|
1
|
Lee SK, Kwon JH, Jang JW, Bae SH, Yoon SK, Jung ES, Choi JY. The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome. Transplantation 2025; 109:784-793. [PMID: 39375899 DOI: 10.1097/tp.0000000000005220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4 + regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.
Collapse
Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Sun Jung
- Department of Pathology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| |
Collapse
|
|
2
|
Lee YJ, Cho ML. Targeting T helper 17 cells: emerging strategies for overcoming transplant rejection. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:309-325. [PMID: 39743231 PMCID: PMC11732763 DOI: 10.4285/ctr.24.0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 01/04/2025]
Abstract
Solid organ transplantation has significantly improved the survival rate of patients with terminal organ failure. However, its success is often compromised by allograft rejection, a process in which T helper 17 (Th17) cells play a crucial role. These cells facilitate rejection by enhancing neutrophil infiltration into the graft and by activating endothelial cells and fibroblasts. Additionally, Th17 cells can trigger the activation of other T cell types, including Th1, Th2, and CD8+ T cells, further contributing to rejection. An imbalance between Th17 and regulatory T cells (Tregs) is known to promote rejection. To counteract this, immunosuppressive drugs have been developed to inhibit T cell activity and foster transplant tolerance. Another approach involves the adoptive transfer of regulatory cells, such as Tregs and myeloid-derived suppressor cells, to dampen T cell functions. This review primarily focuses on the roles of Th17 cells in rejection and their interactions with other T cell subsets. We also explore various strategies aimed at suppressing T cells to induce tolerance.
Collapse
Affiliation(s)
- Young Joon Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Lab of Translational ImmunoMedicine (LaTIM), College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mi-La Cho
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Lab of Translational ImmunoMedicine (LaTIM), College of Medicine, The Catholic University of Korea, Seoul, Korea
| |
Collapse
|
|
3
|
Jin X, Pirenne J, Vos R, Hooft C, Kaes J, Van Slambrouck J, Kortleven P, Vandervelde C, Beeckmans H, Kerckhof P, Carlon MS, Van Raemdonck D, Looney MR, Vanaudenaerde BM, Ceulemans LJ. Donor-Specific Blood Transfusion in Lung Transplantation. Transpl Int 2024; 37:12822. [PMID: 39553536 PMCID: PMC11565953 DOI: 10.3389/ti.2024.12822] [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: 02/08/2024] [Accepted: 10/15/2024] [Indexed: 11/19/2024]
Abstract
Lung transplantation is still hindered by a high rate of chronic rejection necessitating profound immunosuppression with its associated complications. Donor-specific blood transfusion is a pre-transplant strategy aimed at improving graft acceptance. In contrast with standard stored blood or donor-specific regulatory T cells transfusions, this approach utilizes fresh whole blood from the donor prior to allograft transplantation, encompassing all cell types and plasma. The precise mechanisms underlying donor-specific blood transfusion-induced tolerance remain incompletely understood. Associations with regulatory/helper T cells, modulation of mononuclear phagocytic cells or microchimerism have been suggested. While numerous (pre-)clinical studies have explored its application in solid organ transplants like liver, kidney, and intestine, limited attention has been given to the setting of lung transplantation. This comprehensive review summarizes existing knowledge on the mechanisms and outcomes of donor-specific blood transfusion in solid organ transplants both in preclinical and clinical settings. We also address the potential benefits and risks associated with donor-specific blood transfusion in the field of lung transplantation, offering insights into future research directions.
Collapse
Affiliation(s)
- Xin Jin
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Jacques Pirenne
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Robin Vos
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Charlotte Hooft
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Janne Kaes
- Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven), KU Leuven, Leuven, Belgium
| | - Jan Van Slambrouck
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Phéline Kortleven
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Christelle Vandervelde
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Hanne Beeckmans
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Pieterjan Kerckhof
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Marianne S. Carlon
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Dirk Van Raemdonck
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Mark R. Looney
- Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, United States
- Department of Laboratory Medicine, University of California, San Francisco (UCSF), San Francisco, CA, United States
| | - Bart M. Vanaudenaerde
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Laurens J. Ceulemans
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
4
|
Cui Y, Hackett RG, Ascue J, Muralidaran V, Patil D, Kang J, Kaufman SS, Khan K, Kroemer A. Innate and Adaptive Immune Responses in Intestinal Transplant Rejection: Through the Lens of Inflammatory Bowel and Intestinal Graft-Versus-Host Diseases. Gastroenterol Clin North Am 2024; 53:359-382. [PMID: 39068000 DOI: 10.1016/j.gtc.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Intestinal transplantation is a life-saving procedure utilized for patients failing total parenteral nutrition. However, intestinal transplantattion remains plagued with low survival rates and high risk of allograft rejection. The authors explore roles of innate (macrophages, natural killer cells, innate lymphoid cells) and adaptive immune cells (Th1, Th2, Th17, Tregs) in inflammatory responses, particularly inflammatory bowel disease and graft versus host disease, and correlate these findings to intestinal allograft rejection, highlighting which effectors exacerbate or suppress intestinal rejection. Better understanding of this immunology can open further investigation into potential biomolecular targets to develop improved therapeutic treatment options and immunomonitoring techniques to combat allograft rejection and enhance patient lives.
Collapse
Affiliation(s)
- Yuki Cui
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Ryan G Hackett
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jhalen Ascue
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Vinona Muralidaran
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Digvijay Patil
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA
| | - Stuart S Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA.
| |
Collapse
|
|
5
|
Short S, Lewik G, Issa F. An Immune Atlas of T Cells in Transplant Rejection: Pathways and Therapeutic Opportunities. Transplantation 2023; 107:2341-2352. [PMID: 37026708 PMCID: PMC10593150 DOI: 10.1097/tp.0000000000004572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 01/10/2023] [Accepted: 01/28/2023] [Indexed: 04/08/2023]
Abstract
Short-term outcomes in allotransplantation are excellent due to technical and pharmacological advances; however, improvement in long-term outcomes has been limited. Recurrent episodes of acute cellular rejection, a primarily T cell-mediated response to transplanted tissue, have been implicated in the development of chronic allograft dysfunction and loss. Although it is well established that acute cellular rejection is primarily a CD4 + and CD8 + T cell mediated response, significant heterogeneity exists within these cell compartments. During immune responses, naïve CD4 + T cells are activated and subsequently differentiate into specific T helper subsets under the influence of the local cytokine milieu. These subsets have distinct phenotypic and functional characteristics, with reported differences in their contribution to rejection responses specifically. Of particular relevance are the regulatory subsets and their potential to promote tolerance of allografts. Unraveling the specific contributions of these cell subsets in the context of transplantation is complex, but may reveal new avenues of therapeutic intervention for the prevention of rejection.
Collapse
Affiliation(s)
- Sarah Short
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, Oxfordshire, United Kingdom
| | - Guido Lewik
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, Oxfordshire, United Kingdom
| | - Fadi Issa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, Oxfordshire, United Kingdom
| |
Collapse
|
|
6
|
Shah AM, Aral AM, Zamora R, Gharpure N, El-Dehaibi F, Zor F, Kulahci Y, Karagoz H, Barclay DA, Yin J, Breidenbach W, Tuder D, Gorantla VS, Vodovotz Y. Peripheral nerve repair is associated with augmented cross-tissue inflammation following vascularized composite allotransplantation. Front Immunol 2023; 14:1151824. [PMID: 37251389 PMCID: PMC10213935 DOI: 10.3389/fimmu.2023.1151824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/20/2023] [Indexed: 05/31/2023] Open
Abstract
Introduction Vascularized composite allotransplantation (VCA), with nerve repair/coaptation (NR) and tacrolimus (TAC) immunosuppressive therapy, is used to repair devastating traumatic injuries but is often complicated by inflammation spanning multiple tissues. We identified the parallel upregulation of transcriptional pathways involving chemokine signaling, T-cell receptor signaling, Th17, Th1, and Th2 pathways in skin and nerve tissue in complete VCA rejection compared to baseline in 7 human hand transplants and defined increasing complexity of protein-level dynamic networks involving chemokine, Th1, and Th17 pathways as a function of rejection severity in 5 of these patients. We next hypothesized that neural mechanisms may regulate the complex spatiotemporal evolution of rejection-associated inflammation post-VCA. Methods For mechanistic and ethical reasons, protein-level inflammatory mediators in tissues from Lewis rats (8 per group) receiving either syngeneic (Lewis) or allogeneic (Brown-Norway) orthotopic hind limb transplants in combination with TAC, with and without sciatic NR, were compared to human hand transplant samples using computational methods. Results In cross-correlation analyses of these mediators, VCA tissues from human hand transplants (which included NR) were most similar to those from rats undergoing VCA + NR. Based on dynamic hypergraph analyses, NR following either syngeneic or allogeneic transplantation in rats was associated with greater trans-compartmental localization of early inflammatory mediators vs. no-NR, and impaired downregulation of mediators including IL-17A at later times. Discussion Thus, NR, while considered necessary for restoring graft function, may also result in dysregulated and mis-compartmentalized inflammation post-VCA and therefore necessitate mitigation strategies. Our novel computational pipeline may also yield translational, spatiotemporal insights in other contexts.
Collapse
Affiliation(s)
- Ashti M. Shah
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ali Mubin Aral
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ruben Zamora
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Nitin Gharpure
- Department of Surgery, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
| | - Fayten El-Dehaibi
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Fatih Zor
- Department of Surgery, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
| | - Yalcin Kulahci
- Department of Surgery, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
| | - Huseyin Karagoz
- Department of Surgery, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
| | - Derek A. Barclay
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jinling Yin
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | | | - Dmitry Tuder
- Plastic Surgery, San Antonio Military Medical Center, Fort Sam Houston, San Antonio, TX, United States
| | - Vijay S. Gorantla
- Department of Surgery, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
| | - Yoram Vodovotz
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
- Center for Inflammation and Regeneration Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| |
Collapse
|
|
7
|
Seiler LK, Jonczyk R, Lindner P, Phung NL, Falk CS, Kaufeld J, Gwinner W, Scheffner I, Immenschuh S, Blume C. A new lateral flow assay to detect sIL-2R during T-cell mediated rejection after kidney transplantation. Analyst 2021; 146:5369-5379. [PMID: 34337623 DOI: 10.1039/d1an01001h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Kidney is the most frequently transplanted among all solid organs worldwide. Kidney transplant recipients (KTRs) undergo regular follow-up examinations for the early detection of acute rejections. The gold standard for proving a T-cell mediated rejection (TCMR) is a biopsy of the renal graft often occurring as indication biopsy, in parallel to an increased serum creatinine that may indicate deterioration of renal transplant function. The goal of the current work was to establish a lateral flow assay (LFA) for diagnosing acute TCMR to avoid harmful, invasive biopsies. Soluble interleukin-2 (IL-2) receptor (sIl-2R) is a potential biomarker representing the α-subunit of the IL-2 receptor produced by activated T-cells, e.g., after allogen contact. To explore the diagnostic potential of sIL-2R as a biomarker for TCMR and borderline TCMR, plasma and urine samples were collected from three independent KTR cohorts with various distinct histopathological diagnostic findings according to BANFF (containing 112 rsp. 71 rsp. 61 KTRs). Samples were analyzed by a Luminex-based multiplex technique and cut off-ranges were determined. An LFA was established with two specific sIL-2R-antibodies immobilized on a nitrocellulose membrane. A significant association between TCMR, borderline TCMR and sIL-2R in plasma and between TCMR and sIL-2R in urine of KTRs was confirmed using the Mann-Whitney U test. The LFA was tested with sIL-2R-spiked buffer samples establishing a detection limit of 25 pM. The performance of the new LFA was confirmed by analyzing urine samples of the 2nd and 3rd patient cohort with 35 KTRs with biopsy proven TCMRs, 3 KTRs diagnosed with borderline TCMR, 1 mixed AMR/TCMR rsp. AMR/borderline TCMR and 13 control patients with a rejection-free kidney graft proven by protocol biopsies. The new point-of-care assay showed a specificity of 84.6% and sensitivity of 87.5%, and a superior estimated glomerular filtration rate (eGFR) at the time point of biopsy (specificity 30.8%, sensitivity 85%).
Collapse
Affiliation(s)
- Lisa K Seiler
- Institute of Technical Chemistry, Leibniz University Hannover, Callinstrasse 5, 30167 Hannover, Germany.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Oweira H, Khajeh E, Mohammadi S, Ghamarnejad O, Daniel V, Schnitzler P, Golriz M, Mieth M, Morath C, Zeier M, Mehrabi A, Sadeghi M. Pre-transplant CD200 and CD200R1 concentrations are associated with post-transplant events in kidney transplant recipients. Medicine (Baltimore) 2019; 98:e17006. [PMID: 31517819 PMCID: PMC6750316 DOI: 10.1097/md.0000000000017006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
CD200 is an immunoglobulin superfamily membrane protein that binds to a myeloid cell-specific receptor and induces inhibitory signaling. The aim of this study was to investigate the role of CD200 and its receptor (CD200R1) on kidney transplant (KTx) outcome. In a collective of 125 kidney recipients (University hospital, Heidelberg, Germany), CD200 and CD200R1 concentrations were evaluated immediately before transplantation. Recipient baseline and clinical characteristics and KTx outcome, including acute rejection (AR), acute tubular necrosis, delayed graft function, cytomegalovirus (CMV) and human polyomaviridae (BK) virus infections, and graft loss were evaluated during the first post-transplant year. The association of CD200 and CD200R1 concentrations and CD200R1/CD200 ratios with the outcome of KTx was investigated for the first time in a clinical setting in a prospective cohort. There was a positive association between pre-transplant CD200R1 concentrations and CMV (re)activation (P = .041). Also, increased CD200R1 concentration was associated with a longer duration of CMV infection (P = .049). Both the frequency of AR and levels of creatinine (3 and 6 months after KTx) were significantly higher in patients with an increased CD200R1/CD200 ratio (median: 126 vs 78, P = .008). Increased pre-transplant CD200R1/CD200 ratios predict immunocompetence and risk of AR, whereas high CD200R1 concentrations predict immunosuppression and high risk of severe CMV (re)activation after KTx.
Collapse
Affiliation(s)
- Hani Oweira
- Department of General, Visceral and Transplant Surgery
| | - Elias Khajeh
- Department of General, Visceral and Transplant Surgery
| | | | | | | | | | | | - Markus Mieth
- Department of General, Visceral and Transplant Surgery
| | - Christian Morath
- Division of Nephrology, Ruprecht Karls, University of Heidelberg, Heidelberg, Germany
| | - Martin Zeier
- Division of Nephrology, Ruprecht Karls, University of Heidelberg, Heidelberg, Germany
| | | | | |
Collapse
|
|
9
|
Farkas AM, Baranyi U, Böhmig GA, Unger L, Hopf S, Wahrmann M, Regele H, Mahr B, Schwarz C, Hock K, Pilat N, Kristo I, Mraz J, Lupinek C, Thalhamer J, Bond G, Kuessel L, Wlodek E, Martin J, Clatworthy M, Pettigrew G, Valenta R, Wekerle T. Allograft rejection is associated with development of functional IgE specific for donor MHC antigens. J Allergy Clin Immunol 2019; 143:335-345.e12. [PMID: 30009843 DOI: 10.1016/j.jaci.2018.06.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 06/07/2018] [Accepted: 06/14/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Donor-specific antibodies of the IgG isotype are measured routinely for diagnostic purposes in renal transplant recipients and are associated with antibody-mediated rejection and long-term graft loss. OBJECTIVE This study aimed to investigate whether MHC-specific antibodies of the IgE isotype are induced during allograft rejection. METHODS Anti-MHC/HLA IgE levels were measured in sera of mice grafted with skin or heart transplants from various donor strains and in sera of kidney transplant patients with high levels of HLA IgG. Mediator release was triggered in vitro by stimulating basophils that were coated with murine or human IgE-positive serum, respectively, with specific recombinant MHC/HLA antigens. Kidney tissue samples obtained from organ donors were analyzed by using flow cytometry for cells expressing the high-affinity receptor for IgE (FcεRI). RESULTS Donor MHC class I- and MHC class II-specific IgE was found on acute rejection of skin and heart grafts in several murine strain combinations, as well as during chronic antibody-mediated heart graft rejection. Anti-HLA IgE, including donor HLA class I and II specificities, was identified in a group of sensitized transplant recipients. Murine and human anti-MHC/HLA IgE triggered mediator release in coated basophils on stimulation with specific MHC/HLA antigens. HLA-specific IgE was not linked to atopy, and allergen-specific IgE present in allergic patients did not cross-react with HLA antigens. FcεRI+ cells were found in the human renal cortex and medulla and provide targets for HLA-specific IgE. CONCLUSION These results demonstrate that MHC/HLA-specific IgE develops during an alloresponse and is functional in mediating effector mechanisms.
Collapse
Affiliation(s)
- Andreas M Farkas
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Ulrike Baranyi
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria; Cardiac Surgery Laboratory, Medical University of Vienna, Vienna, Austria
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Unger
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Hopf
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Markus Wahrmann
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Heinz Regele
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Benedikt Mahr
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Christoph Schwarz
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Karin Hock
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Nina Pilat
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Ivan Kristo
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Jasmin Mraz
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Christian Lupinek
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Physiology and Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Josef Thalhamer
- Department of Molecular Biology, University of Salzburg, Salzburg, Austria
| | - Gregor Bond
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lorenz Kuessel
- Department for Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Elizabeth Wlodek
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Jack Martin
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Menna Clatworthy
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Gavin Pettigrew
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Rudolf Valenta
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Physiology and Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Thomas Wekerle
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
10
|
Erol A, Arpali E, Murat Yelken B, Kocak B, Calıskan YK, Nane I, Turkmen A, Savran Oguz F. Evaluation of T H17 and T H1 Immune Response Profile in Patients After Renal Transplant. Transplant Proc 2017; 49:467-471. [PMID: 28340814 DOI: 10.1016/j.transproceed.2017.01.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Renal transplantation (RT) is the best treatment option for patients with end-stage renal disease (ESRD) because it improves both quality of life and survival. However, allograft rejection remains the most important barrier to successful transplantation. Underlying immunologic mechanisms should be understood to develop appropriate treatment strategies. METHODS In this prospective study, we followed renal transplant recipients for 6 months. The study population comprised 50 recipients of renal transplants, and these were divided into 2 groups: 44 patients with stable graft function (SGF) and 6 patients with rejection (RX). Peripheral blood samples were drawn from patients on the pre-RT day, at post-RT day 7, month 1, and month 6, and on the day of rejection for analysis of the percentages of cytokines interleukin (IL) 17 and interferon (IFN) γ with the use of flow cytometry and enzyme-linked immunosorbent assay. RESULTS The percentages of intracellular IFN-γ were not significant in the group with RX compared with SGF. Levels of intracellular IL-17 obtained at the 6th month after RT were significantly higher in the RX group than in the SGF group. Plasma levels of pre-RT IL-17 were also higher in the RX group; therefore, it may be a predictive biomarker of acute rejection of renal transplants. CONCLUSIONS The present study provides information about pre-RT and post-RT cytokine profiles of Turkish patients with ESRD. We consider cytokine analysis to be a valuable biomarker panel in the prevention of rejection and in assisting with new treatment strategies for patients undergoing renal transplant.
Collapse
Affiliation(s)
- A Erol
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
| | - E Arpali
- Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
| | - B Murat Yelken
- Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
| | - B Kocak
- Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
| | - Y K Calıskan
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - I Nane
- Department of Urology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - A Turkmen
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - F Savran Oguz
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| |
Collapse
|
|
11
|
Salvadori M, Tsalouchos A. Pre-transplant biomarkers and prediction of post-transplant outcomes in kidney transplantation. J Renal Inj Prev 2017; 6:222-230. [DOI: 10.15171/jrip.2017.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
|
|
12
|
Iwaszkiewicz-Grzes D, Cholewinski G, Kot-Wasik A, Trzonkowski P, Dzierzbicka K. Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cells. Int Immunopharmacol 2017; 44:137-142. [DOI: 10.1016/j.intimp.2017.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/09/2016] [Accepted: 01/08/2017] [Indexed: 10/20/2022]
|
|
13
|
da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
Collapse
|
|
14
|
Pretransplant Immune- and Apoptosis-Related Gene Expression Is Associated with Kidney Allograft Function. Mediators Inflamm 2016; 2016:8970291. [PMID: 27382192 PMCID: PMC4921144 DOI: 10.1155/2016/8970291] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 04/22/2016] [Accepted: 05/09/2016] [Indexed: 12/23/2022] Open
Abstract
Renal transplant candidates present immune dysregulation, caused by chronic uremia. The aim of the study was to investigate whether pretransplant peripheral blood gene expression of immune factors affects clinical outcome of renal allograft recipients. Methods. In a prospective study, we analyzed pretransplant peripheral blood gene expression in87 renal transplant candidates with real-time PCR on custom-designed low density arrays (TaqMan). Results. Immediate posttransplant graft function (14-day GFR) was influenced negatively by TGFB1 (P = 0.039) and positively by IL-2 gene expression (P = 0.040). Pretransplant blood mRNA expression of apoptosis-related genes (CASP3, FAS, and IL-18) and Th1-derived cytokine gene IFNG correlated positively with short- (6-month GFR CASP3: P = 0.027, FAS: P = 0.021, and IFNG: P = 0.029) and long-term graft function (24-month GFR CASP3: P = 0.003, FAS: P = 0.033, IL-18: P = 0.044, and IFNG: P = 0.04). Conclusion. Lowered pretransplant Th1-derived cytokine and apoptosis-related gene expressions were a hallmark of subsequent worse kidney function but not of acute rejection rate. The pretransplant IFNG and CASP3 and FAS and IL-18 genes' expression in the recipients' peripheral blood is the possible candidate for novel biomarker of short- and long-term allograft function.
Collapse
|
|
15
|
Chadet S, Ivanes F, Benoist L, Salmon-Gandonnière C, Guibon R, Velge-Roussel F, Babuty D, Baron C, Roger S, Angoulvant D. Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2015; 195:651-60. [PMID: 26078273 DOI: 10.4049/jimmunol.1500197] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 05/17/2015] [Indexed: 12/20/2022]
Abstract
High concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation.
Collapse
Affiliation(s)
- Stéphanie Chadet
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France
| | - Fabrice Ivanes
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Cardiologie, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France
| | - Lauriane Benoist
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France
| | - Charlotte Salmon-Gandonnière
- Service de Néphrologie et d'Immunologie Clinique, Centre Hospitalier Régional Universitaire de Tours, 37000 Tours, France
| | - Roseline Guibon
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France
| | - Florence Velge-Roussel
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Fédération Hospitalo-Universitaire SUPPORT Tours, Poitiers, Limoges, Université François-Rabelais de Tours, 37032 Tours, France; and
| | - Dominique Babuty
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Cardiologie, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France
| | - Christophe Baron
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Néphrologie et d'Immunologie Clinique, Centre Hospitalier Régional Universitaire de Tours, 37000 Tours, France; Fédération Hospitalo-Universitaire SUPPORT Tours, Poitiers, Limoges, Université François-Rabelais de Tours, 37032 Tours, France; and
| | - Sébastien Roger
- UMR INSERM 1069, "Nutrition, Croissance et Cancer," Université François-Rabelais de Tours, 37032 Tours, France
| | - Denis Angoulvant
- EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Cardiologie, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France; Fédération Hospitalo-Universitaire SUPPORT Tours, Poitiers, Limoges, Université François-Rabelais de Tours, 37032 Tours, France; and
| |
Collapse
|
|
16
|
Kraaij MD, Vereyken EJF, Leenen PJM, van den Bosch TPP, Rezaee F, Betjes MGH, Baan CC, Rowshani AT. Human monocytes produce interferon-gamma upon stimulation with LPS. Cytokine 2014; 67:7-12. [PMID: 24680476 DOI: 10.1016/j.cyto.2014.02.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 12/09/2013] [Accepted: 02/02/2014] [Indexed: 10/25/2022]
Abstract
Representing a crucial T-helper 1 cytokine, IFN-γ acts as an important bridge between innate and adaptive immunity and is involved in many acute and chronic pathologic states, such as autoimmune diseases and solid organ transplant rejection. At present, debate still prevails about the ability of human monocytes to produce IFN-γ. We aimed to investigate whether human monocytes possess the capacity to produce IFN-γ at mRNA and protein level. Using real time PCR, flow cytometric analysis and ELISA, we investigated the capacity of freshly isolated CD14+ monocytes of healthy individuals and kidney transplant recipients to produce IFN-γ after stimulation with IFN-γ and LPS or LPS alone. We observed increased IFN-γ mRNA levels in CD14+ monocytes after stimulation as compared to the unstimulated controls in both populations. In addition, stimulation with IFN-γ and LPS or LPS alone led to a significant increase in the percentage of CD14+ monocytes producing TNF-α and IFN-γ at protein level (p<0.05). A trend towards increased secreted IFN-γ production in supernatants was also observed after LPS stimulation using ELISA. We conclude that human monocytes from healthy individuals and kidney transplant recipients possess the capacity to produce IFN-γ.
Collapse
Affiliation(s)
- Marina D Kraaij
- Department of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Elly J F Vereyken
- Department of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Pieter J M Leenen
- Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Thierry P P van den Bosch
- Department of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Farhad Rezaee
- Department of Cell Biology, University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel G H Betjes
- Department of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Carla C Baan
- Department of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ajda T Rowshani
- Department of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.
| |
Collapse
|
|
17
|
Study of the cytokine polymorphisms in correlation to rejection and graft survival in renal allograft donors and recipients from a homogenous Saudi population. Transpl Immunol 2014; 30:34-9. [DOI: 10.1016/j.trim.2013.11.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 11/28/2013] [Accepted: 11/28/2013] [Indexed: 11/20/2022]
|
|
18
|
A shift towards pro-inflammatory CD16+ monocyte subsets with preserved cytokine production potential after kidney transplantation. PLoS One 2013; 8:e70152. [PMID: 23922945 PMCID: PMC3726371 DOI: 10.1371/journal.pone.0070152] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 06/15/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The presence of monocyte-macrophage lineage cells in rejecting kidney transplants is associated with worse graft outcome. At present, it is still unclear how the monocyte-macrophage related responses develop after transplantation. Here, we studied the dynamics, phenotypic and functional characteristics of circulating monocytes during the first 6 months after transplantation and aimed to establish the differences between kidney transplant recipients and healthy individuals. METHODS Phenotype, activation status and cytokine production capacity of classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++), monocytes were determined by flow cytometry in a cohort of 33 healthy individuals, 30 renal transplant recipients at transplantation, 19 recipients at 3 months and 16 recipients at 6 months after transplantation using a cross-sectional approach. RESULTS The percentage of both CD16+ monocyte subsets was significantly increased in transplant recipients compared to healthy individuals, indicative of triggered innate immunity (p≤0.039). Enhanced production capacity of tumor necrosis factor-α, interferon-γ and interleukin-1β was observed by monocytes at transplantation compared to healthy individuals. Remarkably, three months post-transplant, in presence of potent immunosuppressive drugs and despite improved kidney function, interferon-γ, tumor necrosis factor-α and interleukin-10 production capacity still remained significantly increased. CONCLUSION Our data demonstrate a skewed balance towards pro-inflammatory CD16+ monocytes that is present at the time of transplantation and retained for at least 6 months after transplantation. This shift could be one of the important drivers of early post-transplant cellular immunity.
Collapse
|
|
19
|
Sadeghi M, Daniel V, Wang H, Zeier M, Schemmer P, Mehrabi A, Lahdou I, Morath C, Opelz G. Plasmapheresis adjusts inflammatory responses in potential kidney transplant recipients. Transplantation 2013; 95:1021-1029. [PMID: 23591727 DOI: 10.1097/tp.0b013e318286191b] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Plasmapheresis (PP) has been used in the treatment of various immunologic disorders, and its efficacy has mainly been attributed to the removal of humoral factors and autoantibodies. Besides these effects, PP may induce modifications of the cellular immunologic status, contributing to the restoration of impaired immunologic function. The effect of PP on lymphocyte subpopulations, plasma neopterin, and cytokines in renal transplant recipients was investigated in this study. METHODS We compared pre-PP and post-PP lymphocyte subpopulations and plasma neopterin in 37, and cytokine plasma levels in 30, potential renal transplant recipients. Plasma neopterin and cytokines were measured by enzyme-linked immunosorbent assay kits, lymphocyte subsets were determined using four-color fluorescence flow cytometry. RESULTS Lymphocyte subpopulation counts and ratios including CD45:μL (P=0.005), CD3:μL (P=0.02), CD4DR:μL (P=0.002), CD8:μL (P=0.01), and CD8DR:μL (P=0.005) T cells; CD4DR:CD4 (P=0.009) and CD8DR:CD8 (P=0.0004) ratios; DR cells:μL (P=0.003); CD19 B lymphocytes:μL (P=0.001); and plasma levels of neopterin (P<;0.0001), soluble interleukin-1 receptor antagonist (P<;0.0001), IL-8 (P=0.0001), and tumor necrosis factor-α (P=0.008) were significantly decreased after PP as compared with before PP. The results indicate a decrease of activated DR, CD4, and CD8 T lymphocytes and B lymphocytes, and a decrease of monocyte and macrophage activation as a result of PP. CONCLUSION Based on these results, we conclude that PP not only removes antibodies from the plasma but, in addition, modulates T-lymphocyte activation and the inflammatory response by decreasing plasma proinflammatory cytokines.
Collapse
Affiliation(s)
- Mahmoud Sadeghi
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Carey BS, Jain R, Adams CL, Wong KY, Shaw S, Tse WY, Kaminski ER. Serum neopterin as an indicator of increased risk of renal allograft rejection. Transpl Immunol 2013; 28:81-5. [PMID: 23481351 DOI: 10.1016/j.trim.2013.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 02/11/2013] [Accepted: 02/12/2013] [Indexed: 12/23/2022]
Abstract
Acute rejection remains associated with poor graft outcome. An early predictor of acute renal transplant rejection is the long sought after goal for transplant immunologists. In this study we measured levels of serum neopterin at day 5 post-transplant in a cohort of 216 consecutive renal allograft recipients, and compared this with serum creatinine and acute rejection episodes during the first year post transplant. We compared serum neopterin in recipients from living donors (LD), donors after brain death (DBD) and donors after cardiac death (DCD). In all cases higher neopterin levels were correlated with acute rejection in the first year post transplant, but this was only significant in recipients of DCD kidneys who suffered acute cellular or vascular rejection (p=0.04, odds ratio 1.08, 95% CI 1.003-1.012). The neopterin/creatinine ratio, which takes into account the effect of kidney function on circulating neopterin levels, was significantly higher for all recipients who suffered biopsy proven cellular or vascular rejection in the first year post transplant, compared to all other patients (p=0.001, for an increase of 0.1, odds ratio=1.64, 95% CI 1.21-2.20). The ability to use non-invasive biomarkers in the transplant recipient has the potential to increase transplant survival for these patients.
Collapse
Affiliation(s)
- B Sean Carey
- Department of Immunology, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Bagul A. Ischaemic/reperfusion injury: Role of infliximab. World J Transplant 2012; 2:35-40. [PMID: 24175194 PMCID: PMC3782232 DOI: 10.5500/wjt.v2.i3.35] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Revised: 04/12/2012] [Accepted: 06/01/2012] [Indexed: 02/05/2023] Open
Abstract
Ischaemia/reperfusion (I/R) injury is an underlying complex interrelated patho-physiological process which effects the outcome of many clinical situations, in particular transplantation. Tumor necrosis factor (TNF)-α is a pleiotropic inflammatory cytokine; a trimeric protein encoded within the major histocompatibility complex which plays a pivotal role in this disease process. This review is based at looking into an update, particularly the new insights in the mechanisms of action of TNF antagonist such as infliximab. Infliximab may thus play a dual role in the field of transplantation where it might not only down regulate the I/R injury, it may also have a beneficial role in the reduction of acute rejection.
Collapse
Affiliation(s)
- Atul Bagul
- Atul Bagul, Transplant Division, III Department, University of Leicester, Leicester-UK and University Hospitals of Leicester, Leicester LE5 4PW, United Kingdom
| |
Collapse
|
|
22
|
Hu X, Bai Y, Li S, Zeng K, Xu L, Liu Z, Song X, Lu X, Wang L, Ying B. Donor or recipient TNF-A −308G/A polymorphism and acute rejection of renal allograft: A meta-analysis. Transpl Immunol 2011; 25:61-71. [DOI: 10.1016/j.trim.2011.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 04/28/2011] [Accepted: 04/28/2011] [Indexed: 12/01/2022]
|
|
23
|
Lahdou I, Sadeghi M, Daniel V, Schenk M, Renner F, Weimer R, Löb S, Schmidt J, Mehrabi A, Schnitzler P, Königsrainer A, Döhler B, Opelz G, Terness P. Increased pretransplantation plasma kynurenine levels do not protect from but predict acute kidney allograft rejection. Hum Immunol 2010; 71:1067-72. [DOI: 10.1016/j.humimm.2010.08.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Revised: 07/29/2010] [Accepted: 08/16/2010] [Indexed: 10/19/2022]
|
|
24
|
Donor-specific antibody levels and three generations of crossmatches to predict antibody-mediated rejection in kidney transplantation. Transplantation 2010; 90:160-7. [PMID: 20658760 DOI: 10.1097/tp.0b013e3181e36e08] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND This study evaluated the prognostic impact of pretransplant donor-specific anti-human leukocyte antigen antibodies (DSA) detected by single-antigen beads and compared the three generations of crossmatch (XM) tests in kidney transplantation. METHODS Thirty-seven T-cell complement-dependent cytotoxicity crossmatch (CXM) negative living donor kidney recipients with a retrospectively positive antihuman leukocyte antigen antibody screening assay were included. A single-antigen bead test, a flow cytometry XM, and a Luminex XM (LXM) were retrospectively performed, and the results were correlated with the occurrence of antibody-mediated rejections (AMRs) and graft function. RESULTS We found that (1) pretransplant DSA against class I (DSA-I), but not against class II, are predictive for AMR, resulting in a sensitivity of 75% and a specificity of 90% at a level of 900 mean fluorescence intensity (MFI); (2) with increasing strength of DSA-I, the sensitivity for AMR is decreasing to 50% and the specificity is increasing to 100% at 5200 MFI; (3) the LXM for class I, but not for class II, provides a higher accuracy than the flow cytometry XM and the B-cell CXM. The specificity of all XMs is increased greatly in combination with DSA-I values more than or equal to 900 MFI. CONCLUSIONS In sensitized recipients, the best prediction of AMR and consecutively reduced graft function is delivered by DSA-I alone at high strength or by DSA-I at low strength in combination with the LXM or CXM.
Collapse
|
|
25
|
Karczewski M, Karczewski J, Poniedzialek B, Wiktorowicz K, Smietanska M, Glyda M. Distinct Cytokine Patterns in Different States of Kidney Allograft Function. Transplant Proc 2009; 41:4147-9. [DOI: 10.1016/j.transproceed.2009.08.067] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Revised: 06/30/2009] [Accepted: 08/17/2009] [Indexed: 10/20/2022]
|
|
26
|
Karczewski J, Karczewski M, Glyda M, Wiktorowicz K. Role of TH1/TH2 cytokines in kidney allograft rejection. Transplant Proc 2009; 40:3390-2. [PMID: 19100396 DOI: 10.1016/j.transproceed.2008.07.125] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2008] [Accepted: 07/06/2008] [Indexed: 01/12/2023]
Abstract
One of the major issues in contemporary kidney transplantation is prevention of acute allograft rejection episodes (AREs). Cytokines are crucial mediators of immune reactions leading to AREs. We correlated serum Th1/Th2 cytokine concentrations with AREs. The project included 44 patients undergoing kidney transplantation. During the 3-month period following the transplantation, ARE was diagnosed in 11 patients. Serum samples collected 1 day before and 2, 7, 14, and 30 days after transplantation were tested for interleukin (IL)-2, IL-4, IL-5, IL-10, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha concentrations using flow cytometry. Nonrejection (NONAR) and rejection (ARE) groups of patients did not show significant differences in baseline demographic characteristics. We observed that higher pretransplantation serum levels of IFN-gamma (P = .000003) and IL-10 (P = .000001) were associated with AREs. Our analysis also showed slightly higher IL-4 serum levels among NONAR patients up to 7 days posttransplantation, followed by a drop in concentrations in NONAR patients. In contrast, there was a continuous increase among ARE patients. No significant differences were observed in plasma levels of IL-2, IL-5, IL-10, or TNF-alpha between the two groups. Higher pretransplantation levels of IFN-gamma and IL-10 observed in ARE patients indicated ongoing nondetected, probably nonspecific, inflammatory processes able to intensify an immune response directed against the transplanted organ leading to its acute rejection. Higher levels of IL-4 prior to and shortly after transplantation may have protective effects on graft survival. However, a prolonged, increased production of IL-4 after transplantation can also contribute to AREs.
Collapse
Affiliation(s)
- J Karczewski
- Department of Transplantology and General Surgery, District Hospital, Poznan, Poland
| | | | | | | |
Collapse
|
|
27
|
Delgado JC, Eckels DD. Positive B-cell only flow cytometric crossmatch: Implications for renal transplantation. Exp Mol Pathol 2008; 85:59-63. [DOI: 10.1016/j.yexmp.2008.03.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2007] [Accepted: 03/02/2008] [Indexed: 11/25/2022]
|
|
28
|
Berber I, Yiğit B, Işitmangil G, Tellioğlu G, Ozgezer T, Gülle S, Türkmen F, Titiz I. Evaluation of pretransplant serum cytokine levels in renal transplant recipients. Transplant Proc 2008; 40:92-3. [PMID: 18261555 DOI: 10.1016/j.transproceed.2007.11.048] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
AIM Cytokines are early predictors of graft dysfunction. In this study we evaluated pretransplant cytokine levels and graft outcomes among renal transplant recipients. PATIENTS AND METHODS Donor selection was based on results of blood group matching and negative crossmatches. A panel of 35 human serum samples from patients (female/male = 0.4) awaiting renal transplantation and 15 healty control sera were analyzed for interleukin (IL) 1alpha, IL-2, IL-6, IL-10, tumor necrosis factor-alpha, interferon-gamma, transforming growth factor-beta concentrations by enzyme-linked immunosorbent assay. The average age of the patients was 34.5 +/- 10.1 years (range 15 to 60). The average duration of renal replacement therapy before renal transplantation was 42.1 +/- 57.9 months (range 0 to 288). The types of renal replacement therapy were; hemodialysis (n = 27) and CAPD (n = 8). RESULTS Pretransplant IL-6 levels were higher among recipients who displayed acute rejection episodes compared with those fact of this complications (P < .05) or control sera (P < .05). Pretransplant IL-6 levels were higher among recipients with graft failure than those with a functioning graft (P < .05). Pretransplant IL-10 levels were higher among recipients with acute rejection episodes and graft failure than those without acute rejection or control subjects, but the difference did not reach significance. There was no correlation between pretransplant cytokine levels and age, gender, type, or duration of renal replacement therapy (P > .05). CONCLUSION High pretransplant serum IL-6 levels are associated with an increased risk of acute rejection episodes and graft failure. IL-10 might contribute an anti-inflammatory action to patients with high serum IL-6 levels.
Collapse
Affiliation(s)
- I Berber
- Renal Transplantation and Immunology Unit, Haydarpaşa Numune Education and Research Hospital, Istanbul, Turkey
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Chin GK, Adams CL, Carey BS, Shaw S, Tse WY, Kaminski ER. The value of serum neopterin, interferon-gamma levels and interleukin-12B polymorphisms in predicting acute renal allograft rejection. Clin Exp Immunol 2008; 152:239-44. [PMID: 18341612 DOI: 10.1111/j.1365-2249.2008.03632.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Acute rejection remains a poor predictor of graft outcome. In this study, we measured serum levels of interferon (IFN)-gamma and neopterin by enzyme-linked immunosorbent assay and a single nucleotide polymorphism (SNP) within the 3' untranslated region of the interleukin (IL)-12 B gene (1188 A/C) to determine whether either of these factors could predict acute rejection in renal transplantation. Significantly higher early post-transplant neopterin levels (days 5-7; 35.7 versus 19.9 nmol/l) were observed in recipients who subsequently rejected their grafts. Post-transplant neopterin levels showed a strong positive correlation with 1-month creatinine levels (Spearman's correlation 0.62, P < 0.001), suggesting macrophage activation early after transplantation. Pretransplant neopterin and IFN-gamma levels and the IL-12B gene SNP did not predict acute rejection in this small retrospective study. The ability to predict acute rejection non-invasively early after transplantation could lead to individual tailoring of immunosuppressive regimens and perhaps lead eventually to longer graft survival.
Collapse
Affiliation(s)
- G K Chin
- South-west Transplant Centre, Derriford Hospital, Plymouth, UK
| | | | | | | | | | | |
Collapse
|
|
30
|
Sadeghi M, Daniel V, Naujokat C, Schmidt J, Mehrabi A, Zeier M, Opelz G. Evidence for IFN-? up- and IL-4 downregulation late post-transplant in patients with good kidney graft outcome. Clin Transplant 2007; 21:449-59. [PMID: 17645703 DOI: 10.1111/j.1399-0012.2007.00665.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
We found recently that patients with good graft outcome showed higher IFN-gamma and IL-2, and lower IL-10 plasma levels late post-transplant than early post-transplant. In this retrospective study, we compared cytokine plasma levels in 33 symptom-free outpatients with those of 33 renal transplant recipients with early acute rejection (EAR), 29 with chronic rejection (CR), and 34 healthy controls (HC) to assess whether there is evidence for Th1 activation late post-transplant in patients with good graft outcome. Cytokines were measured pre-transplant, one wk, one month, six months, one yr, and two yr after transplantation. Twelve and 24 months post-transplant, IFN-gamma plasma levels were significantly higher (p = 0.001; p = 0.001, respectively) and IL-4 plasma levels significantly lower (p = 0.028; p = 0.003, respectively) in patients with stable graft function than those in controls. Six, 12, and 24 months post-transplant, patients with stable graft function had similar IFN-gamma and IL-4 plasma levels as patients with successfully treated EAR (p = n.s.), and higher IFN-gamma (p = 0.013; p = 0.001; p = 0.0005, respectively) and lower IL-4 (p = 0.007; p = 0.417; p = 0.0001, respectively) plasma levels than patients with CR. These data suggest that increased plasma IFN-gamma and decreased plasma IL-4 late post-transplant might be involved in the induction of mechanisms that facilitate good long-term graft outcome.
Collapse
Affiliation(s)
- Mahmoud Sadeghi
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Ghafari A, Makhdoomi K, Ahmadpour P, Afshari AT, Lak SS, Fakhri L. Serum T-lymphocyte cytokines cannot predict early acute rejection in renal transplantation. Transplant Proc 2007; 39:958-961. [PMID: 17524862 DOI: 10.1016/j.transproceed.2007.03.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Despite numerous studies, the precise role of Th1/Th2 cytokines in acute renal allograft rejection remains unclear. To provide insight into the role of cytokines in acute allograft rejection, we measured serum T-cell cytokine concentrations for correlation with clinical events after renal transplantation in adults. Serum Th1 (interleukin-2 [IL-2] and interferon-gamma [IFN gamma] and Th2 (IL-4, IL-10) cytokine concentrations were measured in 60 consecutive living donor kidney transplant recipients namely, 40 males, overall mean age 38.82 years), on the day before as well as 7 and 14 days posttransplantation using ELISA. Patients were stratified based upon acute rejection episode (ARE) in the first month after transplantation. Immunosuppression consisted of cyclosporine, mycophenolate mofetil, and prednisolone. ARE was diagnosed based on an increased plasma creatinine of more than 50%, sonographic analysis, radioisotope scan, pathologic findings, or measured cyclosporine blood levels. Twelve ARE were diagnosed among patients (20%). There was no significant difference between the 2 groups with respect to the mean serum concentration values of IL-2, IL-10, IL-4, and IFN gamma on the day before or 7 or 14 days after transplantation. This study showed that there was no correlation between the Th1/Th2 serum cytokine profiles and early ARE in living donor kidney transplantation.
Collapse
Affiliation(s)
- A Ghafari
- Department of Internal Medicine, Urmia University of Medical Sciences, Urmia, Iran.
| | | | | | | | | | | |
Collapse
|
|
32
|
Amirzargar A, Lessanpezeshki M, Fathi A, Amirzargar M, Khosravi F, Ansaripour B, Nikbin B. TH1/TH2 cytokine analysis in Iranian renal transplant recipients. Transplant Proc 2006; 37:2985-7. [PMID: 16213281 DOI: 10.1016/j.transproceed.2005.08.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The pretransplant cytokine profile of donor and recipient blood and tissues may be associated with transplant outcome. A Th1 response is generally associated with transplant rejection, while a Th2 response may lead to tolerance and stable graft survival. A total of 56 (37 male and 19 female) patients of mean 36 +/- 5 years were candidates for living unrelated kidney transplantation. Serum samples were collected 24 hours pretransplantation as well as at 1 and 2 weeks posttransplantation. Immunosuppression consisted of cyclosporine, prednisolone, and mycophenolate mofetil. Among the transplanted patients, 19 (33.9%) individuals experienced an acute rejection episode, as proven by biopsy, as well as an increased serum creatinine and blood urea nitrogen, within 14 days after transplantation. We determined serum concentrations of interleukin (IL) 2 and interferon (IFN)-gamma for Th1 and IL4 and IL10 for Th2 by an enzyme-linked immunosorbent assay method (Bender med system kits, Germany). Among Th1 cytokines, the mean concentration levels for groups with versus without acute rejection were: IL-2 pretransplant 15 pg/mL vs 6.8 pg/mL, respectively (P = .005); IL-2 at 1 week, 19 pg/mL vs 4.85 pg/mL, respectively (P = .001); IL-2 at 2 weeks, 21.1 pg/mL vs 4.65 pg/mL, respectively (P = .0001); IFN-gamma pretransplant 161.1 pg/mL vs 65.2 pg/mL, respectively (P = .001); IFN-gamma at 1 week, 175.6 pg/mL vs 66.5 pg/mL, respectively (P = .001); and IFN-gamma at 2 weeks, 173.7 pg/mL vs 77.1 pg/mL (P = .001). IL-2 and IFN-gamma levels were significantly higher in the group with acute rejection versus those without acute rejection. In conclusion, these data suggest that cytokine analysis, especially of Th1 cytokines, might be a valuable prognotic index of kidney transplant outcome.
Collapse
Affiliation(s)
- A Amirzargar
- Immunology Department, Immunogenetic Laboratory, Medical School, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Bradley BA. Prognostic assays for rejection and tolerance in organ transplantation. Transpl Immunol 2005; 14:193-201. [PMID: 15982563 DOI: 10.1016/j.trim.2005.03.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2005] [Indexed: 10/25/2022]
Abstract
In this review, I have summarised our understanding of acute rejection of organ transplants, and for convenience I have identified three processes, recognition, rejection and regulation. In stark contrast to this text-book picture of acute rejection, I have drawn attention to some of the clinical realities, where processes are altered by powerful immunosuppressive drugs, and where many transplant recipients are pre-sensitised to transplantation antigens prior to engraftment. The ultimate goal is to encourage the emergence of a utopian immunological state, wherein patients tolerate organ transplants for life after being weaned from all immunosuppressive drugs. Assays that may be used in the future to reliably monitor this process are still at a very exciting stage of development.
Collapse
Affiliation(s)
- Benjamin A Bradley
- The East Barn, The Pound, Lower Almondsbury, Bristol BS32 4EF, England, United Kingdom.
| |
Collapse
|
|
34
|
Zeng Z, Ming C, Zhen Z, Sun R, Chen W. Can an allograft become harmonious with its recipient by analogous mechanisms to the long-term survival of a parasite in its host? Transplantation is similar to parasitism and chronic parasite infection can prolong allograft survival. Med Hypotheses 2005; 65:1047-50. [PMID: 16143454 DOI: 10.1016/j.mehy.2005.06.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2005] [Accepted: 06/27/2005] [Indexed: 10/25/2022]
Abstract
Organ transplantation is very similar to the parasitism, the immune responses to the allograft and parasite share some general characters in acute stage. But host-parasite interplay seems harmonious and clinically asymptomatic carriers act as long-term reservoirs for transmission even several decades. It is proposed that the allograft also can survive long-term like the parasite harmonious with the host if we exploit the mechanism of the parasitism. How can the parasite escape the immunologic cleaning? Recent research found that: (1) Almost all the parasites infection can break the balance of Th1/Th2 and induce the Th2 bias. The level of cytokine excreted by Th2 is increased. (2) Parasite infection can interfere in antigen presentation processing through cystatins and "dendritic cell paralysis". (3) Regulatory T cells were found surrounding the local site of parasite worms. (4) Parasite infections can switch of eicosanoid metabolism, and the anti-inflammatory mediator of the plasma is increasingly manifest in the chronic infection stage. And in animal model, chronic infection can prolong the allograft survival. If the hypotheses are correct, it will give another novel therapeutic option for patients with organ transplantation.
Collapse
Affiliation(s)
- Zhigui Zeng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, HuBei Province 430030, PR China
| | | | | | | | | |
Collapse
|
|
35
|
Suresh V, Carey BS, Shaw S, Tse WY, Cartwright N, Akoh J, McGonigle R, Rowe P, Shaw J, Kaminski E. A retrospective study of the prognostic impact of cytokine secretion in mixed lymphocyte culture on long-term graft function following allogeneic renal transplantation. Transpl Int 2005; 18:1067-1071. [PMID: 16101728 DOI: 10.1111/j.1432-2277.2005.00172.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We have previously shown that in vitro measurement of cytokine production prior to renal transplantation can provide predictive information on the risk of acute rejection. Our earlier studies demonstrated that patients who secreted high levels of interferon-gamma (IFN-gamma) in OKT3-stimulated or mixed lymphocyte culture had a significantly increased risk of acute rejection compared with patients who secreted lower levels. In this study, we performed a retrospective analysis of the same cohort of patients in order to determine the prognostic value of cytokine profiles and other variables on long-term graft function. Our results show that high levels of IFN-gamma in pretransplant mixed lymphocyte culture are a highly significant predictor of poorer creatinine levels at 18, 24 and 36 months post-transplant.
Collapse
Affiliation(s)
- Vijayan Suresh
- South West Transplant Centre, Derriford Hospital, Plymouth, UK
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Lessan-Pezeshki M, Amirzargar A, Fathi A, Khatami MR, Einollahi B, Pourfarziani V, Azmandian J, Khosravi F, Ansaripour B, Nikbin B. Value of Pretransplantation Cytokine Profiles for Predicting Acute Rejection in Renal Transplant Recipients. Transplant Proc 2005; 37:2982-4. [PMID: 16213280 DOI: 10.1016/j.transproceed.2005.08.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Episodes of acute rejection may represent an important risk factor for the development of chronic allograft nephropathy. Various studies have shown that pretransplant cytokine profiles in recipient blood are associated with transplant outcome. Serum samples were collected 24 hours before transplantation from 57 patients (38 men and 19 women of age 36 +/- 5 years) receiving kidneys from unrelated living donors. Additional samples were collected at 1 and 2 weeks after transplantation, as well as during every rejection episode. The immunosuppression consisted of a cyclosporine, prednisolone, and mycophenolate mofetil. Among the transplanted patients, 19 (33.3%) individuals experienced an acute rejection episode based on an increased level of serum creatinine and blood urea nitrogen during the first 14 days after transplantation. TGF-beta, IL-2 and IFN-gamma serum levels were determined by an ELISA method using Bindermed system kits. The mean concentration of TGF-beta before transplantation tended to be lower among patients with acute rejection episodes compared to those with stable graft (75,265 versus 85,394 pg/mL; P = .34) and at 1 week after transplantation (77,558 versus 84,390 pg/mL), although the differences were not significant. Among patients with rejection the mean IL-2 concentration was significantly higher before, at 1 week, and at 2 weeks after transplantation (15.0 versus 6.8 pg/mL, P = .005; 19.0 versus 4.9 pg/mL, P = .001; and 21.1 versus 4.7 pg/mL, P = .0001). The mean concentration of IFN-gamma was significantly higher pre- and at 1 and 2 weeks posttransplantation in patients with acute rejection episodes (161.1 versus 65.2, 175.6 versus 66.5 and 173.7 versus 77.1 pg/mL, all P < .001). In conclusion, evaluation of Th1 cytokines before transplantation may represent valuable predictive marker for an acute rejection episode.
Collapse
|
|
37
|
Butani L, Johnson J, Troppmann C, McVicar J, Perez RV. Assessment of pretransplant inflammation in pediatric renal allograft recipients. Transpl Int 2005; 18:949-53. [PMID: 16008745 DOI: 10.1111/j.1432-2277.2005.00168.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Pretransplant (Tx) inflammation is linked to adverse outcomes in adult Tx recipients but no such data exist for children. Our study evaluated the predictive value of three pre-Tx inflammatory markers: serum C-reactive protein (CRP), Neopterin (Neo) and interleukin (IL) 12, in determining outcome. Pre-Tx serum on 51 children (mean age 11 years) transplanted between 1985 and 2000 was analyzed. Data on other variables were abstracted from patient records. Primary end-points were graft survival and acute rejection (AR). Kaplan-Meier and log-rank statistics compared endpoints in patients at different quartiles for each marker. Cox regression analysis was used to determine the independent effect of the markers on the end-points. The mean CRP, Neo, and IL-12 were 1.3 mg/l, 1.78 ng/ml, and 123 pg/ml, respectively. The mean CRP, Neo, and IL-12 were not different between the patients with and without AR or graft loss (P > 0.4 for all). Neither rejection-free survival nor graft survival was affected by CRP, Neo, or IL-12 quartiles. Cox-regression analysis demonstrated no predictive value of any marker on outcome. Unlike adults, a single pre-Tx determination of inflammatory markers was not predictive of AR or graft loss in children, indicating that the pathogenesis of AR may be different in children.
Collapse
Affiliation(s)
- Lavjay Butani
- Section of Pediatric Nephrology, University of California, Davis Medical Center, Sacramento, CA 95817, USA.
| | | | | | | | | |
Collapse
|
|
38
|
Wang YL, Zhang YY, Li G, Tang ZQ, Zhou YL, Zhu ZJ, Yao Z. Correlation of CD95 and soluble CD95 expression with acute rejection status of liver transplantation. World J Gastroenterol 2005; 11:1700-4. [PMID: 15786554 PMCID: PMC4305958 DOI: 10.3748/wjg.v11.i11.1700] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the expression levels of soluble form of CD95, CD95 ligand (sCD95 and sCD95L, respectively) in plasma and CD95 expression on CD3+ cells in liver-transplanted recipients with acute rejection (AR).
METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 30 clinically liver transplanted recipients. CD95 expression on CD3+ cells was quantitatively measured by two-color fluorescence activated cell sorter (FACS) analysis. Lymphocyte surface phenotypes of CD4, CD8, CD16 and CD56 were determined by flow cytometry. Plasma levels of sCD95 and sCD95L were detected by Enzyme Linked-Immuno-Sorbent Assay (ELISA). The results were compared with that from normal healthy volunteers (n = 15 individuals).
RESULTS: FACS analysis showed that CD95 expression on CD3+ T cells was significantly increased in liver transplanted recipients with AR compared to that in stable recipients without rejection and infection or healthy individuals who did not undergo transplantation (18676.93±11588.34/molecule, 6848.20±1712.96/molecule, 6418.01±2001.95/molecule, respectively, P<0.01). Whereas no significant difference was seen between liver-transplanted stable recipients and healthy individuals. Furthermore, no significant differences were detected between each group with CD4/CD8 ratio or the percentage of CD16+56+ cells. Plasma levels of sCD95 were significantly higher in transplanted recipients with AR compared to that in stable recipients or healthy individuals (391.88±196.00, 201.37±30.30, 148.83±58.25 pg/mL, respectively, P<0.01). In contrast, the plasma levels of sCD95L in liver- transplanted recipients were not significantly different from that in healthy individuals.
CONCLUSION: The present results indicate that the increased CD95 expression on CD3+ cells and the increased levels of sCD95 in plasma may modify the immunological situation of the recipients after transplantation or represent the ongoing graft rejection.
Collapse
Affiliation(s)
- Yu-Liang Wang
- Tianjin Institute of Thrombosis and Hemostasis, Laboratory Center, Tianjin First Central Hospital, 24 FuKang Road, Tianjin 300192, China.
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Griffiths EJ, Nelson RE, Dupont PJ, Warrens AN. SKEWING OF PRETRANSPLANT ANTI-HLA CLASS I ANTIBODIES OF IMMUNOGLOBULIN G ISOTYPE SOLELY TOWARD IMMUNOGLOBULIN G1 SUBCLASS IS ASSOCIATED WITH POORER RENAL ALLOGRAFT SURVIVAL. Transplantation 2004; 77:1771-3. [PMID: 15201682 DOI: 10.1097/01.tp.0000129408.07168.40] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Sensitized patients with lymphocytotoxic immunoglobulin (Ig)G anti-human leukocyte antigen (HLA) antibodies have an increased risk of rejection and poorer graft survival. Little is known, however, about the correlation between IgG antibody subclass and clinical outcomes. We identified 20 sensitized renal transplant recipients (panel reactive antibody >15%), all of whom had anti-HLA class I antibodies of an IgG isotype with known specificity before transplantation but who received a crossmatch negative graft. We analyzed the degree of skewing solely toward IgG1 (n=11) or to other IgG subclasses with or without IgG1 (n=9) and correlated these findings with graft survival. At last follow-up (median follow-up 28 months), 6 of 11 patients (55%) with anti-HLA antibodies skewed toward IgG1 had lost their grafts compared with 0 of 9 patients (0%) with anti-HLA antibodies not skewed toward IgG1 (P =0.01 log-rank test). Anti-HLA antibodies of an IgG1 subclass may be a novel marker predicting poor graft outcome.
Collapse
Affiliation(s)
- Emmet J Griffiths
- Department of Immunology, Imperial College London, Hammersmith Campus, London, United Kingdom
| | | | | | | |
Collapse
|