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The role of non-HLA antibodies in solid organ transplantation: a complex deliberation. Curr Opin Organ Transplant 2021; 25:536-542. [PMID: 33044346 DOI: 10.1097/mot.0000000000000811] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW There is tremendous interest in understanding when, if, and how non-HLA antibodies contribute to allograft injury. Numerous non-HLA target antigens have been identified and sensitization to these targets have been associated with delayed allograft function, rejection, and allograft failure. This review focuses on the clinical utility of HLA antibody testing, highlighting the strengths and limitations of current clinical studies, and the need for defining characteristics to inform non-HLA antibody pathogenicity. RECENT FINDINGS Clinical studies continue to show associations between non-HLA antibodies and rejection and reduced allograft survival across multiple transplanted organ types. The worst clinical outcomes continue to be observed among recipients testing positive for both non-HLA and donor-specific HLA antibodies. Mechanistic insights from both animal and clinical studies support a model in which tissue injury accompanied by an inflammatory environment influence non-HLA antibody formation and pathogenicity. SUMMARY Immune triggers that lead to non-HLA antibody formation and pathogenicity are complex and poorly understood. The ability of non-HLA antibodies to mediate allograft injury may depend upon their affinity and strength (titer), target specificity, density of the target antigen, and synergy with donor-specific HLA antibodies.
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Nakamura T, Shirouzu T, Nakata K, Yoshimura N, Ushigome H. The Role of Major Histocompatibility Complex in Organ Transplantation- Donor Specific Anti-Major Histocompatibility Complex Antibodies Analysis Goes to the Next Stage. Int J Mol Sci 2019; 20:E4544. [PMID: 31540289 PMCID: PMC6769817 DOI: 10.3390/ijms20184544] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/04/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Organ transplantation has progressed with the comprehension of the major histocompatibility complex (MHC). It is true that the outcome of organ transplantation largely relies on how well rejection is managed. It is no exaggeration to say that to be well acquainted with MHC is a shortcut to control rejection. In human beings, MHC is generally recognized as human leukocyte antigens (HLA). Under the current circumstances, the number of alleles is still increasing, but the function is not completely understood. Their roles in organ transplantation are of vital importance, because mismatches of HLA alleles possibly evoke both cellular and antibody-mediated rejection. Even though the control of cellular rejection has improved by recent advances of immunosuppressants, there is no doubt that antibody-mediated rejection (AMR), which is strongly correlated with donor-specific anti-HLA antibodies (DSA), brings a poor outcome. Thus, to diagnose and treat AMR correctly is a clear proposition. In this review, we would like to focus on the detection of intra-graft DSA as a recent trend. Overall, here we will review the current knowledge regarding MHC, especially with intra-graft DSA, and future perspectives: HLA epitope matching; eplet risk stratification; predicted indirectly recognizable HLA epitopes etc. in the context of organ transplantation.
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Affiliation(s)
- Tsukasa Nakamura
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Takayuki Shirouzu
- Molecular Diagnositcs Division, Wakunaga Pharmaceutical Co., Led. 4-5-36 Miyahara, Yodogawa-ku, Osaka 532-0003, Japan.
| | - Katsuya Nakata
- Molecular Diagnositcs Division, Wakunaga Pharmaceutical Co., Led. 4-5-36 Miyahara, Yodogawa-ku, Osaka 532-0003, Japan.
| | - Norio Yoshimura
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Hidetaka Ushigome
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
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Sensitization to endothelial cell antigens: Unraveling the cause or effect paradox. Hum Immunol 2019; 80:614-620. [PMID: 31054781 DOI: 10.1016/j.humimm.2019.04.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/02/2019] [Accepted: 04/23/2019] [Indexed: 01/03/2023]
Abstract
Anti-endothelial cell antibodies (AECAs) have been correlated with increased acute and chronic rejection across all organ types and early graft dysfunction in kidney and heart transplantation. Nevertheless, the lack of appropriate tools and clear criteria for defining injurious versus non-injurious AECAs prohibits their routine inclusion in clinical risk assessments and diagnostic algorithms for antibody mediated injury. Clinical characterization of AECAs is complicated due to the wide range of polymorphic and non-polymorphic antigens expressed across different vascular tissues and the diverse array of specificities observed between individuals. This complexity is also reflected in the broad spectrum of reported injury phenotypes. AECAs detected at time of allograft dysfunction may represent biomarkers of past vascular injury or active contributors to a current rejection process. New tools within the fields of proteomics, genomics, bioinformatics, and imaging are currently being validated and hold great promise for unraveling the AECA paradox.
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Qin Y, Sun B, Zhang F, Wang Y, Shen B, Liu Y, Guo Y, Fan Y, Qiu J. Sox7 is involved in antibody-dependent endothelial cell activation and renal allograft injury via the Jagged1-Notch1 pathway. Exp Cell Res 2019; 375:20-27. [PMID: 30639059 DOI: 10.1016/j.yexcr.2019.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 11/28/2018] [Accepted: 01/08/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Antibody-mediated rejection (AMR) can cause graft loss and reduces long-term graft survival after kidney transplantation. Human leukocyte antigen (HLA) and/or non-HLA antibodies play a key role in the pathogenesis of AMR by targeting the allograft epithelium via complement activation and complement-independent mechanisms. However, the precise mechanisms of AMR remain unclear and treatment is still limited. METHODS In this study, we investigated the role of the endothelial-associated transcription factor Sox7 in AMR, using the anti-HLA antibody W6/32, shRNA-mediated Sox7 knockdown, and by manipulating the Notch pathway. We used an in vitro human kidney glomerular endothelial cells (HKGECs) model and an in vivo MHC-mismatched kidney transplantation model. RESULTS Sox7 expression was upregulated and the Jagged1-Notch1 pathway was activated in HKGECs after W6/32 activation. W6/32 antibodies increased the expression of adhesion molecules (VCAM-1, ICAM-1), inflammatory cytokines (IL-6, TNF-α), and chemokines (CXCL8, CXCL10), and Sox7 knockdown and inhibition of the Notch pathway by DAPT significantly reduced these effects. Jagged1 overexpression rescued the inhibitory effects of Sox7 knockdown. In addition, Sox7 knockdown attenuated acute allograft kidney injury in mice and reduced the expression of adhesion molecules and Jagged1-Notch1 signaling after transplantation. CONCLUSIONS Our findings suggest that Sox7 plays an important role in mediating HLA I antibody-dependent endothelial cell activation and acute kidney allograft rejection via the Jagged1-Notch1 pathway. Manipulating Sox7 in donor organs may represent a useful treatment for AMR in solid organ transplantation.
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Affiliation(s)
- Yan Qin
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Bo Sun
- Shanghai Center for Drug Evaluation & Inspection, Shanghai 201203, China
| | - Fang Zhang
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Yong Wang
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Bing Shen
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Yong Liu
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Yifeng Guo
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Yu Fan
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Jianxin Qiu
- Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China.
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5
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Alloimmune-induced intragraft lymphoid neogenesis promotes B-cell tolerance breakdown that accelerates chronic rejection. Curr Opin Organ Transplant 2017; 21:368-74. [PMID: 27258579 DOI: 10.1097/mot.0000000000000329] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Antibody-mediated rejection (AMR) has emerged as a leading cause of allograft loss in solid organ transplantation. A better understanding of AMR immunopathology is a prerequisite to improve its management. RECENT FINDINGS The prevalent dogma considers that AMR is the consequence of a thymo-dependent B-cell response against donor-specific polymorphic antigens (mainly mismatched human leukocyte antigen molecules).Nevertheless, antibodies directed against nonpolymorphic antigens expressed by the graft are also generated during chronic rejection and can contribute to allograft destruction. This implies that a breakdown of self-tolerance occurs during chronic rejection. Accumulating evidence suggests that this event occurs inside the ectopic 'tertiary' lymphoid tissue that develops within rejected allografts.Thus, AMR should be viewed as a complex interplay between allo- and autoimmune humoral responses. SUMMARY The interplay between allo- and autoimmune humoral responses in chronic rejection highlights several unmet medical issues like better diagnosis tools are needed to screen recipients for nonhuman leukocyte antigen alloantibodies and autoantibodies, therapeutic strategies shall aim at blocking the response against alloantigens but also the breakdown of self-tolerance that occurs within tertiary lymphoid tissue.
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Lopez-Soler RI, Borgia JA, Kanangat S, Fhied CL, Conti DJ, Constantino D, Ata A, Chan R, Wang Z. Anti-vimentin Antibodies Present at the Time of Transplantation May Predict Early Development of Interstitial Fibrosis/Tubular Atrophy. Transplant Proc 2017; 48:2023-33. [PMID: 27569939 DOI: 10.1016/j.transproceed.2016.04.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 04/27/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Anti-vimentin (a cytoskeletal protein) autoantibodies in renal transplant recipients have been correlated with interstitial fibrosis/tubular atrophy (IFTA). In this study, we examine the association between pretransplantation anti-vimentin antibodies and the subsequent development of IFTA. METHODS Sera obtained before renal transplantation from 97 transplant recipients were analyzed for the presence of anti-vimentin antibodies via Luminex assays to determine the concentration of anti-vimentin antibodies. Results were correlated with findings of IFTA on biopsy as well as graft function and patient and graft survival. RESULTS In our patient population, 56 of 97 patients were diagnosed by biopsy with IFTA 2.9 (±2.1) years after renal transplantation. Patients with IFTA on biopsy had higher mean concentration of anti-vimentin antibodies when compared to patients without IFTA (32.2 μg/mL [3.97-269.12 μg/mL] vs 14.57 μg/mL [4.71-87.81 μg/mL]). The risk of developing IFTA with a concentration of anti-vimentin antibody >15 μg/mL before transplantation was 1.96 (95% CI = 1.38-2.79, P = .011). Patients with elevated anti-vimentin antibody concentrations (>15 μg/mL) at the time of transplantation also had a higher risk of developing IFTA (81.4% vs 41.2%; P < .05). In addition, graft function was worse at 1, 3, and 5 years posttransplantation in patients with elevated concentrations of pretransplantation anti-vimentin antibody. Although there were more graft losses in the IFTA groups (49.12% vs 25.64%, P = .021) and the IFTA patients loss their grafts earlier (4.3 years vs 3.6 years), there was no statistical difference in graft loss rates. CONCLUSIONS Pretransplantation anti-vimentin antibody concentrations >15 μg/mL may be a risk factor for IFTA.
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Affiliation(s)
- R I Lopez-Soler
- Division of Surgery, Section of Transplantation, Albany Medical Center, Albany, New York.
| | - J A Borgia
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois; Department of Pathology, Rush University Medical Center, Chicago, Illinois
| | - S Kanangat
- Department of Pathology, Rush University Medical Center, Chicago, Illinois
| | - C L Fhied
- Department of Pathology, Rush University Medical Center, Chicago, Illinois
| | - D J Conti
- Division of Surgery, Section of Transplantation, Albany Medical Center, Albany, New York
| | - D Constantino
- Transplant Immunology Laboratory, Albany Medical College, Albany, New York
| | - A Ata
- Division of Surgery, Section of Transplantation, Albany Medical Center, Albany, New York
| | - R Chan
- Division of Surgery, Section of Transplantation, Albany Medical Center, Albany, New York
| | - Z Wang
- Center For Cardiovascular Sciences, Albany Medical College, Albany, New York
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Nakada Y, Yamamoto I, Horita S, Kobayashi A, Mafune A, Katsumata H, Yamakawa T, Katsuma A, Kawabe M, Tanno Y, Ohkido I, Tsuboi N, Yamamoto H, Okumi M, Ishida H, Yokoo T, Tanabe K. The prognostic values of caveolin-1 immunoreactivity in peritubular capillaries in patients with kidney transplantation. Clin Transplant 2016; 30:1417-1424. [PMID: 27543925 DOI: 10.1111/ctr.12833] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2016] [Indexed: 12/24/2022]
Abstract
The low sensitivity of C4d immunoreactivity in peritubular capillaries (PTCs) hinders its use in the diagnosis of chronic active antibody-mediated rejection (CAAMR). C4d-negative CAAMR was defined in the 2013 Banff classification, which included the expression of endothelial-associated transcripts (ENDATs). We previously showed that the ENDAT caveolin-1 (CAV-1) is a distinct feature of CAAMR. In this study, we investigated the prognostic value of CAV-1 immunoreactivity in PTCs in kidney transplant patients. Ninety-eight kidney transplant recipients were included in this study. The prognostic value of CAV-1 immunoreactivity in PTCs was evaluated by double immunostaining for CAV-1 and pathologische Anatomie Leiden endothelium (PAL-E, a PTC marker) in the PTCs of kidney allograft biopsy samples. The patients were divided into two groups: CAV-1/PAL-E<50% and CAV-1/PAL-E≥50%. Kaplan-Meier curves showed that CAV-1/PAL-E≥50% patients had a significantly worse prognosis than that of CAV-1/PAL-E<50% patients (log-rank; P<.001). C4d staining of PTCs was not associated with the development of graft failure (log-rank; P=.345), whereas in a multivariate Cox regression analysis, CAV-1 immunoreactivity in PTCs was independently associated with graft failure (hazard ratio: 11.1; P=.0324). CAV-1 immunoreactivity in PTCs may serve as a prognostic marker for kidney allograft survival.
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Affiliation(s)
- Yasuyuki Nakada
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Izumi Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
| | - Shigeru Horita
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Akimitsu Kobayashi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Aki Mafune
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Haruki Katsumata
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takafumi Yamakawa
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Ai Katsuma
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Mayuko Kawabe
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yudo Tanno
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Ichiro Ohkido
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroyasu Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.,Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan
| | - Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hideki Ishida
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
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8
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González-Molina M, Ruiz-Esteban P, Caballero A, Burgos D, Cabello M, Leon M, Fuentes L, Hernandez D. Immune response and histology of humoral rejection in kidney transplantation. Nefrologia 2016; 36:354-67. [PMID: 27267916 DOI: 10.1016/j.nefro.2016.03.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 02/22/2016] [Accepted: 03/26/2016] [Indexed: 11/15/2022] Open
Abstract
The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ.
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Affiliation(s)
- Miguel González-Molina
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain.
| | - Pedro Ruiz-Esteban
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Abelardo Caballero
- Immunology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Dolores Burgos
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Mercedes Cabello
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Miriam Leon
- Pathology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Laura Fuentes
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Domingo Hernandez
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
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9
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Zilian E, Saragih H, Vijayan V, Hiller O, Figueiredo C, Aljabri A, Blasczyk R, Theilmeier G, Becker JU, Larmann J, Immenschuh S. Heme Oxygenase-1 Inhibits HLA Class I Antibody-Dependent Endothelial Cell Activation. PLoS One 2015; 10:e0145306. [PMID: 26690352 PMCID: PMC4686182 DOI: 10.1371/journal.pone.0145306] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 12/01/2015] [Indexed: 12/27/2022] Open
Abstract
Antibody-mediated rejection (AMR) is a key limiting factor for long-term graft survival in solid organ transplantation. Human leukocyte antigen (HLA) class I (HLA I) antibodies (Abs) play a major role in the pathogenesis of AMR via their interactions with HLA molecules on vascular endothelial cells (ECs). The antioxidant enzyme heme oxygenase (HO)-1 has anti-inflammatory functions in the endothelium. As complement-independent effects of HLA I Abs can activate ECs, it was the goal of the current study to investigate the role of HO-1 on activation of human ECs by HLA I Abs. In cell cultures of various primary human macro- and microvascular ECs treatment with monoclonal pan- and allele-specific HLA I Abs up-regulated the expression of inducible proinflammatory adhesion molecules and chemokines (vascular cell adhesion molecule-1 [VCAM-1], intercellular cell adhesion molecule-1 [ICAM-1], interleukin-8 [IL-8] and monocyte chemotactic protein 1 [MCP-1]). Pharmacological induction of HO-1 with cobalt-protoporphyrin IX reduced, whereas inhibition of HO-1 with either zinc-protoporphyrin IX or siRNA-mediated knockdown increased HLA I Ab-dependent up-regulation of VCAM-1. Treatment with two carbon monoxide (CO)-releasing molecules, which liberate the gaseous HO product CO, blocked HLA I Ab-dependent EC activation. Finally, in an in vitro adhesion assay exposure of ECs to HLA I Abs led to increased monocyte binding, which was counteracted by up-regulation of HO-1. In conclusion, HLA I Ab-dependent EC activation is modulated by endothelial HO-1 and targeted induction of this enzyme may be a novel therapeutic approach for the treatment of AMR in solid organ transplantation.
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Affiliation(s)
- Eva Zilian
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Hendry Saragih
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
- Faculty of Biology, Gadjah Mada University, Yogyakarta, Indonesia
| | - Vijith Vijayan
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Oliver Hiller
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | | | - Abid Aljabri
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Gregor Theilmeier
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Jan Larmann
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Stephan Immenschuh
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
- * E-mail:
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10
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von Rossum A, Laher I, Choy JC. Immune-mediated vascular injury and dysfunction in transplant arteriosclerosis. Front Immunol 2015; 5:684. [PMID: 25628623 PMCID: PMC4290675 DOI: 10.3389/fimmu.2014.00684] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 12/18/2014] [Indexed: 12/16/2022] Open
Abstract
Solid organ transplantation is the only treatment for end-stage organ failure but this life-saving procedure is limited by immune-mediated rejection of most grafts. Blood vessels within transplanted organs are targeted by the immune system and the resultant vascular damage is a main contributor to acute and chronic graft failure. The vasculature is a unique tissue with specific immunological properties. This review discusses the interactions of the immune system with blood vessels in transplanted organs and how these interactions lead to the development of transplant arteriosclerosis, a leading cause of heart transplant failure.
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Affiliation(s)
- Anna von Rossum
- Department of Molecular Biology and Biochemistry, Simon Fraser University , Burnaby, BC , Canada
| | - Ismail Laher
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, BC , Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University , Burnaby, BC , Canada
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11
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Jackson AM, Sigdel TK, Delville M, Hsieh SC, Dai H, Bagnasco S, Montgomery RA, Sarwal MM. Endothelial cell antibodies associated with novel targets and increased rejection. J Am Soc Nephrol 2014; 26:1161-71. [PMID: 25381426 DOI: 10.1681/asn.2013121277] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 08/19/2014] [Indexed: 11/03/2022] Open
Abstract
The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donor-specific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.
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Affiliation(s)
| | - Tara K Sigdel
- Department of Surgery, University of California, San Francisco, California; and
| | | | - Szu-Chuan Hsieh
- Department of Surgery, University of California, San Francisco, California; and
| | - Hong Dai
- Department of Surgery, University of California, San Francisco, California; and
| | | | | | - Minnie M Sarwal
- Department of Surgery, University of California, San Francisco, California; and
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12
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Tittelbach-Helmrich D, Pisarski P, Offermann G, Geyer M, Thomusch O, Hopt UT, Drognitz O. Impact of transplant nephrectomy on peak PRA levels and outcome after kidney re-transplantation. World J Transplant 2014; 4:141-147. [PMID: 25032103 PMCID: PMC4094949 DOI: 10.5500/wjt.v4.i2.141] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 05/16/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To determine the impact of transplant nephrectomy on peak panel reactive antibody (PRA) levels, patient and graft survival in kidney re-transplants.
METHODS: From 1969 to 2006, a total of 609 kidney re-transplantations were performed at the University of Freiburg and the Campus Benjamin Franklin of the University of Berlin. Patients with PRA levels above (5%) before first kidney transplantation were excluded from further analysis (n = 304). Patients with graft nephrectomy (n = 245, NE+) were retrospectively compared to 60 kidney re-transplants without prior graft nephrectomy (NE-).
RESULTS: Peak PRA levels between the first and the second transplantation were higher in patients undergoing graft nephrectomy (P = 0.098), whereas the last PRA levels before the second kidney transplantation did not differ between the groups. Age adjusted survival for the second kidney graft, censored for death with functioning graft, were comparable in both groups. Waiting time between first and second transplantation did not influence the graft survival significantly in the group that underwent nephrectomy. In contrast, patients without nephrectomy experienced better graft survival rates when re-transplantation was performed within one year after graft loss (P = 0.033). Age adjusted patient survival rates at 1 and 5 years were 94.1% and 86.3% vs 83.1% and 75.4% group NE+ and NE-, respectively (P < 0.01).
CONCLUSION: Transplant nephrectomy leads to a temporary increase in PRA levels that normalize before kidney re-transplantation. In patients without nephrectomy of a non-viable kidney graft timing of re-transplantation significantly influences graft survival after a second transplantation. Most importantly, transplant nephrectomy is associated with a significantly longer patient survival.
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13
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Clinical evaluation of the endothelial tie-2 crossmatch in ABO compatible and ABO incompatible renal transplants. Hum Immunol 2013; 74:1425-30. [DOI: 10.1016/j.humimm.2013.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 02/20/2013] [Accepted: 06/07/2013] [Indexed: 01/18/2023]
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14
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[Kidney nephrectomy after allograft failure]. Nephrol Ther 2013; 9:189-94. [PMID: 23410951 DOI: 10.1016/j.nephro.2012.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Revised: 08/28/2012] [Accepted: 09/20/2012] [Indexed: 01/16/2023]
Abstract
The number of kidney-transplant patients that return to dialysis therapy after a failed kidney allograft is increasing sharply. These patients differ from patients treated with chronic dialysis, but who have never received a transplant; i.e., former transplanted patients display a higher risk of morbidity-mortality, particularly from cardiovascular and infectious complications. The management of immunosuppression has not been codified for patients with a failed kidney allograft: immunosuppressive therapy can be either abruptly stopped or progressively reduced. In addition, nephrectomy of the failed allograft is debatable. Some advocate this procedure only when there is intolerance, e.g., gross hematuria, local pain, or unexplained inflammatory syndrome. In contrast, others propose a systematic nephrectomy, mainly to reveal anti-HLA antibodies within peripheral blood that may have been adsorbed within the failed allograft, and are not detected, even using sensitive techniques. Prospective studies are warranted to answer these issues.
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15
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Salinas GF, Braza F, Brouard S, Tak PP, Baeten D. The role of B lymphocytes in the progression from autoimmunity to autoimmune disease. Clin Immunol 2012. [PMID: 23202542 DOI: 10.1016/j.clim.2012.10.005] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Autoimmunity, defined as the presence of autoreactive T and/or B lymphocytes in the periphery, is a frequent and probably even physiological condition. It is mainly caused by the fact that the central tolerance mechanisms, which are responsible for counter-selection of autoreactive lymphocytes, are not perfect and thus a limited number of these autoreactive cells can mature and enter the periphery. Nonetheless, autoreactive cells do not lead automatically to autoimmune disease as evidenced by a multitude of experimental and human data sets. Interestingly, the progression from autoimmunity to autoimmune disease is not only determined by the degree of central tolerance leakage and thus the amount of autoreactive lymphocytes in the periphery, but also by peripheral mechanism of activation and control of the autoreactive cells. In this review, we discuss the contribution of peripheral B lymphocytes in this process, ranging from activation of T cells and epitope spreading to control of the autoimmune process by regulatory mechanisms. We also discuss the parallels with the role of B cells in the induction and control of alloimmunity in the context of organ transplantation, as more precise knowledge of the pathogenic antigens and time of initiation of the immune response in allo- versus auto-immunity allows better dissection of the exact role of B cells. Since peripheral mechanisms may be easier to modulate than central tolerance, a more thorough understanding of the role of peripheral B cells in the progression from autoimmunity to autoimmune disease may open new avenues for treatment and prevention of autoimmune disorders.
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Affiliation(s)
- Gabriela Franco Salinas
- Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands
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16
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Porcheray F, DeVito J, Helou Y, Dargon I, Fraser JW, Nobecourt P, Ferdman J, Germana S, Girouard TC, Kawai T, Saidman SL, Wong W, Colvin RB, Leguern C, Zorn E. Expansion of polyreactive B cells cross-reactive to HLA and self in the blood of a patient with kidney graft rejection. Am J Transplant 2012; 12:2088-97. [PMID: 22510337 PMCID: PMC3402627 DOI: 10.1111/j.1600-6143.2012.04053.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Antibody rejection is often accompanied by nondonor HLA specific antibodies (NDSA) and self-reactive antibodies that develop alongside donor-specific antibodies (DSA). To determine the source of these antibodies, we immortalized 107 B-cell clones from a kidney transplant recipient with humoral rejection. Two of these clones reacted to HLA class I or MICA. Both clones were also reactive to self-antigens and a lysate of a kidney cell line, hence revealing a pattern of polyreactivity. Monoclonality was verified by the identification of a single rearranged immunoglobulin heavy chain variable region (VH) sequence for each clone. By tracking their unique CDR3 sequence, we found that one such polyreactive clone was highly expanded in the patient blood, representing ~0.2% of circulating B cells. The VH sequence of this clone showed evidence of somatic mutations that were consistent with its memory phenotype and its expansion. Lastly, the reactivity of the expanded polyreactive B-cell clone was found in the patient serum at time of rejection. In conclusion, we provide here proof of principle at the clonal level that human antibodies can cross-react to HLA and self. Our findings strongly suggest that polyreactive antibodies contribute to DSA, NDSA as well as autoantibodies, in transplant recipients.
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Affiliation(s)
- Fabrice Porcheray
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Julie DeVito
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Ynes Helou
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Ian Dargon
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - James W. Fraser
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Priscilla Nobecourt
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Jack Ferdman
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Sharon Germana
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Timothy C. Girouard
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Tatsuo Kawai
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Susan L. Saidman
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Waichi Wong
- Renal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Christian Leguern
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - Emmanuel Zorn
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston MA
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17
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Kafetzi ML, Iniotaki AG, Liapis GC, N Darema M, Doxiadis IIN, Boletis JN. IgM antibodies towards pre-endothelial cells: strong indication for an association with accelerated rejection. A case report. NDT Plus 2011; 4:416-7. [PMID: 25984211 PMCID: PMC4421673 DOI: 10.1093/ndtplus/sfr147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 09/13/2011] [Indexed: 11/13/2022] Open
Abstract
A 27-year-old woman developed a graft loss due to an accelerated humoral rejection after receiving a blood group identical, human leucocyte antigens (HLA) haploidentical living-related kidney, despite the fact that she did not refer any sensitization event before transplantation. The complement-dependent cytotoxicity and flow cytometry crossmatches were negative for T and B cells. Retrospectively, IgM antibodies against donor precursor endothelial Tie-2(+) cells were detected using a commercially available assay and the pre-transplant serum sample. This case illustrates the necessity of detection of other than the classical HLA-directed antibodies prior organ grafting.
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Affiliation(s)
- Maria L Kafetzi
- Immunology Laboratory and National Tissue Typing Center, General Hospital of Athens "G.Gennimatas", Greece
| | - Aliki G Iniotaki
- Immunology Laboratory and National Tissue Typing Center, General Hospital of Athens "G.Gennimatas", Greece
| | - George C Liapis
- Department of Pathology, Laikon University Hospital of Athens, Greece
| | - Maria N Darema
- Department of Nephrology and Transplantation Centre, Laikon University Hospital of Athens, Greece
| | - Ilias I N Doxiadis
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, the Netherlands
| | - John N Boletis
- Department of Nephrology and Transplantation Centre, Laikon University Hospital of Athens, Greece
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18
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CHIU JENGJIANN, LEE PEILING, USAMI SHUNICHI, CHIEN SHU. DIFFERENTIAL EFFECTS OF SHEAR STRESS ON THE EXPRESSIONS OF ICAM-1 AND VCAM-1 INDUCED BY TNF-α IN ENDOTHELIAL CELLS. J MECH MED BIOL 2011. [DOI: 10.1142/s0219519405001321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Vascular endothelial cells (ECs) are subjected to shear stress and cytokine stimulation. We studied the interplay between shear stress and cytokine in modulating the expression of adhesion molecule genes and the adhesive function of ECs. Shear stress (20 dynes/cm2) was applied to ECs prior to or following the addition of tumor necrosis factor (TNF)-α. Shear stress increased the TNF-α-induced expression of intercellular adhesion molecule-1 (ICAM-1) at both mRNA and surface protein levels, but decreased the TNF-α-induced expression of vascular adhesion molecule-1 (VCAM-1). The TNF-α-induced increase in EC adhesiveness for monocytic THP-1 cells was reduced by shear stress. After 24-h pre-shearing followed by 1 h of static incubation, the effect of pre-shearing on TNF-α-induced ICAM-1 mRNA expression vanished. The recovery of the TNF-α-induced VCAM-1 mRNA expression following pre-shearing, however, required a static incubation time of >6 h (completely recovery at 24 h). Pre- and post-shearing caused a reduction in the nuclear factor (NF)-κB-DNA binding activity induced by TNF-α in the EC nucleus. Our findings suggest that shear stress plays differential roles in modulating the TNF-α-induced EC expressions of ICAM-1 and VCAM-1 genes, which serve similar functions in vascular biology.
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Affiliation(s)
- JENG-JIANN CHIU
- Division of Medical Engineering Research, National Health Research Institutes, Taipei 114, Taiwan, R.O.C
- Institute of Biomedical Engineering, National Yang-Ming University, Taipei 112, Taiwan, R.O.C
| | - PEI-LING LEE
- Division of Medical Engineering Research, National Health Research Institutes, Taipei 114, Taiwan, R.O.C
| | - SHUNICHI USAMI
- Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, CA 92093-0427, USA
| | - SHU CHIEN
- Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, CA 92093-0427, USA
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19
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Non-human leukocyte antigen antibodies reactive with endothelial cells could be involved in early loss of renal allografts. Transplant Proc 2011; 43:1345-8. [PMID: 21620126 DOI: 10.1016/j.transproceed.2011.03.059] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Preformed donor-specific human leukocyte antigen (HLA) antibodies have been associated with allograft dysfunction and failure. However, recipients of HLA-identical kidneys can develop acute humoral rejection, implicating putative pathogenic antibodies that are directed against non-HLA antigens. We investigated the presence of endothelial cell-reactive antibodies in 11 patients who experienced early loss of their transplanted kidneys owing to humoral rejection and 1 loss from renal venal thrombosis. We examined the potential efficacy of intravenous immunoglobulin to block the binding of these antibodies, as previously suggested for anti-HLA antibodies.
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20
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Clinical relevance and IgG subclass determination of non-HLA antibodies identified using endothelial cell precursors isolated from donor blood. Transplantation 2011; 92:54-60. [PMID: 21516064 DOI: 10.1097/tp.0b013e31821b60e9] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND ABO and human leukocyte antigen (HLA) alloantibodies provide major immunologic barriers to successful transplantation; however, there is increasing recognition for the role of anti-endothelial cell antibodies (AECAs) in allograft rejection. We investigated the relationship between AECAs identified using donor-derived endothelial cell precursors (ECPs) and kidney allograft rejection and function. METHODS Sixty live donor kidney recipients were tested pretransplant for AECAs and HLA-antibodies using flow cytometric crossmatch tests and solid-phase bead immunoassays. Renal allograft function was assessed by serum creatinine (SCr) values collected at early (mean, 50 days) and late (mean, 815 days) time points posttransplant and by incidence and type of rejection. Immunoglobulin G (IgG) subtype determination of both AECAs and HLA antibodies bound to ECPs was performed using flow cytometry. RESULTS Fourteen patients (23%) tested positive for donor-reactive IgG AECAs and had statistically higher SCr values and incidences of cellular rejection early posttransplant compared with 46 patients who tested negative (P=0.014 and P<0.05). SCr values were not statistically different late posttransplant. IgG subclass determination showed AECAs to be enriched for IgG2 and IgG4, subclasses that do not activate complement effectively. Detection of donor-reactive immunoglobulin M (IgM) AECAs did not correlate with increased SCr or incidence of rejection. CONCLUSION Crossmatch tests performed using donor-derived ECPs allow for the identification of alloantibodies that are associated with cellular rejection and are distinct from alloantibodies detected using lymphocytes.
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21
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Sener A, Khakhar AK, Nguan CY, House AA, Jevnikar AM, Luke PP. Early but not late allograft nephrectomy reduces allosensitization after transplant failure. Can Urol Assoc J 2011; 5:E142-7. [PMID: 21388588 DOI: 10.5489/cuaj.10032] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Allosensitization is a significant obstacle to retransplantation for patients with primary renal graft failure. METHODS We assessed the impact of allograft nephrectomy (Group I) and weaning of immunosuppression (Group II) on percent panel reactive antibody (%PRA) at various time points after graft failure in 132 patients with a median follow-up of 47 months. Of these, 68% had allograft nephrectomy while 32% were placed on the waiting list and were either taken off immunosuppression, left on prednisone or on low-dose immunosuppressive therapy. RESULTS When groups were stratified into early (<6 months) and late (>6 months) graft failure, patients who had transplant nephrectomy for early failure demonstrated a decline in %PRA from 46% at time of graft failure to 27% at last follow-up (p = 0.02); conversely, %PRA continued to rise in Group II experiencing early allograft failure. Both Groups I and II patients with late graft failure maintained elevated %PRA at last follow-up. CONCLUSION Allograft nephrectomy may play a role in limiting allosensitization in patients with early but not late graft failures.
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Affiliation(s)
- Alp Sener
- Department of Surgery, Division of Urology, Multi-Organ Transplant Program, UBC, Vancouver, BC
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22
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Zhang Q, Reed EF. Non-MHC antigenic targets of the humoral immune response in transplantation. Curr Opin Immunol 2010; 22:682-8. [PMID: 20833523 DOI: 10.1016/j.coi.2010.08.009] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 08/15/2010] [Indexed: 02/07/2023]
Abstract
There is a growing body of data supporting a role for non-HLA antibodies in acute and chronic rejection of solid organ transplants. While many of these non-HLA antigens remain poorly defined, the principal antigenic targets are expressed on cells of the allograft including endothelium and epithelium. These non-HLA antigens are classified as either alloantigens, such as the major histocompatibility complex class I chain-related gene A (MICA) or MICB, or tissue-specific autoantigens such as vimentin, cardiac myosin (CM), collagen V (Col V), agrin, and angiotensin II receptor type I (AT1). Herein we provide an overview of the non-MHC antigenic targets that have been implicated in graft rejection and discuss the interplay between alloimmunity and autoreactivity in graft rejection.
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Affiliation(s)
- Qiuheng Zhang
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
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23
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Chronic humoral rejection of human kidney allografts associates with broad autoantibody responses. Transplantation 2010; 89:1239-46. [PMID: 20445487 DOI: 10.1097/tp.0b013e3181d72091] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Chronic humoral rejection (CHR) is a major complication after kidney transplantation. The cause of CHR is currently unknown. Autoantibodies have often been reported in kidney transplant recipients alongside antidonor human leukocyte antigen antibodies. Yet, the lack of comprehensive studies has limited our understanding of this autoimmune component in the pathophysiology of CHR. METHODS By using a series of ELISA and immunocytochemistry assays, we assessed the development of autoantibodies in 25 kidney transplant recipients with CHR and 25 patients with stable graft function. We also compared the reactivity of five CHR and five non-CHR patient sera with 8027 recombinant human proteins using protein microarrays. RESULTS We observed that a majority of CHR patients, but not non-CHR control patients, had developed antibody responses to one or several autoantigens at the time of rejection. Protein microarray assays revealed a burst of autoimmunity at the time of CHR. Remarkably, microarray analysis showed minimal overlap between profiles, indicating that each CHR patient had developed autoantibodies to a unique set of antigenic targets. CONCLUSION The breadth of autoantibody responses, together with the absence of consensual targets, suggests that these antibody responses result from systemic B-cell deregulation.
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24
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Baldwin WM, Valujskikh A, Fairchild RL. Antibody-mediated rejection: emergence of animal models to answer clinical questions. Am J Transplant 2010; 10:1135-42. [PMID: 20346069 PMCID: PMC2975939 DOI: 10.1111/j.1600-6143.2010.03065.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Decades of experiments in small animals had tipped the balance of opinion away from antibodies as a cause of transplant rejection. However, clinical experience, especially with sensitized patients, has convinced basic immunologists of the need to develop models to investigate mechanisms underlying antibody-mediated rejection (AMR). This resurgent interest has resulted in several new rodent models to investigate antibody-mediated mechanisms of heart and renal allograft injury, but satisfactory models of chronic AMR remain more elusive. Nevertheless, these new studies have begun to reveal many insights into the molecular and pathological sequelae of antibody binding to the allograft endothelium. In addition, complement-independent and complement-dependent effects of antibodies on endothelial cells have been identified in vitro. As small animal models become better defined, it is anticipated that they will be more widely used to answer further questions concerning mechanisms of antibody-mediated tissue injury as well as to design therapeutic interventions.
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Affiliation(s)
- William M Baldwin
- Department of Immunology and the Glickman Urological and Kidney Disease Institute, The Cleveland Clinic, Cleveland, OH, USA.
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25
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Sequential analysis by immunoprecipitation-MALDI-TOF: a novel method for detection and identification of alloantibody specificities. Hum Immunol 2010; 71:462-7. [PMID: 20149830 DOI: 10.1016/j.humimm.2010.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2009] [Revised: 01/21/2010] [Accepted: 02/01/2010] [Indexed: 12/14/2022]
Abstract
Alloantibodies are known to influence transplant outcomes. Apart from human leukocyte antigens (HLA), non-HLA targets have been suggested to play a significant role, but little is known about their nature. Here, we present a novel method for identification and characterization of cell surface antigens bound by alloreactive antibodies. Our method consists of 2 consecutive steps: first, immunoprecipitation of cell surface proteins is carried out with serum and, second, matrix-assisted laser desorption/ionization-time-of-flight is used to fingerprint the precipitated cell-surface proteins. As an example, we performed immunoprecipitation with peripheral blood lymphocytes, which had been incubated with an alloreactive serum; immune complexes were coupled to protein-G beads and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis; differential protein fractions were then analyzed by matrix-assisted laser desorption/ionization-time-of-flight. The method was validated with serum as well as with plasmapheresis material, which contained antibodies of known HLA specificities, demonstrating its applicability for clinical use.
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26
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Abstract
Patients developing posttransplant antibodies against HLA and non-HLA antigens expressed by the endothelium of the graft undergo more frequent episodes of rejection and have decreased long-term graft survival. Antibodies against the endothelium can alter/damage the cells of the graft through several mechanisms. Historically, antibodies were thought to elicit endothelial cell injury via complement-dependent mechanisms. New research has shown that antibodies can also contribute to the process of transplant rejection by stimulating proinflammatory and proproliferation signals. Antibody ligation leads to several functional alterations in EC including Weibel Palade body exocytosis, leukocyte recruitment, growth factor expression and cell proliferation. In contrast, under certain circumstances, antibodies may induce prosurvival signals and graft accommodation. The signaling events regulating accommodation vs. rejection appear to be influenced by the specificity and concentration of the anti-HLA antibody and the degree of molecular aggregation. Knowledge of the HLA and non-HLA antibody-mediated signaling pathways has the potential to identify new therapeutic targets to promote accommodation and prevent acute and chronic antibody-mediated rejection.
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Affiliation(s)
- X. Zhang
- Department of Pathology, UCLA Immunogenetics Center, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - E. F. Reed
- Department of Pathology, UCLA Immunogenetics Center, David Geffen School of Medicine, University of California, Los Angeles, CA
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27
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Han F, Lv R, Jin J, Wu J, Chen Y, Wang H, Chen J. Pre-transplant serum concentrations of anti-endothelial cell antibody in panel reactive antibody negative renal recipients and its impact on acute rejection. Clin Chem Lab Med 2009; 47:1265-9. [DOI: 10.1515/cclm.2009.283] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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28
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Heinemann FM, Roth I, Rebmann V, Arnold ML, Witzke O, Wilde B, Spriewald BM, Grosse-Wilde H. Immunoglobulin isotype-specific characterization of anti-human leukocyte antigen antibodies eluted from explanted renal allografts. Hum Immunol 2007; 68:500-6. [PMID: 17509449 DOI: 10.1016/j.humimm.2007.02.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2006] [Revised: 01/22/2007] [Accepted: 02/21/2007] [Indexed: 10/23/2022]
Abstract
To evaluate the immunoglobulin isotypes of anti-human leukocyte antigen (HLA) antibodies harbored in rejected renal allografts, we isolated proteins by acid elution accumulated in 94 rejected and explanted kidneys and characterized their antibody specificities by complement-dependent cytotoxicity, enzyme-linked immunosorbent assay, and flow cytometry (Luminex) techniques. In addition, we differentially analyzed non-complement-binding immunolglobulin (Ig) G2/4 and IgA1/2 antibodies in the eluates using two modified solid phase assays. We found non-complement-binding IgG2 and IgG4 antibodies in 16/58 (28%) of the IgGall-positive eluates, 15 eluates with anti-HLA class I and 4 with anti-HLA class II specificities, respectively. Anti-HLA class I IgG2/4 antibodies directed against the donor were found in 7 eluates (54% of the IgG2/4-pos. eluates), whereas 2 eluates (50%) had class II IgG2/4 antibodies directed against the donor. IgA1/2 antibodies could be detected in 9 eluates (16%); 5 of them had anti-HLA class I and 5 anti-HLA class II antibodies. We could clearly exhibit that explanted kidney allografts harbor anti-HLA antibodies. Moreover, our study demonstrates that non-complement-binding anti-HLA antibodies accumulate in rejected renal allografts.
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Affiliation(s)
- Falko M Heinemann
- Institut für Immunologie, Universitätsklinikum Essen, Essen, Germany
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29
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Pollinger HS, Stegall MD, Gloor JM, Moore SB, Degoey SR, Ploeger NA, Park WD, Pollinger HS, Stegall MD, Gloor JM, Moore SB, Degoey SR, Ploeger NA, Park WD. Kidney transplantation in patients with antibodies against donor HLA class II. Am J Transplant 2007; 7:857-63. [PMID: 17295642 DOI: 10.1111/j.1600-6143.2006.01699.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The immunologic risk associated with donor-specific antibodies (DSA) against Class II human leukocyte antigens (HLA) in kidney transplant (KTx) recipients is unclear. The aim of this study was to determine the outcome of KTx when DSA was detected only against HLA Class II. To isolate the impact of anti-Class II DSA, we retrospectively analyzed 12 KTx recipients who at baseline had a positive B-cell flow cytometric crossmatch (FXM) and a negative T-cell FXM. Using alloantibody specification analysis, 58.3% (7/12) had DSA against donor Class II and 41.7% had no demonstrable DSA. Biopsy-proven AMR occurred in 57% (4/7) in the Class II(+) group and 0% in the Class II(-) group (p > 0.05). Peritubular capillaries stained positive for C4d in 86% (6/7) of the Class II(+) patients and in 40% (2/5) of the Class II(-) patients (p > 0.05). One patient in the Class II(+) group lost their graft at 3 months to accelerated transplant glomerulopathy, while all other grafts were functioning 3-37 months posttransplant despite the persistence of anti-Class II DSA. We conclude that KTx recipients with clearly defined anti-Class II DSA are at risk for humoral rejection suggesting that desensitization and/or close posttransplant monitoring may be needed to prevent AMR.
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Affiliation(s)
- H S Pollinger
- Division of Transplantation Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA
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30
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Lerut E, Van Damme B, Noizat-Pirenne F, Emonds MP, Rouger P, Vanrenterghem Y, Pirenne J, Ansart-Pirenne H. Duffy and Kidd blood group antigens: minor histocompatibility antigens involved in renal allograft rejection? Transfusion 2007; 47:28-40. [PMID: 17207227 DOI: 10.1111/j.1537-2995.2007.01060.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Minor histocompatibility antigens have been poorly defined. Whether Duffy (FY) and Kidd (JK), polymorphic and immunogenic blood group antigens, widely distributed in human organs, expressed and functional in the kidney, could function as minor histocompatibility antigens and be implicated in renal allograft rejection was questioned. STUDY DESIGN AND METHODS A retrospective, homogeneous, single-center cohort of 370 renal transplants was analyzed. In all donor/recipient pairs, FY and JK polymorphisms were identified by real-time polymerase chain reaction. In all donor/recipient pairs the matching (m) or mismatching (mm) status was defined for both systems. All biopsies were reviewed, and historical screening results for FY and JK alloantibodies and graft survival were retrospectively analyzed. RESULTS Although graft survival was not different between the groups, it was observed that FY mm grafts had significantly more chronic lesions compared to FY m grafts. HLA-DR11 was more frequent in both recipients (p = 0.0081) and donors (p = 0.0104) of FY mm couples without chronic allograft nephropathy, suggesting a protective effect for this molecule. JK mm grafts had more interstitial inflammation than JK m grafts (p = 0.0369). CONCLUSION This renal model unmasks for the first time the role of FY and-to a lesser extent-JK antigens as minor histocompatibility antigens and suggests their potential role for other clinical transplant settings.
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Affiliation(s)
- Evelyne Lerut
- Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
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Fahim T, Böhmig GA, Exner M, Huttary N, Kerschner H, Kandutsch S, Kerjaschki D, Bramböck A, Nagy-Bojarszky K, Regele H. The cellular lesion of humoral rejection: predominant recruitment of monocytes to peritubular and glomerular capillaries. Am J Transplant 2007; 7:385-93. [PMID: 17283488 DOI: 10.1111/j.1600-6143.2006.01634.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Accumulation of inflammatory cells within capillaries is a common morphologic feature of humoral renal allograft rejection and is most easily appreciated if it occurs in glomeruli. The aim of our study was to determine the amount and composition of immune cells within glomeruli and peritubular capillaries (PTC) in cellular and humoral allograft rejection. Immunofluorescent double-labeling for CD31 and CD3 or CD68 was used for phenotyping and enumerating immune cells within glomeruli and PTC. The major findings are: (1) accumulation of immune cells in PTC is far more common than it would be anticipated based on the assessment by conventional histology; (2) it is not the absolute number of immune cells accumulating within capillaries, but rather the composition of the intracapillary cell population that distinguishes humoral rejection from cellular rejection and (3) in C4d positive biopsies a predominantly monocytic cell population accumulates not only within glomeruli but also within PTC. The median value of monocyte/T-cell ratio within PTC was 2.3 in C4d positive biopsies but only 1 (p = 0.0008) in C4d negative biopsies. Given their prominent presence within capillaries and their extensive biological versatility monocytes might contribute to the capillary damage observed in acute and chronic allograft rejection.
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Affiliation(s)
- T Fahim
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
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Glotz D, Lucchiari N, Pegaz-Fiornet B, Suberbielle-Boissel C. Endothelial cells as targets of allograft rejection. Transplantation 2006; 82:S19-21. [PMID: 16829788 DOI: 10.1097/01.tp.0000231348.55262.5a] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Endothelial cells harbor many antigenic determinants that may be targets for antibodies and, as such, induce acute or chronic antibody-mediated rejections. In certain cases of organ transplantation, antibodies reacting with endothelial cells, but not with ABO or human leukocyte antigens, can be observed and these are probably responsible for the rejection of the graft. The antigenic targets, however, are still poorly defined and the mechanisms of action of such antibodies would appear to be diverse, leading to the lack of a relevant in vitro assay for the detection of those antibodies. Increasing data suggest that, apart from direct alloimmune responses, autoimmune mechanisms might be triggered by alloreactivity and also play a significant role in the pathogenesis of the vascular lesions, the so-called chronic rejection, observed in organ allografts.
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Affiliation(s)
- Denis Glotz
- Department of Nephrology and Transplantation, Hôpital Saint-Louis, Paris, France.
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33
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Lair D, Coupel S, Giral M, Hourmant M, Karam G, Usal C, Bignon JD, Brouard S, Soulillou JP. The effect of a first kidney transplant on a subsequent transplant outcome: An experimental and clinical study. Kidney Int 2005; 67:2368-75. [PMID: 15882281 DOI: 10.1111/j.1523-1755.2005.00343.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Second kidney transplantations have a roughly similar clinical outcome to first transplantations. Nevertheless, the effect of the presence of the first, nonfunctional transplant at the time of the second transplantation may also influence its outcome and has not yet been specifically studied. METHODS We analyzed the effect of the presence of a first graft on the outcome of a second graft in a rodent allograft model and in a cohort of 240 human second kidney allograft recipients. RESULTS In rodents, 100 days subsequent to the rejection of the first graft, we observed an increase in blood but not spleen CD4(+)CD25(+) T cells, whereas no differences were observed in transcriptional patterns. Adoptive transfer of day 100 splenocytes did not prolong graft survival. Moreover, the presence of a first rejected graft does not prolong the survival of a second graft performed at a later date. In the human context, a higher incidence of patients with anti-HLA immunization and a higher % of PRA were observed in retransplant recipients with primary allograft nephrectomy. Despite a relatively low statistical power, our data do not suggest significant differences in graft outcome between recipients of second transplants with primary allograft nephrectomy and those without. CONCLUSION Collectively, the data from both an experimental model and a large cohort of human recipients of a second graft do not suggest a beneficial effect of the presence of a first rejected graft at the time of a second transplantation.
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Affiliation(s)
- David Lair
- Institut National de la Santé Et de la Recherche Médicale-Unité 643: "Immunointervention dans les Allo et Xenotransplantations" and Institut de Transplantation Et de Recherche en Transplantation, CHU-Hotel Dieu, Nantes Cedex, France
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Rifle G, Mousson C, Martin L, Guignier F, Hajji K. Donor-Specific Antibodies in Allograft Rejection: Clinical and Experimental Data. Transplantation 2005; 79:S14-8. [PMID: 15699738 DOI: 10.1097/01.tp.0000153292.49621.60] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The ability of donor-specific major histocompatibility complex alloantibodies to destroy a transplanted organ within minutes, the so-called hyperacute rejection phenomenon, has been known for a long time. It is a clear demonstration of the possible cytotoxic effect of antibodies. Apart from this particular situation, the role of antibodies in inducing acute or chronic allograft rejection remains controversial. Many clinical data have shown that transplant recipients capable of developing class I or class II anti-HLA antibodies experienced shorter survival periods than those who were not. This fact, in accordance with experimental data, only demonstrates that high antibody responders reject a transplant more easily than low responders. More interestingly, there is now increasing evidence that posttransplant appearance of donor-specific alloantibodies, and probably of alloreactive-induced autoantibodies, is strongly correlated with reduced graft survival rate, especially from chronic rejection. We demonstrated that donor-specific HLA antibodies can be found in more than 70% of transplanted kidneys with chronic allograft nephropathy, and that the intragraft presence of such antibodies is significantly correlated with high numbers of plasma cells on early biopsies and C4d deposits, a recognized marker of humoral rejection. It is likely that non-HLA antibodies also play a deleterious role in organ transplant outcome, particularly the heterogeneous group of anti-endothelial cells antibodies, anti-MIC antibodies, autoantibodies and some others with no recognized target. Convincing experimental data, especially using B cell and T cell deficient mice, strongly suggest that B cells and donor-specific antibodies are required for fully developed chronic allograft rejection. The role of antibodies in inducing the cascade of cytokines and growth factors leading to tissue lesions is of increasing interest since it is now possible to control B cell proliferation and antibody production.
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Affiliation(s)
- Gérard Rifle
- UPRES EA563, Faculty of Medicine, Dijon, France.
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35
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Vongwiwatana A, Tasanarong A, Hidalgo LG, Halloran PF. The role of B cells and alloantibody in the host response to human organ allografts. Immunol Rev 2003; 196:197-218. [PMID: 14617206 DOI: 10.1046/j.1600-065x.2003.00093.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Some human organ transplants deteriorate slowly over a period of years, often developing characteristic syndromes: transplant glomerulopathy (TG) in kidneys, bronchiolitis obliterans in lungs, and coronary artery disease in hearts. In the past, we attributed late graft deterioration to "chronic rejection", a distinct but mysterious immunologic process different from conventional rejection. However, it is likely that much of chronic rejection is explained by conventional T-cell-mediated rejection (TMR), antibody-mediated rejection (AMR), and other insults. Recently, criteria have emerged to now permit us to diagnose AMR in kidney transplants, particularly C4d deposition in peritubular capillaries and circulating antibody against donor human leukocyte antigens (HLA). Some cases with AMR develop TG, although the relationship of TG to AMR is complex. Thus, a specific diagnosis of AMR in kidney can now be made, based on graft damage, C4d deposition, and donor-specific alloantibodies. Criteria for AMR in other organs must be defined. Not all late rejections are AMR; some deteriorating organs probably have smoldering TMR. The diagnosis of late ongoing AMR raises the possibility of treatment to suppress the alloantibody, but efficacy of the available treatments requires further study.
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Affiliation(s)
- Attapong Vongwiwatana
- Department of Medicine, Division of Nephrology & Transplantation Immunology, University of Alberta, 250 Heritage Medical Research Center, Edmonton, Alberta, Canada T6G 2S2
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36
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Magro CM, Klinger DM, Adams PW, Orosz CG, Pope-Harman AL, Waldman WJ, Knight D, Ross P. Evidence that humoral allograft rejection in lung transplant patients is not histocompatibility antigen-related. Am J Transplant 2003; 3:1264-72. [PMID: 14510700 DOI: 10.1046/j.1600-6143.2003.00229.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We have recently recognized humoral rejection (HR) in lung allograft recipients and its association with acute and chronic graft dysfunction. We have shown that C4d, a stable marker of classic complement activation, is deposited in lung allografts, correlating with clinical rejection and parenchymal injury. The antigenic target may be endothelium in the setting of recurrent acute rejection while varying components of the bronchial wall may be important in chronic graft dysfunction. We sought to establish whether there is a role for antibodies with histocompatibility antigen specificity in the lung humoral allograft phenomenon. Flow cytometric and ELISA assays to assess donor-specific antigens were conducted on sera from 25 lung transplant recipients who had experienced one or more episodes of clinical rejection; in addition, the serum samples were tested for evidence of antiendothelial cell antibody activity. Morphologically, each case had biopsies showing septal capillary injury with significant deposits of immunoreactants with microvascular localization and positive indirect immunofluorescent antiendothelial cell antibody assay. Panel-reactive antibody testing showed absence of MHC Class I/II alloantibodies; ELISA based crossmatch detecting donor-specific MHC Class I/II specific antibodies was negative. HR can occur in the absence of antibodies with HLA specificity; antigenic targets may be of endothelial cell origin.
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Affiliation(s)
- Cynthia M Magro
- Department of Pathology, The Ohio State University, Columbus, OH, USA
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Groth J, Kaden J, May G, Schönemann C. The dynamics of antidonor antibody formation early after clinical kidney transplantation measured by flow cytometry and microcytotoxicity test. Clin Transplant 2003; 17:259-67. [PMID: 12780678 DOI: 10.1034/j.1399-0012.2003.00046.x] [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: 11/23/2022]
Abstract
To study the dynamics of antidonor sensitization 92 patients were monitored for antibodies against donor T and B spleen lymphocytes before transplantation, within the first month after transplantation and 3 months after transplantation. Patients were monitored for donorreactive antibodies (DRA) of immunoglobulin G (IgG), IgA, and IgM isotype using flow cytometry (FC) and the standard microcytotoxicity test (CYT). Graft function was followed for at least 2 yrs, 51% of patients for 3 yrs after transplantation. Within the first month after transplantation the percentage of patients with antidonor sensitization detected by FC rose dramatically, so that the overall sensitization rate increased from 28 (30.4%) of 92 patients prior to transplantation to 63 (68.5%) of 92 patients after transplantation. Whereas preoperatively only one isotype (IgM for T lymphocytes, IgG for B lymphocytes) and only one target cell type (either T or B lymphocytes) dominated, the postoperative patterns of positive FC results were more variable regarding target and isotype, whereby FC-DRA of the IgA class substantially contributed. Appearance of donor-directed antibodies early after kidney transplantation is a frequent event. In our cases, sensitization with FC-DRA per se seemed not to be detrimental to the graft outcome (p > 0.05) but CYT-DRA did resulting in a significant poor graft outcome 3 months after transplantation (p < 0.001).
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Affiliation(s)
- Jürgen Groth
- Department of Laboratory Medicine, Friedrichshain Hospital, Berlin, Germany
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38
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Chiu JJ, Chen LJ, Lee PL, Lee CI, Lo LW, Usami S, Chien S. Shear stress inhibits adhesion molecule expression in vascular endothelial cells induced by coculture with smooth muscle cells. Blood 2003; 101:2667-74. [PMID: 12468429 DOI: 10.1182/blood-2002-08-2560] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Vascular endothelial cells (ECs), which exist in close proximity to vascular smooth muscle cells (SMCs), are constantly subjected to blood flow-induced shear stress. Although the effect of shear stress on endothelial biology has been extensively studied, the influence of SMCs on endothelial response to shear stress remains largely unexplored. We examined the potential role of SMCs in regulating the shear stress-induced gene expression in ECs, using a parallel-plate coculture flow system in which these 2 types of cells were separated by a porous membrane. In this coculture system, SMCs tended to orient perpendicularly to the flow direction, whereas the ECs were elongated and aligned with the flow direction. Under static conditions, coculture with SMCs induced EC gene expression of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin, while attenuating EC gene expression of endothelial nitric oxide synthase (eNOS). Shear stress significantly inhibited SMC-induced adhesion molecule gene expression. These EC responses under static and shear conditions were not observed in the absence of close communication between ECs and SMCs, and they were also not observed when ECs were cocultured with fibroblasts instead of SMCs. Our findings indicate that under static conditions, coculture with SMCs induces ICAM-1, VCAM-1, and E-selectin gene expression in ECs. These coculture effects are inhibited by shear stress and require specific interaction between ECs and SMCs in close contact.
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Affiliation(s)
- Jeng-Jiann Chiu
- Division of Medical Engineering Research, National Health Research Institutes, Taipei, Taiwan, Republic of China.
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Karpinski M, Rush D, Jeffery J, Exner M, Regele H, Dancea S, Pochinco D, Birk P, Nickerson P. Flow cytometric crossmatching in primary renal transplant recipients with a negative anti-human globulin enhanced cytotoxicity crossmatch. J Am Soc Nephrol 2001; 12:2807-2814. [PMID: 11729251 DOI: 10.1681/asn.v12122807] [Citation(s) in RCA: 160] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Flow cytometric crossmatching (FCXM) and panel reactive antibody (PRA) screening techniques are more sensitive than anti-human globulin enhanced cytotoxicity (AHG-CDC) techniques at detecting anti-HLA antibodies. The clinical significance of a positive FCXM in primary renal transplant recipients with a negative AHG-CDC crossmatch is unclear. We performed retrospective FCXM and flow cytometric panel reactive antibody (FlowPRA) determinations in primary renal transplant recipients with a negative T cell AHG-CDC crossmatch and a negative B cell CDC crossmatch pretransplant. Eighteen (13%) of 143 patients exhibited a positive retrospective T cell FCXM. Of these patients, six (33%) experienced early graft loss with explant histology, demonstrating antibody-mediated rejection in five of six cases. The 12 patients with positive T cell FCXM who maintained their grafts experienced more adverse events posttransplant, including more early, steroid-resistant, and recurrent rejection. Furthermore, in a subgroup of patients undergoing protocol biopsies, those with a positive T cell FCXM exhibited more subclinical rejection. Anti-HLA antibodies were detected by FlowPRA in all 18 patients with a positive T cell FCXM, whereas AHG-CDC PRA detected antibodies in only 8 of 18 patients. Therefore, flow cytometric techniques identify sensitized primary renal transplant recipients undetected by AHG-CDC techniques. In those patients, a positive T cell FCXM is associated with an increased risk of early graft loss due to antibody-mediated rejection and may represent a relative contraindication to transplantation. Moreover, those patients are also at increased risk of severe and recurrent rejection, which may carry implications for long-term graft outcomes.
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Affiliation(s)
- Martin Karpinski
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - David Rush
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - John Jeffery
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - Markus Exner
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - Heinz Regele
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - Silvia Dancea
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - Denise Pochinco
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - Patricia Birk
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
| | - Peter Nickerson
- Departments of *Medicine, Pathology, and Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Laboratory Medicine and Clinical Pathology, University of Vienna, Austria
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Pontes LF, Carvalho L, Stumbo AC, Porto LC. Detection and localization of non-HLA-ABC antigenic sites relevant to kidney rejection on endothelial cells. J Immunol Methods 2001; 251:73-80. [PMID: 11292483 DOI: 10.1016/s0022-1759(01)00309-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Immunological rejection of kidney allografts is usually attributed to presensitization to HLA antigens. However, data on HLA identical transplant rejections indicate that non-HLA antigens may also be involved, and it has been suggested that vascular endothelium represents the main target cell. The purpose of the present study is to describe a method of detecting non-HLA antibodies immunocytochemically. We showed the molecular independence between HLA-ABC molecules identified by the monoclonal antibody w6/32, and antigenic sites identified by a kidney rejection patient serum, previously characterized, on cultured endothelial cells isolated from human umbilical cords by collagenase digestion. Single immunofluorescence staining indicated the molecular independence between these antigenic sites, as the first serum showed a granular pattern, diffused throughout the cytoplasm and the other a reticular pattern restricted to the same cytoplasmic region. This result was confirmed by double labeling. Immunoelectronmicroscopy study also confirmed site independence, showing labeling patterns with different intensities and distinct localizations, using 10- and 20-nm colloidal gold particles to reveal HLA-ABC and non-HLA-ABC determinants, respectively. In conclusion, cultured endothelial cells may be used immunocytochemically to detect non-HLA-ABC determinants of antibody reactivity in renal graft recipients, and the indirect immunofluorescence may be the methodology of choice, since it is easy, reliable and low cost.
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Affiliation(s)
- L F Pontes
- Histocompatibility Laboratory and Cell Culture Laboratory, State University of Rio de Janeiro, Rua Prof. Manuel de Abreu 444, Rio de Janeiro, Brazil
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Crespo M, Pascual M, Tolkoff-Rubin N, Mauiyyedi S, Collins AB, Fitzpatrick D, Farrell ML, Williams WW, Delmonico FL, Cosimi AB, Colvin RB, Saidman SL. Acute humoral rejection in renal allograft recipients: I. Incidence, serology and clinical characteristics. Transplantation 2001; 71:652-8. [PMID: 11292296 DOI: 10.1097/00007890-200103150-00013] [Citation(s) in RCA: 259] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Acute rejection (AR) associated with de novo production of donor-specific antibodies (DSA) is a clinicopathological entity that carries a poor prognosis (acute humoral rejection, AHR). The aim of this study was to determine the incidence and clinical characteristics of AHR in renal allograft recipients, and to further analyze the antibodies involved. METHODS During a 4-year period, 232 renal transplants (Tx) were performed at our institution. Assays for DSA included T and B cell cytotoxic and/or flow cytometric cross-matches and cytotoxic antibody screens (PRA). C4d complement staining was performed on frozen biopsy tissue. RESULTS A total of 81 patients (35%) suffered at least one episode of AR within the first 3 months: 51 had steroid-insensitive AR whereas the remaining 30 had steroid-sensitive AR. No DSA were found in patients with steroid-sensitive AR. In contrast, circulating DSA were found in 19/51 patients (37%) with steroid-insensitive AR, and widespread C4d deposits in peritubular capillaries were present in 18 of these 19 (95%). In at least three cases, antibodies were against donor HLA class II antigens. DSA were not found in the remaining 32 patients but C4d staining was positive in 2 of 32. The DSA/C4d positive (n=18) and DSA/C4d negative (n=30) groups differed in pre-Tx PRA levels, percentage of re-Tx patients, refractoriness to antilymphocyte therapy, and outcome. Plasmapheresis and tacrolimus-mycophenolate mofetil rescue reversed rejection in 9 of 10 recipients with refractory AHR. CONCLUSION More than one-third of the patients with steroid-insensitive AR had evidence of AHR, often resistant to antilymphocyte therapy. Most cases (95%) with DSA at the time of rejection had widespread C4d deposits in peritubular capillaries, suggesting a pathogenic role of the circulating alloantibody. Combined DSA testing and C4d staining provides a useful approach for the early diagnosis of AHR, a condition that often necessitates a more intensive therapeutic rescue regimen.
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Affiliation(s)
- M Crespo
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA
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