07/11/2023] [Accepted: 08/21/2023] [Indexed: 09/12/2023] Open
Abstract
BACKGROUND Endothelial cells are vital in the transplant immune system as semiprofessional antigen-presenting cells. Few studies have investigated the importance of anti-endothelin subtype A receptor (ETAR) antibodies in kidney transplantation. Here, we aimed to analyze the association between anti-angiotensin II type I receptor (AT1R) and anti-ETAR antibodies and the association between the presence of anti-endothelial antibodies and the risk of allograft rejection in kidney transplantation. METHODS In total, 252 patients who underwent kidney transplantation were enrolled in this study. Antibodies for human leukocyte antigens (HLAs) and non-HLAs were analyzed immediately before transplantation. Patients were categorized based on the occurrence of antibody-mediated rejection (AMR) or T-cell-mediated rejection (TCMR) by 2017 Banff classification. All p-values were two-tailed, and statistical significance was set at p < 0.05. RESULTS Patients with anti-AT1R antibodies had a 3.49-fold higher risk of TCMR than those without anti-AT1R antibodies. Patients with anti-ETAR antibodies had a 5.84-fold higher risk of AMR than those without anti-ETAR antibodies. The hazard ratio of AMR in patients with both HLA DSAs and anti-ETAR antibodies, relative to patients without anti-ETAR antibodies and HLA DSAs, was 32.85 (95% CI = 1.82-592.91). CONCLUSION Our findings indicated that anti-ETAR antibodies are associated with AMR, and patients with both anti-ETAR antibodies and de novo HLA DSAs were at a high risk of AMR.
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Affiliation(s)
- Hyun Ji Lee
- Department of Laboratory MedicinePusan National University School of MedicineYangsanKorea
- Transplant Research Center, Research Institute for Convergence of Biomedical Science and TechnologyPusan National University Yangsan HospitalYangsanKorea
| | - Kyung‐Hwa Shin
- Department of Laboratory MedicinePusan National University School of MedicineYangsanKorea
| | - Il Young Kim
- Transplant Research Center, Research Institute for Convergence of Biomedical Science and TechnologyPusan National University Yangsan HospitalYangsanKorea
- Department of Internal MedicinePusan National University School of MedicineYangsanKorea
| | - Byung Hyun Choi
- Transplant Research Center, Research Institute for Convergence of Biomedical Science and TechnologyPusan National University Yangsan HospitalYangsanKorea
- Department of SurgeryPusan National University School of MedicineYangsanKorea
| | - Hyung‐Hoi Kim
- BioMedical Informatics UnitPusan National University School of MedicineBusanKorea
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8
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Rao JS, Ivkov R, Sharma A. Nanoparticle-Based Interventions for Liver Transplantation. Int J Mol Sci 2023; 24:7496. [PMID: 37108659 PMCID: PMC10144867 DOI: 10.3390/ijms24087496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/29/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Liver transplantation is the only treatment for hepatic insufficiency as a result of acute and chronic liver injuries/pathologies that fail to recover. Unfortunately, there remains an enormous and growing gap between organ supply and demand. Although recipients on the liver transplantation waitlist have significantly higher mortality, livers are often not allocated because they are (i) classified as extended criteria or marginal livers and (ii) subjected to longer cold preservation time (>6 h) with a direct correlation of poor outcomes with longer cold ischemia. Downregulating the recipient's innate immune response to successfully tolerate a graft having longer cold ischemia times or ischemia-reperfusion injury through induction of immune tolerance in the graft and the host would significantly improve organ utilization and post-transplant outcomes. Broadly, technologies proposed for development aim to extend the life of the transplanted liver through post-transplant or recipient conditioning. In this review, we focus on the potential benefits of nanotechnology to provide unique pre-transplant grafting and recipient conditioning of extended criteria donor livers using immune tolerance induction and hyperthermic pre-conditioning.
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Affiliation(s)
- Joseph Sushil Rao
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Robert Ivkov
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Department of Oncology, Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Mechanical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Anirudh Sharma
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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9
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Yan W, Rafieerad A, Alagarsamy KN, Saleth LR, Arora RC, Dhingra S. Immunoengineered MXene nanosystem for mitigation of alloantigen presentation and prevention of transplant vasculopathy. NANO TODAY 2023; 48:None. [PMID: 37187503 PMCID: PMC10181944 DOI: 10.1016/j.nantod.2022.101706] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 09/27/2022] [Accepted: 11/23/2022] [Indexed: 05/17/2023]
Abstract
MXenes are an emerging class of nanomaterials with significant potential for applications in nanomedicine. Amongst MXene technologies, titanium carbide (Ti3C2Tx) nanomaterials are the most mature and have received significant attention to tackle longstanding clinical challenges due to its tailored physical and material properties. Cardiac allograft vasculopathy is an aggressive form of atherosclerosis and a major cause of mortality among patients with heart transplants. Blood vessel endothelial cells (ECs) stimulate alloreactive T-lymphocytes to result in sustained inflammation. Herein, we report the first application of Ti3C2Tx MXene nanosheets for prevention of allograft vasculopathy. MXene nanosheets interacted with human ECs and downregulated the expression of genes involved in alloantigen presentation, and consequently reduced the activation of allogeneic lymphocytes. RNA-Seq analysis of lymphocytes showed that treatment with MXene downregulated genes responsible for transplant-induced T-cell activation, cell-mediated rejection, and development of allograft vasculopathy. In an in vivo rat model of allograft vasculopathy, treatment with MXene reduced lymphocyte infiltration and preserved medial smooth muscle cell integrity within transplanted aortic allografts. These findings highlight the potential of Ti3C2Tx MXene in treatment of allograft vasculopathy and inflammatory diseases.
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Affiliation(s)
- Weiang Yan
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
- Section of Cardiac Surgery, Department of Surgery, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0W2, Canada
| | - Alireza Rafieerad
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Keshav Narayan Alagarsamy
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Leena Regi Saleth
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Rakesh C. Arora
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
- Section of Cardiac Surgery, Department of Surgery, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0W2, Canada
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
- Correspondence to: Institute of Cardiovascular Sciences St. Boniface Hospital Research Centre Department of Physiology and Pathophysiology Rady Faculty of Health Sciences, University of Manitoba, R-3028-2, 351 Tache Avenue, Winnipeg R2H2A6, Canada.
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10
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Song G, Wang S, Barkestani MN, Mullan C, Fan M, Jiang B, Jiang Q, Li X, Jane-wit D. Membrane attack complexes, endothelial cell activation, and direct allorecognition. Front Immunol 2022; 13:1020889. [PMID: 36211400 PMCID: PMC9539657 DOI: 10.3389/fimmu.2022.1020889] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 09/07/2022] [Indexed: 11/18/2022] Open
Abstract
Endothelial cells (ECs) form a critical immune interface regulating both the activation and trafficking of alloreactive T cells. In the setting of solid organ transplantation, donor-derived ECs represent sites where alloreactive T cells encounter major and minor tissue-derived alloantigens. During this initial encounter, ECs may formatively modulate effector responses of these T cells through expression of inflammatory mediators. Direct allorecognition is a process whereby recipient T cells recognize alloantigen in the context of donor EC-derived HLA molecules. Direct alloresponses are strongly modulated by human ECs and are galvanized by EC-derived inflammatory mediators. Complement are immune proteins that mark damaged or foreign surfaces for immune cell activation. Following labeling by natural IgM during ischemia reperfusion injury (IRI) or IgG during antibody-mediated rejection (ABMR), the complement cascade is terminally activated in the vicinity of donor-derived ECs to locally generate the solid-phase inflammatory mediator, the membrane attack complex (MAC). Via upregulation of leukocyte adhesion molecules, costimulatory molecules, and cytokine trans-presentation, MAC strengthen EC:T cell direct alloresponses and qualitatively shape the alloimmune T cell response. These processes together promote T cell-mediated inflammation during solid organ transplant rejection. In this review we describe molecular pathways downstream of IgM- and IgG-mediated MAC assembly on ECs in the setting of IRI and ABMR of tissue allografts, respectively. We describe work demonstrating that MAC deposition on ECs generates 'signaling endosomes' that sequester and post-translationally enhance the stability of inflammatory signaling molecules to promote EC activation, a process potentiating EC-mediated direct allorecognition. Additionally, with consideration to first-in-human xenotransplantation procedures, we describe clinical therapeutics based on inhibition of the complement pathway. The complement cascade critically mediates EC activation and improved understanding of relevant effector pathways will uncover druggable targets to obviate dysregulated alloimmune T cell infiltration into tissue allografts.
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Affiliation(s)
- Guiyu Song
- Section of Cardiovascular Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shaoxun Wang
- Section of Cardiovascular Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - Mahsa Nouri Barkestani
- Section of Cardiovascular Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Clancy Mullan
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Matthew Fan
- Section of Cardiovascular Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Bo Jiang
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
- Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Quan Jiang
- Section of Cardiovascular Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Xue Li
- Section of Cardiovascular Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Dan Jane-wit
- Section of Cardiovascular Medicine, Dept of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
- Department of Cardiology, West Haven VA Medical Center, West Haven, CT, United States
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11
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Hang Z, Wei J, Zheng M, Gui Z, Chen H, Sun L, Fei S, Han Z, Tao J, Wang Z, Tan R, Gu M. Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4. Front Pharmacol 2022; 13:865363. [PMID: 35614941 PMCID: PMC9125033 DOI: 10.3389/fphar.2022.865363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant.Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague–Dawley (SD) rats were pre-sensitized with donors of Wistar rats in skin transplantation and a rat renal transplant ABMR model was established from the donors to skin pre-sensitized recipients. Subsequently, IGT was treated on the ABMR model. Routine staining and immunofluorescence (IF) staining were performed to observe the pathological changes in each group and flow cytometry was performed to detect the changes of DSA titers in peripheral blood. In addition, bone-marrow-derived macrophage (BMDM) was extracted and interfered with IGT to explore the effect of IGT in vivo. PCR, IF staining, and Western blot were used to detect the expression of related genes and proteins.Results: Bioinformatics analysis revealed that several immune cells were significantly infiltrated in the ABMR allograft, while M1 macrophage was noticed with the most significance. Results of IF staining and PCR proved the findings of the bioinformatics analysis. Based on this, IGT was observed to significantly attenuate the degree of peritubular capillary vasculitis and arteriolitis in the rat renal transplant ABMR model, whereas it decreases the expression of C4d and reduces the titer of DSA. Results in vitro suggested that M1 macrophage-related transcripts and proteins were significantly reduced by the treatment of IGT in a dose- and time-dependent manner. Furthermore, IGT intervention could remarkably decrease the expression of KLF4.Conclusion: Polarization of M1 macrophages may aggravate ABMR after renal transplant by promoting DSA-mediated endothelial cell injury, and IGT may attenuate the pathogenesis of ABMR by targeting KLF4.
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Affiliation(s)
- Zhou Hang
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jintao Wei
- Department of Emergency Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming Zheng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zeping Gui
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuang Fei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Zijie Wang, ; Min Gu, ; Ruoyun Tan,
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Zijie Wang, ; Min Gu, ; Ruoyun Tan,
| | - Min Gu
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Zijie Wang, ; Min Gu, ; Ruoyun Tan,
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12
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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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13
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Buchwald JE, Martins PN. Designer organs: The future of personalized transplantation. Artif Organs 2022; 46:180-190. [DOI: 10.1111/aor.14151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Julianna E. Buchwald
- Division of Transplantation Department of Surgery University of Massachusetts Chan Medical School Worcester Massachusetts USA
- RNA Therapeutics Institute University of Massachusetts Chan Medical School Worcester Massachusetts USA
| | - Paulo N. Martins
- Division of Transplantation Department of Surgery University of Massachusetts Chan Medical School Worcester Massachusetts USA
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14
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Have we hit a wall with whole kidney decellularization and recellularization: A review. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2021. [DOI: 10.1016/j.cobme.2021.100335] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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15
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Nowańska K, Wiśnicki K, Kuriata-Kordek M, Krajewska M, Banasik M. The role of endothelin II type A receptor (ETAR) in transplant injury. Transpl Immunol 2021; 70:101505. [PMID: 34793957 DOI: 10.1016/j.trim.2021.101505] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Antibody-mediated rejection is the leading cause of deterioration of graft function and graft loss after kidney transplantation. Recent studies have reported an increasing role of non-HLA antibodies in the humoral injury after kidney transplantation. We decided to present the influence of non-HLA antibodies - anti-endothelin II type A receptor (ETAR) on a transplanted kidney and characterize the significance of their receptor. RECENT FINDINGS The role of non-HLA antibodies is still uncertain. Many studies suggest that the presence of non-HLA antibodies, including anti-ETAR antibodies, is among the risk factors for antibody-mediated rejection, graft injury, and graft loss. The discovery of new antigen targets and antibodies, which participate in the humoral response, has provided a significantly better understanding of the mechanism of antibody-mediated rejection after organ transplantation. SUMMARY Endothelin and its receptors play an important role in physiology and pathophysiology after solid organ transplantation. ETAR and antibodies against ETAR may participate in humoral rejection and graft damage. The measurement of anti-ETAR antibodies may identify patients with an increased risk of rejection and even loss of a transplanted organ. Expression of ETAR detected in biopsy of transplant could become an additional tool used to better understand humoral activity. More research is needed to address many questions about non-HLA directed rejection and graft damage.
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Affiliation(s)
- Katarzyna Nowańska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Krzysztof Wiśnicki
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Magdalena Kuriata-Kordek
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland.
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16
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Rafieerad A, Yan W, Alagarsamy KN, Srivastava A, Sareen N, Arora RC, Dhingra S. Fabrication of Smart Tantalum Carbide MXene Quantum Dots with Intrinsic Immunomodulatory Properties for Treatment of Allograft Vasculopathy. ADVANCED FUNCTIONAL MATERIALS 2021; 31:2106786. [PMID: 35153642 PMCID: PMC8820728 DOI: 10.1002/adfm.202106786] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/24/2021] [Indexed: 05/04/2023]
Abstract
MXene nanomaterials have sparked significant interest among interdisciplinary researchers to tackle today's medical challenges. In particular, colloidal MXene quantum dots (MQDs) offer the high specific surface area and compositional flexibility of MXene while providing improvements to aqueous stability and material-cell interactions. The current study for the first time reports the development and application of immunoengineered tantalum-carbide (Ta4C3T x ) MQDs for in vivo treatment of transplant vasculopathy. This report comes at a critical juncture in the field as poor long-term safety of other MXene compositions challenge the eventual clinical translatability of these materials. Using rational design and synthesis strategies, the Ta4C3T x MQDs leverage the intrinsic anti-inflammatory and antiapoptotic properties of tantalum to provide a novel nanoplatform for biomedical engineering. In particular, these MQDs are synthesized with high efficiency and purity using a facile hydrofluoric acid-free protocol and are enriched with different bioactive functional groups and stable surface TaO2 and Ta2O5. Furthermore, MQDs are spontaneously uptaken into antigen-presenting endothelial cells and alter surface receptor expression to reduce their activation of allogeneic T-lymphocytes. Finally, when applied in vivo, Ta4C3T x MQDs ameliorate the cellular and structural changes of early allograft vasculopathy. These findings highlight the robust potential of tailored Ta4C3T x MQDs for future applications in medicine.
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Affiliation(s)
- Alireza Rafieerad
- Regenerative Medicine Program Department of Physiology and Pathophysiology Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
- Institute of Cardiovascular Sciences Albrechtsen St. Boniface Research Centre University of Manitoba Winnipeg Manitoba R2H 2A6 Canada
| | - Weiang Yan
- Regenerative Medicine Program Department of Physiology and Pathophysiology Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
- Institute of Cardiovascular Sciences Albrechtsen St. Boniface Research Centre University of Manitoba Winnipeg Manitoba R2H 2A6 Canada
- Section of Cardiac Surgery Department of Surgery Max Rady College of Medicine Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
| | - Keshav Narayan Alagarsamy
- Regenerative Medicine Program Department of Physiology and Pathophysiology Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
- Institute of Cardiovascular Sciences Albrechtsen St. Boniface Research Centre University of Manitoba Winnipeg Manitoba R2H 2A6 Canada
| | - Abhay Srivastava
- Regenerative Medicine Program Department of Physiology and Pathophysiology Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
- Institute of Cardiovascular Sciences Albrechtsen St. Boniface Research Centre University of Manitoba Winnipeg Manitoba R2H 2A6 Canada
| | - Niketa Sareen
- Regenerative Medicine Program Department of Physiology and Pathophysiology Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
- Institute of Cardiovascular Sciences Albrechtsen St. Boniface Research Centre University of Manitoba Winnipeg Manitoba R2H 2A6 Canada
| | - Rakesh C Arora
- Institute of Cardiovascular Sciences Albrechtsen St. Boniface Research Centre University of Manitoba Winnipeg Manitoba R2H 2A6 Canada
- Section of Cardiac Surgery Department of Surgery Max Rady College of Medicine Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
| | - Sanjiv Dhingra
- Regenerative Medicine Program Department of Physiology and Pathophysiology Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba R3E 0W2 Canada
- Institute of Cardiovascular Sciences Albrechtsen St. Boniface Research Centre University of Manitoba Winnipeg Manitoba R2H 2A6 Canada
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17
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Siren EMJ, Luo HD, Tam F, Montgomery A, Enns W, Moon H, Sim L, Rey K, Guan Q, Wang JJ, Wardell CM, Monajemi M, Mojibian M, Levings MK, Zhang ZJ, Du C, Withers SG, Choy JC, Kizhakkedathu JN. Prevention of vascular-allograft rejection by protecting the endothelial glycocalyx with immunosuppressive polymers. Nat Biomed Eng 2021; 5:1202-1216. [PMID: 34373602 DOI: 10.1038/s41551-021-00777-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/30/2021] [Indexed: 02/07/2023]
Abstract
Systemic immunosuppression for the mitigation of immune rejection after organ transplantation causes adverse side effects and constrains the long-term benefits of the transplanted graft. Here we show that protecting the endothelial glycocalyx in vascular allografts via the enzymatic ligation of immunosuppressive glycopolymers under cold-storage conditions attenuates the acute and chronic rejection of the grafts after transplantation in the absence of systemic immunosuppression. In syngeneic and allogeneic mice that received kidney transplants, the steric and immunosuppressive properties of the ligated polymers largely protected the transplanted grafts from ischaemic reperfusion injury, and from immune-cell adhesion and thereby immunocytotoxicity. Polymer-mediated shielding of the endothelial glycocalyx following organ procurement should be compatible with clinical procedures for transplant preservation and perfusion, and may reduce the damage and rejection of transplanted organs after surgery.
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Affiliation(s)
- Erika M J Siren
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.,Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Haiming D Luo
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.,Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Franklin Tam
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Ashani Montgomery
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Winnie Enns
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Haisle Moon
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Lyann Sim
- Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Kevin Rey
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Qiunong Guan
- Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Jiao-Jing Wang
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA
| | - Christine M Wardell
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.,Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Mahdis Monajemi
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.,Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Majid Mojibian
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.,Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Megan K Levings
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.,Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada.,School of Biomedical Engineering, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Zheng J Zhang
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA
| | - Caigan Du
- Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Stephen G Withers
- Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
| | - Jayachandran N Kizhakkedathu
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada. .,Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada. .,Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. .,School of Biomedical Engineering, The University of British Columbia, Vancouver, British Columbia, Canada.
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18
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Markiewicz-Kijewska M, Kaliciński P, Torres Canizales J, Di Giorgio A, Baumann U, Jorns C, Baker A, Lopes MF, Frauca Remacha E, Lopez-Granados E, Jara Vega P, Basso MS, Kowalewski G, Kamińska D, Ferreira S, Liccardo D, Pietrobattista A, Spada M, on behalf of ERN TransplantChild Healthcare Working Group. ABO Incompatible Liver Transplantation in Children: A 20 Year Experience from Centres in the TransplantChild European Reference Network. CHILDREN-BASEL 2021; 8:children8090760. [PMID: 34572193 PMCID: PMC8468154 DOI: 10.3390/children8090760] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 11/23/2022]
Abstract
An increasing number of AB0-incompatible (AB0i) liver transplantations (LT) are being undertaken internationally in recent years due to organ shortages and the need for urgent transplantation. The aim of our study was establish the value of ABOi LT from available retrospective results of AB0i pediatric liver transplantations performed in European reference centers now belonging to the TransplantChild, European Reference Network (ERN). Data from medical records were analyzed, including demographic data, diagnosis, urgency of transplantation, time on the waiting list, PELD/MELD score, desensitization procedures, immunosuppression, selected post-transplant complications, and patient and graft survival. A total of 142 patients (pts) with transplants between 1986 and 2018 in 8 European transplant centers were included in the study. The indications for liver transplantation were: cholestatic diseases in 62 pts, acute liver failure in 42 pts, and other conditions in the remaining 38 pts. Sixty-six patients received grafts from living donors, and seventy-six received grafts from deceased donors. Both patient and graft survival were significantly affected by deceased donor type, urgent transplantation, and the development of vascular complications. In the multivariate analysis, vascular complications had a negative impact on patient and graft survival, while a longer time from the first AB0i LT in the study showed better results, suggesting an international learning experience. In conclusion, we believe that AB0i LT in children is now a safe procedure that may be adopted more readily in children.
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Affiliation(s)
- Małgorzata Markiewicz-Kijewska
- Department of Pediatric Surgery and Organ Transplantation, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.M.-K.); (G.K.)
| | - Piotr Kaliciński
- Department of Pediatric Surgery and Organ Transplantation, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.M.-K.); (G.K.)
- Correspondence: ; Tel.: +48-22-615-13-60
| | - Juan Torres Canizales
- Center for Biomedical Network Research on Rare Diseases (CIBERER U767), Lymphocyte Pathophysiology in Immunodeficiencies Group, Immunology Unit, La Paz Institute of Biomedical Research (IdiPAZ), La Paz University Hospital, 28046 Madrid, Spain; (J.T.C.); (E.L.-G.)
| | - Angelo Di Giorgio
- Department of Pediatric Hepatology, Gastroenterology and Transplantation, ASST Hospital Papa Giovanni XXIII, 24127 Bergamo, Italy;
| | - Ulrich Baumann
- Division of Pediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany;
| | - Carl Jorns
- Department of Transplantation Surgery, Karolinska University Hospital, 171 76 Stockholm, Sweden;
| | - Alastair Baker
- Pediatric Liver, Gastrointestinal and Nutrition Centre, King’s College London School of Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, UK;
| | - Maria Francelina Lopes
- Department of Pediatric Surgery, Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Faculty of Medicine, University of Coimbra, 3000-075 Coimbra, Portugal;
| | - Esteban Frauca Remacha
- Servicio de Hepatología Pediátrica, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.F.R.); (P.J.V.)
| | - Eduardo Lopez-Granados
- Center for Biomedical Network Research on Rare Diseases (CIBERER U767), Lymphocyte Pathophysiology in Immunodeficiencies Group, Immunology Unit, La Paz Institute of Biomedical Research (IdiPAZ), La Paz University Hospital, 28046 Madrid, Spain; (J.T.C.); (E.L.-G.)
| | - Paloma Jara Vega
- Servicio de Hepatología Pediátrica, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.F.R.); (P.J.V.)
| | - Maria-Sole Basso
- Department of Hepatology, Gastroenterology and Nutrition, Ospedale Pediatrico Bambino Gesu, 00165 Roma, Italy; (M.-S.B.); (D.L.); (A.P.)
| | - Grzegorz Kowalewski
- Department of Pediatric Surgery and Organ Transplantation, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.M.-K.); (G.K.)
| | - Diana Kamińska
- The Department of Gastroenterology, Hepatology, Nutrition Disorder and Pediatric, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
| | - Sandra Ferreira
- Hepatology and Pediatric Liver Transplantation Unit, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal;
| | - Daniela Liccardo
- Department of Hepatology, Gastroenterology and Nutrition, Ospedale Pediatrico Bambino Gesu, 00165 Roma, Italy; (M.-S.B.); (D.L.); (A.P.)
| | - Andrea Pietrobattista
- Department of Hepatology, Gastroenterology and Nutrition, Ospedale Pediatrico Bambino Gesu, 00165 Roma, Italy; (M.-S.B.); (D.L.); (A.P.)
| | - Marco Spada
- Department of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, 00165 Rome, Italy;
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19
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Huang Y, Miao H, Xia C, Feng H, Xu S, Liang Z, Wang Y, Zhao C, Qin G, Ou X, Zhao F. High VCAM-1 Predicts Poor Prognosis and is Associated with Chemotherapy Resistance in Nasopharyngeal Carcinoma. Onco Targets Ther 2021; 14:1633-1641. [PMID: 33688210 PMCID: PMC7936694 DOI: 10.2147/ott.s292259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 02/16/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose Nasopharyngeal carcinoma (NPC) is a malignant tumor endemic in southern China and Southeast Asia with a poor prognosis. Vascular cell adhesion protein 1 (VCAM-1) is highly expressed in NPC; however, it is unclear whether VCAM-1 is correlated with chemotherapy resistance and prognosis in NPC. Patients and Methods To further explore the role of VCAM-1 in chemotherapy resistance and prognosis in NPC, we examined the expression of VCAM-1, the sensitivity of chemotherapy drugs, and clinical follow-up data from 73 patients with NPC. Then, the results of VCAM-1 expression were analyzed in response to chemotherapy drugs, progression-free survival (PFS), and overall survival (OS). Results The expression of VCAM-1 protein in NPC was significantly higher than that in chronic inflammatory tissue. No significant differences in the expression of VCAM-1 among gender, age, pathologic classification, tumor classification, lymph node status, metastasis status, and overall clinical stage were found. The periods of PFS and OS in patients with high VCAM-1 expression were significantly shorter than those in patients with low VCAM-1 expression. The sensitivity rates of NPC to eight chemotherapy drugs were different; carboplatin and docetaxel showed the highest chemotherapy sensitivity and resistance rates, respectively. The resistance rates to paclitaxel were different between the patients with high VCAM-1 expression and those with low VCAM-1 expression. Conclusion Our data indicated that VCAM-1 was highly expressed in NPC. Patients with high VCAM-1 expression were more prone to shorter periods of PFS and OS. VCAM-1 could be a prognostic marker of NPC patients. The detection of VCAM-1 expression in NPC may be valuable for chemotherapy drug evaluation and management of patients with NPC in the clinic.
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Affiliation(s)
- Yu Huang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Hongbin Miao
- Department of Otolaryngology-Head and Neck Surgery, The People's Hospital of Bishan District, Chongqing Medical University, Bishan, 402760, Chongqing, People's Republic of China
| | - Chenxi Xia
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Huajun Feng
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Shengen Xu
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Zhuoping Liang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Yuanyuan Wang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Chong Zhao
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Gang Qin
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Xiaoyi Ou
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Feipeng Zhao
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
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20
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Yu S, Huh HJ, Lee KW, Park JB, Kim SJ, Huh W, Jang HR, Kwon GY, Moon HH, Kang ES. Pre-Transplant Angiotensin II Type 1 Receptor Antibodies and Anti-Endothelial Cell Antibodies Predict Graft Function and Allograft Rejection in a Low-Risk Kidney Transplantation Setting. Ann Lab Med 2021; 40:398-408. [PMID: 32311853 PMCID: PMC7169631 DOI: 10.3343/alm.2020.40.5.398] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/17/2020] [Accepted: 03/03/2020] [Indexed: 11/24/2022] Open
Abstract
Background Non-HLA antibodies, anti-angiotensin II type 1 receptor antibodies (anti-AT1R) and anti-endothelial cell antibodies (AECA), are known to play a role in allograft rejection. We evaluated the role of both antibodies in predicting post-transplant outcomes in low-risk living donor kidney transplantation (LDKT) recipients. Methods In 94 consecutive LDKT recipients who were ABO compatible and negative for pre-transplant HLA donor-specific antibodies, we determined the levels of anti-AT1Rs using an enzyme-linked immunosorbent assay and the presence of AECAs using a flow cytometric endothelial cell crossmatch (ECXM) assay with pre-transplant sera. Hazard ratio (HR) was calculated to predict post-transplant outcomes. Results Pre-transplant anti-AT1Rs (≥11.5 U/mL) and AECAs were observed in 36 (38.3%) and 22 recipients (23.4%), respectively; 11 recipients had both. Pre-transplant anti-AT1Rs were a significant risk factor for the development of acute rejection (AR) (HR 2.09; P=0.018), while a positive AECA status was associated with AR or microvascular inflammation only (HR 2.47; P=0.004) throughout the follow-up period. In particular, AECA (+) recipients with ≥11.5 U/mL anti-AT1Rs exhibited a significant effect on creatinine and estimated glomerular filtration rate (P<0.001; P=0.028), although the risk of AR was not significant. Conclusions Pre-transplant anti-AT1Rs and AECAs have independent negative effects on post-transplant outcomes in low-risk LDKT recipients. Assessment of both antibodies would be helpful in stratifying the pre-transplant immunological risk, even in low-risk LDKT recipients.
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Affiliation(s)
- Shinae Yu
- Department of Laboratory Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Hee Jae Huh
- Department of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyo Won Lee
- Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea.,Organ Transplantation Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Berm Park
- Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea.,Organ Transplantation Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung-Joo Kim
- Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea.,Organ Transplantation Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wooseong Huh
- Organ Transplantation Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye Ryoun Jang
- Organ Transplantation Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ghee Young Kwon
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyung Hwan Moon
- Department of Surgery Kosin University Gospel Hospital, Medical College of Kosin University, Busan, Korea
| | - Eun-Suk Kang
- Department of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine, Seoul, Korea.,Organ Transplantation Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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21
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Lee J, Lee S, Ahmad T, Madhurakkat Perikamana SK, Lee J, Kim EM, Shin H. Human adipose-derived stem cell spheroids incorporating platelet-derived growth factor (PDGF) and bio-minerals for vascularized bone tissue engineering. Biomaterials 2020; 255:120192. [PMID: 32559565 DOI: 10.1016/j.biomaterials.2020.120192] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 04/06/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022]
Abstract
Stem cells with mineralized materials have been used for bone regeneration; however, engineering the complex vascularized structure of the natural bone remains a challenge. Here, we developed platelet-derived growth factor (PDGF) and bio-mineral coated fibers which were then assembled with human adipose-derived stem cells (hADSCs) to form spheroids as building blocks for vascularized bone regeneration. The PDGF incorporated within the spheroid increased the proliferation of hADSCs, which was characterized by Ki-67 staining and DNA contents. Furthermore, the PDGF enhanced not only osteogenic differentiation, but also endothelial differentiation of hADSCs; the cells within the spheroids showed significantly greater gene expression by 2.46 ± 0.14 fold for osteocalcin (OCN) and by 12.85 ± 3.36 fold for von Willebrand factor (vWF) than those without PDGF. Finally, at two months following transplantation of PDGF-incorporated spheroids onto in vivo mouse calvarial defect, the regenerated bone area (42.48 ± 10.84%) was significantly enhanced and the greatest number of capillaries and arterioles with indication of transplanted hADSCs were observed. Moreover, millimeter-scale in vitro tissue prepared by fused assembly of the spheroids exhibited greater mRNA expression-associated to endothelial lineage. Taken together, these findings indicate that stem cell spheroids incorporating PDGF and bio-minerals could be used as a module for successful vascularized bone regeneration.
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Affiliation(s)
- Jinkyu Lee
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Sangmin Lee
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Taufiq Ahmad
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Sajeesh Kumar Madhurakkat Perikamana
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Jinki Lee
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Eun Mi Kim
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Heungsoo Shin
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea; Institute of Nano Science and Technology, Hanyang University, Seoul, 04763, Republic of Korea.
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22
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Kummer L, Zaradzki M, Vijayan V, Arif R, Weigand MA, Immenschuh S, Wagner AH, Larmann J. Vascular Signaling in Allogenic Solid Organ Transplantation - The Role of Endothelial Cells. Front Physiol 2020; 11:443. [PMID: 32457653 PMCID: PMC7227440 DOI: 10.3389/fphys.2020.00443] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
Graft rejection remains the major obstacle after vascularized solid organ transplantation. Endothelial cells, which form the interface between the transplanted graft and the host’s immunity, are the first target for host immune cells. During acute cellular rejection endothelial cells are directly attacked by HLA I and II-recognizing NK cells, macrophages, and T cells, and activation of the complement system leads to endothelial cell lysis. The established forms of immunosuppressive therapy provide effective treatment options, but the treatment of chronic rejection of solid organs remains challenging. Chronic rejection is mainly based on production of donor-specific antibodies that induce endothelial cell activation—a condition which phenotypically resembles chronic inflammation. Activated endothelial cells produce chemokines, and expression of adhesion molecules increases. Due to this pro-inflammatory microenvironment, leukocytes are recruited and transmigrate from the bloodstream across the endothelial monolayer into the vessel wall. This mononuclear infiltrate is a hallmark of transplant vasculopathy. Furthermore, expression profiles of different cytokines serve as clinical markers for the patient’s outcome. Besides their effects on immune cells, activated endothelial cells support the migration and proliferation of vascular smooth muscle cells. In turn, muscle cell recruitment leads to neointima formation followed by reduction in organ perfusion and eventually results in tissue injury. Activation of endothelial cells involves antibody ligation to the surface of endothelial cells. Subsequently, intracellular signaling pathways are initiated. These signaling cascades may serve as targets to prevent or treat adverse effects in antibody-activated endothelial cells. Preventive or therapeutic strategies for chronic rejection can be investigated in sophisticated mouse models of transplant vasculopathy, mimicking interactions between immune cells and endothelium.
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Affiliation(s)
- Laura Kummer
- Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Marcin Zaradzki
- Institute of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Vijith Vijayan
- Institute for Transfusion Medicine, Hannover Medical School, Hanover, Germany
| | - Rawa Arif
- Institute of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus A Weigand
- Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephan Immenschuh
- Institute for Transfusion Medicine, Hannover Medical School, Hanover, Germany
| | - Andreas H Wagner
- Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Jan Larmann
- Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany
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23
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Yuzefovych Y, Valdivia E, Rong S, Hack F, Rother T, Schmitz J, Bräsen JH, Wedekind D, Moers C, Wenzel N, Gueler F, Blasczyk R, Figueiredo C. Genetic Engineering of the Kidney to Permanently Silence MHC Transcripts During ex vivo Organ Perfusion. Front Immunol 2020; 11:265. [PMID: 32140158 PMCID: PMC7042208 DOI: 10.3389/fimmu.2020.00265] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/31/2020] [Indexed: 12/29/2022] Open
Abstract
Organ gene therapy represents a promising tool to correct diseases or improve graft survival after transplantation. Polymorphic variation of the major histocompatibility complex (MHC) antigens remains a major obstacle to long-term graft survival after transplantation. Previously, we demonstrated that MHC-silenced cells are protected against allogeneic immune responses. We also showed the feasibility to silence MHC in the lung. Here, we aimed at the genetic engineering of the kidney toward permanent silencing of MHC antigens in a rat model. We constructed a sub-normothermic ex vivo perfusion system to deliver lentiviral vectors encoding shRNAs targeting β2-microglobulin and the class II transactivator to the kidney. In addition, the vector contained the sequence for a secreted nanoluciferase. After kidney transplantation (ktx), we detected bioluminescence in the plasma and urine of recipients of an engineered kidney during the 6 weeks of post-transplant monitoring, indicating a stable transgene expression. Remarkably, transcript levels of β2-microglobulin and the class II transactivator were decreased by 70% in kidneys expressing specific shRNAs. Kidney genetic modification did not cause additional cell death compared to control kidneys after machine perfusion. Nevertheless, cytokine secretion signatures were altered during perfusion with lentiviral vectors as revealed by an increase in the secretion of IL-10, MIP-1α, MIP-2, IP-10, and EGF and a decrease in the levels of IL-12, IL-17, MCP-1, and IFN-γ. Biodistribution assays indicate that the localization of the vector was restricted to the graft. This study shows the potential to generate immunologically invisible kidneys showing great promise to support graft survival after transplantation and may contribute to reduce the burden of immunosuppression.
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Affiliation(s)
- Yuliia Yuzefovych
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Emilio Valdivia
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Song Rong
- Department of Nephrology, Hannover Medical School, Hanover, Germany
| | - Franziska Hack
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Tamina Rother
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Jessica Schmitz
- Hannover Medical School, Institute for Pathology, Hanover, Germany
| | | | - Dirk Wedekind
- Hannover Medical School, Institute for Laboratory Animal Science, Hanover, Germany
| | - Cyril Moers
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Nadine Wenzel
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Faikah Gueler
- Department of Nephrology, Hannover Medical School, Hanover, Germany
| | - Rainer Blasczyk
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Constanca Figueiredo
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
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24
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Wang J, Wang P, Wang S, Tan J. Donor-specific HLA Antibodies in Solid Organ Transplantation: Clinical Relevance and Debates. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2019; 000:1-11. [DOI: 10.14218/erhm.2019.00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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25
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Louis K, Hertig A, Taupin JL, Buob D, Jamme M, Brocheriou I, Luque Y, Jouanneau C, Ouali N, Audouin M, Rondeau E, Xu-Dubois YC. Markers of graft microvascular endothelial injury may identify harmful donor-specific anti-HLA antibodies and predict kidney allograft loss. Am J Transplant 2019; 19:2434-2445. [PMID: 30836425 DOI: 10.1111/ajt.15340] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 01/29/2019] [Accepted: 02/22/2019] [Indexed: 01/25/2023]
Abstract
Graft microvasculature is a major target of donor-specific antibodies (DSA) and endothelial damage is direct evidence of antibody-mediated rejection (ABMR). Using immunohistochemistry, we analyzed the expression of three microvascular endothelial activation markers (fascin, vimentin, and hsp47), suggestive of endothelial-to-mesenchymal transition (EndMT) in 351 graft biopsies from 248 kidney recipients, with concomitant screening of circulating antihuman leukocyte antigen (HLA) DSA at the time of the biopsy. The factors associated with EndMT marker expression were DSA and the presence of microvascular inflammation (MI). EndMT expressing grafts had significantly more allograft loss compared to EndMT negative grafts (P < .0001). The expression of EndMT markers positively correlated with anti-HLA DSA class II mean fluorescence intensity (MFI) levels and especially identified DQ and DR antibodies as being more closely associated with microvascular injury. Moreover, only DSA linked to positive EndMT score affected allograft survival, regardless of DSA MFI levels or presence of C4d deposition. Thus, EndMT markers could represent a clinically relevant tool for early identification of ongoing endothelial injury, harmful DSA, and patients at high risk for allograft failure.
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Affiliation(s)
- Kevin Louis
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Alexandre Hertig
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France
| | - Jean-Luc Taupin
- AP-HP, Hôpital Saint Louis, Laboratoire d'immunologie et d'histocompatibilité, Paris, France
| | - David Buob
- Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France.,AP-HP, Hôpital Tenon, Service d'Anatomo-Pathologie, Paris, France
| | - Matthieu Jamme
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Isabelle Brocheriou
- Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France.,AP-HP, Hôpital Pitié-Salpétrière, Service d'Anatomo-Pathologie, Paris, France
| | - Yosu Luque
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France
| | - Chantal Jouanneau
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Nacera Ouali
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France
| | - Marie Audouin
- APHP, Hôpital Tenon, Service d'urologie, Paris, France
| | - Eric Rondeau
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR S 1155, Paris, France
| | - Yi-Chun Xu-Dubois
- Sorbonne University, Inserm UMR_S1155, AP-HP, Hôpital Tenon, F-75020, Paris, France.,APHP, Hôpital Tenon, Service de Santé publique, Paris, France
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26
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Qureshi MS, Alsughayyir J, Chhabra M, Ali JM, Goddard MJ, Devine CA, Conlon TM, Linterman MA, Motallebzadeh R, Pettigrew GJ. Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy. J Autoimmun 2019; 98:44-58. [DOI: 10.1016/j.jaut.2018.11.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 11/27/2018] [Accepted: 11/30/2018] [Indexed: 12/18/2022]
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27
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Emerging approaches and technologies in transplantation: the potential game changers. Cell Mol Immunol 2019; 16:334-342. [PMID: 30760918 DOI: 10.1038/s41423-019-0207-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 01/18/2019] [Indexed: 12/27/2022] Open
Abstract
Newly emerging technologies are rapidly changing conventional approaches to organ transplantation. In the modern era, the key challenges to transplantation include (1) how to best individualize and possibly eliminate the need for life-long immunosuppression and (2) how to expand the donor pool suitable for human transplantation. This article aims to provide readers with an updated review of three new technologies that address these challenges. First, single-cell RNA sequencing technology is rapidly evolving and has recently been employed in settings related to transplantation. The new sequencing data indicate an unprecedented cellular heterogeneity within organ transplants, as well as exciting new molecular signatures involved in alloimmune responses. Second, sophisticated nanotechnology platforms provide a means of therapeutically delivering immune modulating reagents to promote transplant tolerance. Tolerogenic nanoparticles with regulatory molecules and donor antigens are capable of targeting host immune responses with tremendous precision, which, in some cases, results in donor-specific tolerance. Third, CRISPR/Cas9 gene editing technology has the potential to precisely remove immunogenic molecules while inserting desirable regulatory molecules. This technology is particularly useful in generating genetically modified pigs for xenotransplantation to solve the issue of the shortage of human organs. Collectively, these new technologies are positioning the transplant community for major breakthroughs that will significantly advance transplant medicine.
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28
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Lee YH, Kim SY, Moon H, Seo JW, Kim DJ, Park SH, Kim YG, Moon JY, Kim JS, Jeong KH, Lim SJ, Kim CD, Park JB, Chung BH, Kim YH, Yang J, Yang HI, Kim KS, Lee SH. Endocan as a marker of microvascular inflammation in kidney transplant recipients. Sci Rep 2019; 9:1854. [PMID: 30755622 PMCID: PMC6372712 DOI: 10.1038/s41598-018-37975-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 12/13/2018] [Indexed: 12/14/2022] Open
Abstract
Endocan is a water-soluble proteoglycan exclusively secreted by vascular endothelium. Endocan levels may be elevated in kidney transplant recipients experiencing antibody-mediated rejection (ABMR), which is characterized by vascular inflammation in transplanted kidney. We evaluated the clinical relevance of endocan as markers of microvascular inflammation in patients who underwent kidney transplantation. Plasma and urinary endocan levels were measured in 203 kidney transplant recipients and were compared across different etiologies of allograft dysfunction and various pathologic scores. Both plasma and urinary endocan levels were significantly higher in patients with acute ABMR than those in patients with normal pathology, acute tubular necrosis (ATN), acute pyelonephritis, BK virus associated nephropathy (BKVN), and T-cell mediated rejection (TCMR). Patients with chronic active ABMR also exhibited significantly higher plasma and urinary endocan levels than patients with long-term graft survival. Scores of glomerulitis and peritubular capillaritis, which are typical features of microvascular inflammation, were significantly elevated in patients with higher plasma and/or urinary endocan levels. Furthermore, plasma and urinary endocan levels could effectively discriminate ABMR from ATN, BKVN, and TCMR. Finally, patients exhibiting high urinary and plasma endocan levels in acute ABMR group showed significantly worse renal survival. Altogether, plasma and urinary endocan levels may serve as potential markers of microvascular inflammation in kidney transplant recipients.
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Affiliation(s)
- Yu Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Se-Yun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Haena Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Jung-Woo Seo
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Dong-Jin Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Seon Hwa Park
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Yang-Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Jin Sug Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Kyung-Hwan Jeong
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea
| | - Sung-Jig Lim
- Department of Pathology, Kyung Hee University, Seoul, South Korea
| | - Chan-Duck Kim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea
| | - Jae Berm Park
- Department of Surgery, Samsung Medical Center, Seoul, South Korea
| | - Byung Ha Chung
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The St. Mary's Hospital of Catholic University of Korea, Seoul, South Korea
| | - Yeong Hoon Kim
- Division of Nephrology, Department of Internal Medicine, Inje University College of Medicine, Busan, South Korea
| | - Jaeseok Yang
- Transplantation Center, Seoul National University Hospital, Seoul, South Korea
| | - Hyung-In Yang
- East-West Bone & Joint Disease Research Institute, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
| | - Kyoung Soo Kim
- East-West Bone & Joint Disease Research Institute, Kyung Hee University Hospital at Gangdong, Seoul, South Korea. .,Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, South Korea.
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.
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Penack O, Luft T. Editorial: Endothelial Dysfunction During Inflammation and Alloimmunity. Front Immunol 2018; 9:2886. [PMID: 30581438 PMCID: PMC6292946 DOI: 10.3389/fimmu.2018.02886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 11/26/2018] [Indexed: 12/14/2022] Open
Affiliation(s)
- Olaf Penack
- Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Luft
- Medizinische Fakultät Heidelberg, Universität Heidelberg, Heidelberg, Germany
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30
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Kong DH, Kim YK, Kim MR, Jang JH, Lee S. Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. Int J Mol Sci 2018; 19:ijms19041057. [PMID: 29614819 PMCID: PMC5979609 DOI: 10.3390/ijms19041057] [Citation(s) in RCA: 444] [Impact Index Per Article: 63.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 03/30/2018] [Accepted: 03/31/2018] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that triggers the expression of inflammatory molecules, including other cytokines and cell adhesion molecules. TNFα induces the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 was originally identified as a cell adhesion molecule that helps regulate inflammation-associated vascular adhesion and the transendothelial migration of leukocytes, such as macrophages and T cells. Recent evidence suggests that VCAM-1 is closely associated with the progression of various immunological disorders, including rheumatoid arthritis, asthma, transplant rejection, and cancer. This review covers the role and relevance of VCAM-1 in inflammation, and also highlights the emerging potential of VCAM-1 as a novel therapeutic target in immunological disorders and cancer.
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Affiliation(s)
- Deok-Hoon Kong
- Research Center, Scripps Korea Antibody Institute, Chuncheon 200-701, Korea.
| | - Young Kwan Kim
- Research Center, Scripps Korea Antibody Institute, Chuncheon 200-701, Korea.
| | - Mi Ra Kim
- Research Center, Scripps Korea Antibody Institute, Chuncheon 200-701, Korea.
| | - Ji Hye Jang
- Research Center, Scripps Korea Antibody Institute, Chuncheon 200-701, Korea.
| | - Sukmook Lee
- Research Center, Scripps Korea Antibody Institute, Chuncheon 200-701, Korea.
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31
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Abstract
Chronic diseases are defined diseases whose symptoms last for at least six months and tend to worsen over time. In Europe, they cause at least 86% of deaths. In this speculative unifying model I set a new hypothesis for the etiology of the majority of chronic diseases. The main aim is to put order and observe our organism in a systemic way, connecting pathologies we now see as disconnected phenomena, with the conceptual frameworks of complex systems and network medicine. Chronic diseases could be caused by a first unsolved acute infection. In case the pathogen cannot be completely eliminated, it becomes a persistent infectious. After the acute episode, some mild symptoms will occur and probably disappear; the chronic disease will remain latent over time. It will manifest even after years or decades, in the presence of another acute infection, a particular stress, trauma, or another event. The presence of the persistent infectious elicits changes in the immune and systemic regulation, and these processes degenerate over time. They will assume their rules and patterns, being independent from the initial stimulus. The key to understand the dynamics and individuality of chronic diseases is the immune system and its networks. The immune mechanisms that can lead to the persistent response are mainly the switch from the Th1 to the Th2 immunity and the molecular mimicry. The first persistent infectious will also modify the susceptibility to other pathogens, facilitating new infections and new consequent persistent infectious. From the immune point of view, our organism is divided into three compartments: the outer one, which comprehend all the surfaces in contact with the environment, the intermediate one, which comprehend the internal organs and tissues, and the innermost one, comprehending the Central Nervous System and the adluminal compartment of the seminiferous tubule. The immune key-role is played respectively by the mucosa-associated lymphoid tissue, the endothelium, the blood-brain barrier and blood-testis barrier. The chronic diseases follow a progressive scheme, involving the three compartments from the outer to the innermost one. The primer microorganism at the origin of the majority of diseases could be streptococcus, or staphylococcus. Both cause acute in children, with a great variability of responses and symptoms, and both cause molecular mimicry. This model can be tested and proved in more ways, I propose here some of them. It could pave the way to a radical change in our comprehension and therapeutic approaches to chronic diseases.
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32
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Virzì GM, Zhang J, Nalesso F, Ronco C, McCullough PA. The Role of Dendritic and Endothelial Cells in Cardiorenal Syndrome. Cardiorenal Med 2018; 8:92-104. [PMID: 29617002 DOI: 10.1159/000485937] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/29/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUNDS Dendritic cells (DCs) are antigen-presenting cells that play a central role in innate and adaptive immune responses; however, the cross talk between cardiac and renal DCs in cardiorenal syndrome (CRS) has not yet been fully elucidated. In this setting, endothelial cells (ECs) also contribute to immune responses. SUMMARY DC and EC activation and dysfunction have a central role in the pathogenesis of CRS. Regarding immune responses in CRS, it is unknown whether ECs may serve as antigen-presenting cells or act synergistically with DCs to actively participate in innate and adaptive immune responses. This review first focuses on the burden of concomitant heart and renal DCs in the context of CRS; it examines what is known of DCs in animal models, and proposes a central role for DCs in all types of CRS. Second, this review briefly describes the role of ECs in the context of CRS. Key Messages: Understanding the role of DCs and ECs in immune response could lead to the development of novel therapies for the prevention and treatment of CRS.
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Affiliation(s)
- Grazia Maria Virzì
- Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza, Italy.,IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy
| | - Jun Zhang
- Baylor Heart and Vascular Institute, Dallas, Texas, USA
| | - Federico Nalesso
- Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza, Italy.,IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy
| | - Claudio Ronco
- Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza, Italy.,IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy
| | - Peter A McCullough
- Baylor Heart and Vascular Institute, Dallas, Texas, USA.,Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas, USA.,Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Texas, USA.,The Heart Hospital, Plano, Texas, USA
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Daniel V, Süsal C, Scherer S, Tran H, Gombos P, Trojan K, Sadeghi M, Morath C, Opelz G. Endothelial precursor cell cross-match using Tie-2-enriched spleen cells. Clin Transplant 2017; 31. [PMID: 28925558 DOI: 10.1111/ctr.13118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2017] [Indexed: 11/28/2022]
Abstract
BACKGROUND Non-HLA antibodies against human endothelial progenitor cells (EPC) in pre-transplant recipient serum can have a deleterious influence on the graft. EPC enriched from peripheral blood have been commonly used for EPC cross-matching. In the present study, we describe cross-matches using EPC enriched from fresh or frozen-thawed spleen cell preparations, thereby widening the sample source for deceased-donor cross-matching and retrospective studies. METHODS EPC cross-matches were performed retrospectively using spleen cells and the flow cytometric XM-ONE cross-match test kit. RESULTS Healthy controls (n = 28) showed no IgG antibodies against EPC. When sera of 11 random dialysis patients were studied, 2 patients (18%) exhibited IgG EPC antibodies. When pre-transplant sera of 20 kidney graft recipients with good long-term graft outcome (serum creatinine 1.0 ± 0.2 mg/dL measured 2463 ± 324 days post-transplant) were investigated using frozen-thawed and then separated Tie-2-enriched spleen cells of the original transplant donor, 3 patients (15%) had pre-transplant IgG EPC antibodies. When pre-transplant sera of 5 patients with intra-operative graft loss were studied employing the original donor spleen cells, 4 (80%) patients showed IgG EPC antibodies. CONCLUSIONS Cross-matches with spleen cell-derived EPC using the XM-ONE assay are technically possible. Our very preliminary experience suggests clinical relevance.
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Affiliation(s)
- Volker Daniel
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany
| | - Caner Süsal
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany
| | - Sabine Scherer
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany
| | - Hien Tran
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany
| | - Petra Gombos
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany.,Department of Surgery, University-Hospital Heidelberg, Heidelberg, Germany
| | - Karina Trojan
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany
| | - Mahmoud Sadeghi
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany.,Department of Surgery, University-Hospital Heidelberg, Heidelberg, Germany
| | - Christian Morath
- Department of Nephrology, Center for Internal Medicine, University-Hospital Heidelberg, Heidelberg, Germany
| | - Gerhard Opelz
- Transplantation-Immunology, Institute of Immunology, University-Hospital Heidelberg, Heidelberg, Germany
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34
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Diehl R, Ferrara F, Müller C, Dreyer AY, McLeod DD, Fricke S, Boltze J. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol 2016; 14:146-179. [PMID: 27721455 PMCID: PMC5301156 DOI: 10.1038/cmi.2016.39] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 05/30/2016] [Accepted: 05/30/2016] [Indexed: 02/06/2023] Open
Abstract
Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.
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Affiliation(s)
- Rita Diehl
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Fabienne Ferrara
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany.,Institute of Vegetative Physiology, Charite University Medicine and Center for Cardiovascular Research, Berlin 10115, Germany
| | - Claudia Müller
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Antje Y Dreyer
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | | | - Stephan Fricke
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Johannes Boltze
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany.,Fraunhofer Research Institution for Marine Biotechnology and Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck 23562, Germany
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35
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Thamm K, Njau F, Van Slyke P, Dumont DJ, Park JK, Haller H, David S. Pharmacological Tie2 activation in kidney transplantation. World J Transplant 2016; 6:573-582. [PMID: 27683636 PMCID: PMC5036127 DOI: 10.5500/wjt.v6.i3.573] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/24/2016] [Accepted: 07/18/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the therapeutic potential of vasculotide (VT) - a Tie2 activating therapeutic - in kidney transplantation.
METHODS We performed a murine MHC-mismatched renal transplant model (C57Bl/6 male into Balb/c female) with 60 min cold and 30 min warm ischemia time. 500 ng VT was administered i.p. to donor mice 1 h before organ removal. In addition, recipients received 500 ng VT i.p. directly and 3 d after surgery. Survival was monitored and remaining animals were sacrificed 28 d after transplantation. In this model, we analyzed: (1) organ function; (2) Kaplan-Meier survival; (3) organ damage (periodic acid Schiff staining) via semi-quantitative scoring [0-4 (0 = no injury/inflammation to 4 = very severe injury/inflammation)]; (4) expression of renal endothelial adhesion molecules (ICAM-1) via immunofluorescence (IF) staining, immunoblotting and qPCR; (5) infiltration of inflammatory cells (IF Gr-1, F4/80); and (6) fibrosis via staining of α-smooth muscle actin (αSMA), Sirius red staining and immunoblotting of SMAD3 activation.
RESULTS Exogenous activation of Tie2 with VT resulted in diminished expression of peritubular and glomerular endothelial adhesion molecules. Consequently, infiltration of inflammatory cells (analyzed as ICAM-1, Gr-1 and F4/80 positive cells) was reduced in VT-treated mice compared to controls. Additionally, VT was protective against fibrogenesis after kidney transplantation. Trends towards lower serum creatinine (vehicle: 142 ± 17 μmol/L vs VT: 94 ± 23 μmol/L), urea (vehicle: 76 ± 5 mmol/L vs VT: 60 ± 8 mmol/L) and lactate dehydrogenase (vehicle: 1288 ± 383 iU vs VT: 870 ± 275 iU) were observed on day 6 after transplantation. Kaplan-Meier survival analysis showed improved survival rates in the VT-treated mice that did not reach statistical significance (27% vs 54%, P = 0.24, n = 11 per group). Exogenous activation of Tie2 via VT might reduce infiltration of inflammatory cells into renal tissue thereby protecting the transplant from early graft dysfunction potentially affecting long-term function.
CONCLUSION Protection of the endothelial microvasculature via the Tie2 axis in the early transplant setting might hold promise as a therapeutic target.
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36
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Johnson CP, Schiller JJ, Zhu YR, Hariharan S, Roza AM, Cronin DC, Shames BD, Ellis TM. Renal Transplantation With Final Allocation Based on the Virtual Crossmatch. Am J Transplant 2016; 16:1503-15. [PMID: 26602886 DOI: 10.1111/ajt.13606] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 10/28/2015] [Accepted: 10/31/2015] [Indexed: 01/25/2023]
Abstract
Solid phase immunoassays (SPI) are now routinely used to detect HLA antibodies. However, the flow cytometric crossmatch (FCXM) remains the established method for assessing final donor-recipient compatibility. Since 2005 we have followed a protocol whereby the final allocation decision for renal transplantation is based on SPI (not the FCXM). Here we report long-term graft outcomes for 508 consecutive kidney transplants using this protocol. All recipients were negative for donor-specific antibody by SPI. Primary outcomes are graft survival and incidence of acute rejection within 1 year (AR <1 year) for FCXM+ (n = 54) and FCXM- (n = 454) recipients. Median follow-up is 7.1 years. FCXM+ recipients were significantly different from FCXM- recipients for the following risk factors: living donor (24% vs. 39%, p = 0.03), duration of dialysis (31.0 months vs. 13.5 months, p = 0.008), retransplants (17% vs. 7.3%, p = 0.04), % sensitized (63% vs. 19%, p = 0.001), and PRA >80% (20% vs. 4.8%, p = 0.001). Despite these differences, 5-year actual graft survival rates are 87% and 84%, respectively. AR <1 year occurred in 13% FCXM+ and 12% FCXM- recipients. Crossmatch status was not associated with graft outcomes in any univariate or multivariate model. Renal transplantation can be performed successfully, using SPI as the definitive test for donor-recipient compatibility.
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Affiliation(s)
- C P Johnson
- Department of Surgery (Division of Transplantation), Medical College of Wisconsin, Milwaukee, WI
| | - J J Schiller
- Histocompatibility and Immunogenetics, Blood Center of Wisconsin, Milwaukee, WI
| | - Y R Zhu
- Department of Surgery (Division of Transplantation), Medical College of Wisconsin, Milwaukee, WI
| | - S Hariharan
- Department of Medicine (Division of Nephrology), Medical College of Wisconsin, Milwaukee, WI
| | - A M Roza
- Department of Surgery (Division of Transplantation), Medical College of Wisconsin, Milwaukee, WI
| | - D C Cronin
- Department of Surgery (Division of Transplantation), Medical College of Wisconsin, Milwaukee, WI
| | - B D Shames
- Department of Surgery (Division of Transplantation), Medical College of Wisconsin, Milwaukee, WI
| | - T M Ellis
- Department of Surgery (Division of Transplantation), Medical College of Wisconsin, Milwaukee, WI
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37
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Ali JM, Negus MC, Conlon TM, Harper IG, Qureshi MS, Motallebzadeh R, Willis R, Saeb-Parsy K, Bolton EM, Bradley JA, Pettigrew GJ. Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It. Cell Rep 2016; 14:1232-1245. [PMID: 26804905 PMCID: PMC5405053 DOI: 10.1016/j.celrep.2015.12.099] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 11/23/2015] [Accepted: 12/21/2015] [Indexed: 01/03/2023] Open
Abstract
MHC alloantigen is recognized by two pathways: "directly," intact on donor cells, or "indirectly," as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.
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Affiliation(s)
- Jason M Ali
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - Margaret C Negus
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - Thomas M Conlon
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - Ines G Harper
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - M Saeed Qureshi
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - Reza Motallebzadeh
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - Richard Willis
- NIH Tetramer Facility, Emory/Yerkes, 954 Gatewood Road, Atlanta, GA 30329, USA
| | - Kourosh Saeb-Parsy
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - Eleanor M Bolton
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - J Andrew Bradley
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK
| | - Gavin J Pettigrew
- University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
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38
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Daniel V, Sadeghi M, Suesal C, Scherer S, Tran H, Gombos P, Trojan K, Morath C, Opelz G. Clinical relevance of preformed IgG and IgM antibodies against donor endothelial progenitor cells in recipients of living donor kidney grafts. Clin Transplant 2015; 30:124-30. [DOI: 10.1111/ctr.12665] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2015] [Indexed: 01/30/2023]
Affiliation(s)
- Volker Daniel
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
| | - Mahmoud Sadeghi
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
| | - Caner Suesal
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
| | - Sabine Scherer
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
| | - Hien Tran
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
| | - Petra Gombos
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
| | - Karina Trojan
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
| | - Christian Morath
- Department of Nephrology; University Hospital; Heidelberg Germany
| | - Gerhard Opelz
- Department of Transplantation-Immunology; University Hospital; Heidelberg Germany
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39
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Abstract
PURPOSE OF REVIEW This review focuses on the known mechanisms of alloimmunity that occur after transplantation and what is being done in order to improve graft and patient survival, particularly in the long term. RECENT FINDINGS The presence of mismatched antigens and epitopes might relate directly to the development of de-novo donor-specific antibodies (DSA), and thus, rejection. In an abdominal wall transplant, the skin graft could be the first to show signs of rejection. The epithelial or endothelial cells are the main targets in acute and chronic rejection, respectively. Possible therapeutical targets are gut homing T cells and cells of the innate immune system. Chimerism development might mostly occur in isolated lymph nodes, but also in the epithelium, particularly after transplantation of bone marrow mesenchymal stromal cells. SUMMARY Ischemia-reperfusion, surgical injury, and bacterial translocation trigger the innate immune system, starting acute rejection. Interaction between donor and recipient immune cells generate injury and tolerance, which occur mostly in secondary lymphoid organs, lamina propria, and epithelium. Chronic rejection mostly affects the endothelial cells, generating graft dysfunction. DSA increase the risk of graft rejection both acutely and chronically, and the liver protects against their effects. Induction therapies deplete lymphocytes prior to implantation, and maintenance therapies inhibit T-cell expansion. Rejection rates are the lowest when depleting drugs and a combination of interleukin 2 receptor blockade, inhibition of T-cell expansion, and steroids are used as maintenance therapy. Chimerism and tolerogenic regiments that induce Tregs and prevent the development of DSA are important treatment goals for the future.
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40
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McDonald-Hyman C, Turka LA, Blazar BR. Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation. Sci Transl Med 2015; 7:280rv2. [PMID: 25810312 PMCID: PMC4425354 DOI: 10.1126/scitranslmed.aaa6853] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome.
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Affiliation(s)
- Cameron McDonald-Hyman
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
| | - Laurence A Turka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.Immune Tolerance Network, Massachusetts General Hospital, Boston, MA 02114, USA. Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.Immune Tolerance Network, Massachusetts General Hospital, Boston, MA 02114, USA.
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
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