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Nair S, Ravichandran R, Heilman R, Jaramillo A, Buras M, Kaplan B, Itabashi Y, Ramon D, Hacke K, Smith B, Mohanakumar T. Study of association between antibodies to non-HLA kidney self-antigens and progression to chronic immune injury after kidney transplantation. Hum Immunol 2023; 84:509-514. [PMID: 37507262 DOI: 10.1016/j.humimm.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 07/02/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023]
Abstract
BACKGROUND Immune response to several kidney self-antigens (KSAg) such as Collagen IV (Col-IV), Perlecan (PL), and Fibronectin (FN) have been associated with antibody-mediated damage and poor allograft survival. Thus, the aim of this study was to determine if humoral immune responses to KSAg correlates with progression of chronic immune injury (CII) changes at 1 year or 2 years. METHODS Kidney transplant recipients who underwent 1- or 2-year biopsies, with chronic interstitial inflammation (ci > 1) and/or glomerular membrane double contouring (cg > 0) were analyzed with matched controls. Sera were analyzed retrospectively for antibodies against KSAg using ELISA. The presence of antibodies to KSAg were compared at 0, 4, 12, and 24 months using logistic regression. RESULTS We identified a cohort of 214 kidney transplant recipients. Of these, we identified 33 cases and matched 66 controls. Logistical regression showed an odds ratio of 1 with the confidence interval crossing 1 for the presence of response to KSAg at all the time points. CONCLUSIONS Humoral immune responses to either KSAg alone or in combination with donor-specific anti-HLA antibodies are not associated with progression to CII at 1 and 2 years after kidney transplantation.
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Affiliation(s)
- Sumi Nair
- Department of Medicine, Mayo Clinic, Phoenix, AZ, United States.
| | | | - Raymond Heilman
- Department of Medicine, Mayo Clinic, Phoenix, AZ, United States
| | - Andrés Jaramillo
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ, United States
| | - Matthew Buras
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, United States
| | - Bruce Kaplan
- University of Colorado, Aurora, CO, United States
| | - Yoshihiro Itabashi
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Daniel Ramon
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Katrin Hacke
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ, United States
| | - Byron Smith
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
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See SB, Yang X, Burger C, Lamarthée B, Snanoudj R, Shihab R, Tsapepas DS, Roy P, Larivière-Beaudoin S, Hamelin K, Rojas AM, van Besouw NM, Bartosic A, Daniel N, Vasilescu ER, Mohan S, Cohen D, Ratner L, Baan CC, Bromberg JS, Cardinal H, Anglicheau D, Sun Y, Zorn E. Natural Antibodies Are Associated With Rejection and Long-term Renal Allograft Loss in a Multicenter International Cohort. Transplantation 2023; 107:1580-1592. [PMID: 36728359 PMCID: PMC10290575 DOI: 10.1097/tp.0000000000004472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells. METHODS In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes. RESULTS Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.71; 95% confidence interval [CI], 1.15-6.39; P = 0.0232), the composite endpoint of graft loss or severe graft dysfunction (HR 2.40; 95% CI, 1.13-5.10; P = 0.0232), and T cell-mediated rejection (odds ratio [OR] 1.77; 95% CI, 1.07-3.02; P = 0.0310). High pretransplant Nabs together with donor-specific antibodies (DSAs) were associated with increased risk of composite outcomes (HR 6.31; 95% CI, 1.81-22.0; P = 0.0039). In patients with high pretransplant Nabs, the subsequent development of posttransplant Nabs was associated with both T cell-mediated rejection (OR 3.64; 95% CI, 1.61-8.36; P = 0.0021) and mixed rejection (OR 3.10; 95% CI, 1.02-9.75; P = 0.0473). Finally, elevated pre- and posttransplant Nabs combined with DSAs were associated with increased risk of composite outcomes (HR 3.97; 95% CI, 1.51-10.43; P = 0.0052) and T cell-mediated rejection (OR 7.28; 95% CI, 2.16-25.96; P = 0.0016). CONCLUSIONS The presence of pre- and posttransplant Nabs, together with DSAs, was associated with increased risk of poor graft outcomes and rejection after renal transplantation.
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Affiliation(s)
- Sarah B. See
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, USA
| | - Xue Yang
- Department of Biostatistics, Columbia University Irving Medical Center, New York, USA
| | - Carole Burger
- Department of Kidney Transplantation, Hôpital Universitaire Necker-Assistance Publique Hopitaux de Paris, France
| | - Baptiste Lamarthée
- Necker-Enfants Malades Institute, Inserm U1151, Université de Paris, Paris, France
| | - Renaud Snanoudj
- Department of Kidney Transplantation, Hôpital Kremlin Bicêtre, Paris, France
| | - Ronzon Shihab
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, USA
| | - Demetra S. Tsapepas
- Department of Surgery, Columbia University Vagelos College of Physicians & Surgeons, New York, USA
| | - Poulomi Roy
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, USA
| | - Stéphanie Larivière-Beaudoin
- Research Center, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
- Canadian Donation and Transplantation Research Program, Edmonton, Canada
| | - Katia Hamelin
- Research Center, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
| | - Aleixandra Mendoza Rojas
- Department of Internal Medicine – Nephrology and Transplantation, Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Nicole M. van Besouw
- Department of Internal Medicine – Nephrology and Transplantation, Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Amanda Bartosic
- Department of Surgery, University of Maryland School of Medicine, Baltimore, USA
| | - Nikita Daniel
- Department of Surgery, University of Maryland School of Medicine, Baltimore, USA
| | - E. Rodica Vasilescu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, USA
| | - Sumit Mohan
- Department of Medicine, Division of Nephrology, Columbia University College of Physicians & Surgeons, New York, USA
- Department of Epidemiology, Columbia University Mailman School of Public Health, New York, USA
| | - David Cohen
- Department of Medicine, Division of Nephrology, Columbia University College of Physicians & Surgeons, New York, USA
| | - Lloyd Ratner
- Department of Medicine, Division of Nephrology, Columbia University College of Physicians & Surgeons, New York, USA
| | - Carla C. Baan
- Department of Internal Medicine – Nephrology and Transplantation, Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Jonathan S. Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, USA
| | - Héloïse Cardinal
- Research Center, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
- Canadian Donation and Transplantation Research Program, Edmonton, Canada
| | - Dany Anglicheau
- Department of Kidney Transplantation, Hôpital Universitaire Necker-Assistance Publique Hopitaux de Paris, France
| | - Yifei Sun
- Department of Biostatistics, Columbia University Irving Medical Center, New York, USA
| | - Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, USA
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Mashiko S, Shihab RR, See SB, Schahadat LGZ, Aguiar TFM, Roy P, Porcheray F, Zorn E. Broad responses to chemical adducts shape the natural antibody repertoire in early infancy. SCIENCE ADVANCES 2023; 9:eade8872. [PMID: 37172087 PMCID: PMC10181178 DOI: 10.1126/sciadv.ade8872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Natural antibodies are an integral part of innate humoral immunity yet their development and polyreactive nature are still enigmatic. Here, we show that characteristic monoclonal natural antibodies recognize common chemical moieties or adducts, supporting the view that polyreactive antibodies may often correspond to anti-adduct antibodies. We next examined the development of immunoglobulin M (IgM) and IgG to 81 ubiquitous adducts from birth to old age. Newborn IgM only reacted to a limited number of consensus determinants. This highly restricted neonatal repertoire abruptly diversified around 6 months of age through the development of antibodies to environmental antigens and age-driven epigenetic modifications. In contrast, the IgG repertoire was diverse across the entire life span. Our studies reveal an unrecognized component of humoral immunity directed to common adducts. These findings set the ground for further investigations into the role of anti-adduct B cell responses in homeostatic functions and pathological conditions.
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Affiliation(s)
- Shunya Mashiko
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Ronzon R Shihab
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Sarah B See
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Luca G Z Schahadat
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Talita F M Aguiar
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Poulomi Roy
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Fabrice Porcheray
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
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Crane C, Loop L, Anterasian C, Geng B, Ingulli E. Balancing B cell responses to the allograft: implications for vaccination. Front Immunol 2022; 13:948379. [PMID: 35967363 PMCID: PMC9363634 DOI: 10.3389/fimmu.2022.948379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Balancing enough immunosuppression to prevent allograft rejection and yet maintaining an intact immune system to respond to vaccinations, eliminate invading pathogens or cancer cells is an ongoing challenge to transplant physicians. Antibody mediated allograft rejection remains problematic in kidney transplantation and is the most common cause of graft loss despite current immunosuppressive therapies. The goal of immunosuppressive therapies is to prevent graft rejection; however, they prevent optimal vaccine responses as well. At the center of acute and chronic antibody mediated rejection and vaccine responses is the B lymphocyte. This review will highlight the role of B cells in alloimmune responses including the dependency on T cells for antibody production. We will discuss the need to improve vaccination rates in transplant recipients and present data on B cell populations and SARS-CoV-2 vaccine response rates in pediatric kidney transplant recipients.
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Affiliation(s)
- Clarkson Crane
- Department of Pediatrics, Division of Pediatric Nephrology, University of California at San Diego and Rady Children’s Hospital, San Diego, CA, United States
| | - Lauren Loop
- Department of Pediatrics, Division of Allergy and Immunology, University of California at San Diego and Rady Children’s Hospital, San Diego, CA, United States
| | - Christine Anterasian
- Department of Pediatrics, Division of Allergy and Immunology, University of California at San Diego and Rady Children’s Hospital, San Diego, CA, United States
- Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Washington and Seattle Children's Hospital, Seattle, WA, United States
| | - Bob Geng
- Department of Pediatrics, Division of Allergy and Immunology, University of California at San Diego and Rady Children’s Hospital, San Diego, CA, United States
| | - Elizabeth Ingulli
- Department of Pediatrics, Division of Pediatric Nephrology, University of California at San Diego and Rady Children’s Hospital, San Diego, CA, United States
- *Correspondence: Elizabeth Ingulli,
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Nowańska K, Wiśnicki K, Kuriata-Kordek M, Krajewska M, Banasik M. The role of endothelin II type A receptor (ETAR) in transplant injury. Transpl Immunol 2021; 70:101505. [PMID: 34793957 DOI: 10.1016/j.trim.2021.101505] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Antibody-mediated rejection is the leading cause of deterioration of graft function and graft loss after kidney transplantation. Recent studies have reported an increasing role of non-HLA antibodies in the humoral injury after kidney transplantation. We decided to present the influence of non-HLA antibodies - anti-endothelin II type A receptor (ETAR) on a transplanted kidney and characterize the significance of their receptor. RECENT FINDINGS The role of non-HLA antibodies is still uncertain. Many studies suggest that the presence of non-HLA antibodies, including anti-ETAR antibodies, is among the risk factors for antibody-mediated rejection, graft injury, and graft loss. The discovery of new antigen targets and antibodies, which participate in the humoral response, has provided a significantly better understanding of the mechanism of antibody-mediated rejection after organ transplantation. SUMMARY Endothelin and its receptors play an important role in physiology and pathophysiology after solid organ transplantation. ETAR and antibodies against ETAR may participate in humoral rejection and graft damage. The measurement of anti-ETAR antibodies may identify patients with an increased risk of rejection and even loss of a transplanted organ. Expression of ETAR detected in biopsy of transplant could become an additional tool used to better understand humoral activity. More research is needed to address many questions about non-HLA directed rejection and graft damage.
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Affiliation(s)
- Katarzyna Nowańska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Krzysztof Wiśnicki
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Magdalena Kuriata-Kordek
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław, Poland.
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Increased Autoantibodies Against Ro/SS-A, CENP-B, and La/SS-B in Patients With Kidney Allograft Antibody-mediated Rejection. Transplant Direct 2021; 7:e768. [PMID: 34557585 PMCID: PMC8454907 DOI: 10.1097/txd.0000000000001215] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 07/02/2021] [Indexed: 01/20/2023] Open
Abstract
Supplemental Digital Content is available in the text. Antibody-mediated rejection (AMR) causes more than 50% of late kidney graft losses. In addition to anti-human leukocyte antigen (HLA) donor-specific antibodies, antibodies against non-HLA antigens are also linked to AMR. Identifying key non-HLA antibodies will improve our understanding of AMR.
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Parlakpinar H, Gunata M. Transplantation and immunosuppression: a review of novel transplant-related immunosuppressant drugs. Immunopharmacol Immunotoxicol 2021; 43:651-665. [PMID: 34415233 DOI: 10.1080/08923973.2021.1966033] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Immunosuppressive drugs used in the transplantation period are generally defined as induction and maintenance therapy. The use of immunosuppressants, which are particularly useful and have fewer side effects, decreased both mortality and morbidity. Many drugs such as steroids, calcineurin inhibitors (cyclosporine-A, tacrolimus), antimetabolites (mycophenolate mofetil, azathioprine), and mTOR inhibitors (sirolimus, everolimus) are used as immunosuppressive agents. Although immunosuppressant drugs cause many side effects such as hypertension, infection, and hyperlipidemia, they are the agents that should be used to prevent organ rejection. This shows the importance of individualized drug use. The optimal immunosuppressive therapy post-transplant is not established. Therefore, discovering less toxic but more potent new agents is of great importance, and new experimental and clinical studies are needed in this regard.Our review discussed the mechanism of immunosuppressants, new agents' discovery, and current therapeutic protocols in the transplantation.
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Affiliation(s)
- Hakan Parlakpinar
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Mehmet Gunata
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
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Crespo M, Llinàs-Mallol L, Redondo-Pachón D, Butler C, Gimeno J, Pérez-Sáez MJ, Burballa C, Buxeda A, Arias-Cabrales C, Folgueiras M, Sanz-Ureña S, Valenzuela NM, Reed EF, Pascual J. Non-HLA Antibodies and Epitope Mismatches in Kidney Transplant Recipients With Histological Antibody-Mediated Rejection. Front Immunol 2021; 12:703457. [PMID: 34305943 PMCID: PMC8300190 DOI: 10.3389/fimmu.2021.703457] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/15/2021] [Indexed: 01/03/2023] Open
Abstract
Background Correlation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved. Methods We retrospectively assessed patients with transplant biopsies scored following Banff'15 classification. Pre- and post-transplant serum samples were checked for HLA and non-HLA antibodies [MICA-Ab, angiotensin-II type-1-receptor (AT1R)-Ab, endothelin-1 type-A-receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)]. We also analyzed HLA epitope mismatches (HLA-EM) between donors and recipients to explore their role in ABMR histology (ABMRh) with and without HLA-DSA. Results One-hundred eighteen patients with normal histology (n = 19), ABMRh (n = 52) or IFTA (n = 47) were studied. ABMRh patients were HLA-DSApos (n = 38, 73%) or HLA-DSAneg (n = 14, 27%). Pre-transplant HLA-DSA and AT1R-Ab were more frequent in ABMRh compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMRhDSAneg cases showed non-HLA antibodies. ABMRhDSAneg and ABMRhDSApos cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMRhDSApos but not with ABMRhDSAneg. Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31-10.37], p = 0.013) and AT1R-Ab (OR: 5.47 [1.78-16.76], p = 0.003) were independent predictors of ABMRhDSApos. Conclusions In conclusion, pre-transplant AT1R-Ab is frequently found in ABMRhDSApos patients. However, AT1R-Ab, MICA-Ab, ETAR-Ab or EC-XM+ are rarely found among ABMRhDSAneg patients. Pre-transplant AT1R-Ab may act synergistically with preformed or de novo HLA-DSA to produce ABMRhDSApos but not ABMRhDSAneg. HLA epitope mismatch associates with ABMRhDSApos compared with ABMRhDSAneg, suggesting factors other than HLA are responsible for the damage.
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Affiliation(s)
- Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Laura Llinàs-Mallol
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Dolores Redondo-Pachón
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Carrie Butler
- UCLA Immunogenetics Center, University of California Los Angeles, Los Angeles, CA, United States
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - Javier Gimeno
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
- Department of Pathology, Hospital del Mar, Barcelona, Spain
| | - María José Pérez-Sáez
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Carla Burballa
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Anna Buxeda
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Carlos Arias-Cabrales
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Montserrat Folgueiras
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Sara Sanz-Ureña
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Nicole M. Valenzuela
- UCLA Immunogenetics Center, University of California Los Angeles, Los Angeles, CA, United States
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - Elaine F. Reed
- UCLA Immunogenetics Center, University of California Los Angeles, Los Angeles, CA, United States
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
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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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Ye Y, Wang M, Huang H. Follicular regulatory T cell biology and its role in immune-mediated diseases. J Leukoc Biol 2021; 110:239-255. [PMID: 33938586 DOI: 10.1002/jlb.1mr0321-601rr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Follicular regulatory T (Tfr) cells are recently found to be a special subgroup of regulatory T (Treg) cells. Tfr cells play an important role in regulating the germinal center (GC) response, especially modulating follicular helper T (Tfh) cells and GC-B cells, thereby affecting the production of antibodies. Tfr cells are involved in the generation and development of many immune-related and inflammatory diseases. This article summarizes the advances in several aspects of Tfr cell biology, with special focus on definition and phenotype, development and differentiation, regulatory factors, functions, and interactions with T/B cells and molecules involved in performance and regulation of Tfr function. Finally, we highlight the current understanding of Tfr cells involvement in autoimmunity and alloreactivity, and describe some drugs targeting Tfr cells. These latest studies have answered some basic questions in Tfr cell biology and explored the roles of Tfr cells in immune-mediated diseases.
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Affiliation(s)
- Yishan Ye
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Mowang Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
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11
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Sorohan BM, Ismail G, Leca N, Tacu D, Obrișcă B, Constantinescu I, Baston C, Sinescu I. Angiotensin II type 1 receptor antibodies in kidney transplantation: An evidence-based comprehensive review. Transplant Rev (Orlando) 2020; 34:100573. [DOI: 10.1016/j.trre.2020.100573] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022]
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12
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See SB, Mantell BS, Clerkin KJ, Ray B, Vasilescu ER, Marboe CC, Naka Y, Restaino S, Colombo PC, Addonizio LJ, Farr MA, Zorn E. Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation. Am J Transplant 2020; 20:2571-2580. [PMID: 32190967 PMCID: PMC8117249 DOI: 10.1111/ajt.15871] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 02/24/2020] [Accepted: 03/11/2020] [Indexed: 01/25/2023]
Abstract
Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor human leukocyte antigen (HLA) is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non-HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single-center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥ pAMR1 (n = 43) and non-AMR (n = 21) were tested for reactivity against a panel of 44 non-HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non-AMR (P = .002) and healthy controls (n = 94, P < .0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (P < .0001) and AMR patients with DSA and PRA > 10% were identified as the subgroup with significantly elevated responses. Reactivity to 4 antigens, vimentin, beta-tubulin, lamin A/C, and apolipoprotein L2, was significantly different between AMR and non-AMR patients. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non-HLA are associated with DSA-positive AMR although their specific role in mediating allograft injury is not yet understood.
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Affiliation(s)
- Sarah B. See
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY
| | - Benjamin S. Mantell
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY,Department of Pediatrics, Division of Pediatric Cardiology, Columbia University Irving Medical Center, New York, NY
| | - Kevin J. Clerkin
- Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, NY
| | | | - E. Rodica Vasilescu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Charles C. Marboe
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Yoshifumi Naka
- Department of Surgery, Division of Cardiothoracic Surgery, Columbia University Irving Medical Center, New York, NY
| | - Susan Restaino
- Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, NY
| | - Paolo C. Colombo
- Department of Pediatrics, Division of Pediatric Cardiology, Columbia University Irving Medical Center, New York, NY
| | - Linda J. Addonizio
- Department of Pediatrics, Division of Pediatric Cardiology, Columbia University Irving Medical Center, New York, NY
| | - Maryjane A. Farr
- Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, NY
| | - Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY
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13
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Siu JH, Motallebzadeh R, Pettigrew GJ. Humoral autoimmunity after solid organ transplantation: Germinal ideas may not be natural. Cell Immunol 2020; 354:104131. [DOI: 10.1016/j.cellimm.2020.104131] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/11/2020] [Accepted: 05/11/2020] [Indexed: 12/22/2022]
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14
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Liu Y, Hu J, Liu D, Zhou S, Liao J, Liao G, Yang S, Guo Z, Li Y, Li S, Chen H, Guo Y, Li M, Fan L, Li L, Lin A, Zhao M. Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection. Am J Cancer Res 2020; 10:8851-8862. [PMID: 32754283 PMCID: PMC7392010 DOI: 10.7150/thno.48201] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/18/2020] [Indexed: 12/11/2022] Open
Abstract
Rationale: Single-cell RNA sequencing (scRNA-seq) has provided an unbiased assessment of specific profiling of cell populations at the single-cell level. Conventional renal biopsy and bulk RNA-seq only average out the underlying differences, while the extent of chronic kidney transplant rejection (CKTR) and how it is shaped by cells and states in the kidney remain poorly characterized. Here, we analyzed cells from CKTR and matched healthy adult kidneys at single-cell resolution. Methods: High-quality transcriptomes were generated from three healthy human kidneys and two CKTR biopsies. Unsupervised clustering analysis of biopsy specimens was performed to identify fifteen distinct cell types, including major immune cells, renal cells and a few types of stromal cells. Single-sample gene set enrichment (ssGSEA) algorithm was utilized to explore functional differences between cell subpopulations and between CKTR and normal cells. Results: Natural killer T (NKT) cells formed five subclasses, representing CD4+ T cells, CD8+ T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs) and natural killer cells (NKs). Memory B cells were classified into two subtypes, representing reverse immune activation. Monocytes formed a classic CD14+ group and a nonclassical CD16+ group. We identified a novel subpopulation [myofibroblasts (MyoF)] in fibroblasts, which express collagen and extracellular matrix components. The CKTR group was characterized by increased numbers of immune cells and MyoF, leading to increased renal rejection and fibrosis. Conclusions: By assessing functional differences of subtype at single-cell resolution, we discovered different subtypes that correlated with distinct functions in CKTR. This resource provides deeper insights into CKTR biology that will be helpful in the diagnosis and treatment of CKTR.
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15
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Abstract
Antibody-mediated rejection continues to hinder long-term survival of solid organ allografts. Natural antibodies (Nabs) with polyreactive and autoreactive properties have recently emerged as potential contributors to antibody-mediated graft rejection. This review discusses Nabs, their functions in health and disease, their significance in rejection following kidney, heart, and lung transplantation, and their implication in serum reactivity to key antigens associated with rejection. Finally, potential effector mechanisms of Nabs in the context of transplantation are explored.
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16
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Syu GD, Dunn J, Zhu H. Developments and Applications of Functional Protein Microarrays. Mol Cell Proteomics 2020; 19:916-927. [PMID: 32303587 PMCID: PMC7261817 DOI: 10.1074/mcp.r120.001936] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/24/2020] [Indexed: 12/19/2022] Open
Abstract
Protein microarrays are crucial tools in the study of proteins in an unbiased, high-throughput manner, as they allow for characterization of up to thousands of individually purified proteins in parallel. The adaptability of this technology has enabled its use in a wide variety of applications, including the study of proteome-wide molecular interactions, analysis of post-translational modifications, identification of novel drug targets, and examination of pathogen-host interactions. In addition, the technology has also been shown to be useful in profiling antibody specificity, as well as in the discovery of novel biomarkers, especially for autoimmune diseases and cancers. In this review, we will summarize the developments that have been made in protein microarray technology in both in basic and translational research over the past decade. We will also introduce a novel membrane protein array, the GPCR-VirD array, and discuss the future directions of functional protein microarrays.
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Affiliation(s)
- Guan-Da Syu
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan R.O.C..
| | - Jessica Dunn
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Heng Zhu
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Viral Oncology Program, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
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17
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Dieudé M, Turgeon J, Karakeussian Rimbaud A, Beillevaire D, Qi S, Patey N, Gaboury LA, Boilard É, Hébert M. Extracellular vesicles derived from injured vascular tissue promote the formation of tertiary lymphoid structures in vascular allografts. Am J Transplant 2020; 20:726-738. [PMID: 31729155 PMCID: PMC7064890 DOI: 10.1111/ajt.15707] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 09/16/2019] [Accepted: 10/10/2019] [Indexed: 01/25/2023]
Abstract
Tertiary lymphoid structures (TLS) accumulate at sites of chronic injury where they function as an ectopic germinal center, fostering local autoimmune responses. Vascular injury leads to the release of endothelial-derived apoptotic exosome-like vesicles (ApoExo) that contribute to rejection in transplanted organs. The purpose of the study was to evaluate the impact of ApoExo on TLS formation in a model of vascular allograft rejection. Mice transplanted with an allogeneic aortic transplant were injected with ApoExo. The formation of TLS was significantly increased by ApoExo injection along with vascular remodeling and increased levels of antinuclear antibodies and anti-perlecan/LG3 autoantibodies. ApoExo also enhanced allograft infiltration by γδT17 cells. Recipients deficient in γδT cells showed reduced TLS formation and lower autoantibodies levels following ApoExo injection. ApoExo are characterized by proteasome activity, which can be blocked by bortezomib. Bortezomib treated ApoExo reduced the recruitment of γδT17 cells to the allograft, lowered TLS formation, and reduced autoantibody production. This study identifies vascular injury-derived extracellular vesicles (ApoExo), as initiators of TLS formation and demonstrates the pivotal role of γδT17 in coordinating TLS formation and autoantibody production. Finally, our results suggest proteasome inhibition with bortezomib as a potential option for controlling TLS formation in rejected allografts.
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Affiliation(s)
- Mélanie Dieudé
- Research CentreCentre hospitalier de l'Université de Montréal (CRCHUM)MontréalQuébecCanada,Université de MontréalMontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
| | - Julie Turgeon
- Research CentreCentre hospitalier de l'Université de Montréal (CRCHUM)MontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
| | - Annie Karakeussian Rimbaud
- Research CentreCentre hospitalier de l'Université de Montréal (CRCHUM)MontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
| | - Déborah Beillevaire
- Research CentreCentre hospitalier de l'Université de Montréal (CRCHUM)MontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
| | - Shijie Qi
- Research CentreCentre hospitalier de l'Université de Montréal (CRCHUM)MontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
| | - Nathalie Patey
- Centre de recherche du CHU Ste‐JustineDépartement de pathologieUniversité de MontréalMontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
| | - Louis A. Gaboury
- Institute for Research in Immunology and Cancer & Department of Pathology and Cell BiologyUniversity of MontrealMontréalQuébecCanada
| | - Éric Boilard
- Centre de Recherche du CHU de QuébecUniversité LavalMontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
| | - Marie‐Josée Hébert
- Research CentreCentre hospitalier de l'Université de Montréal (CRCHUM)MontréalQuébecCanada,Université de MontréalMontréalQuébecCanada,Canadian National Transplantation Research ProgramEdmontonAlbertaCanada
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18
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Reindl-Schwaighofer R, Heinzel A, Gualdoni GA, Mesnard L, Claas FHJ, Oberbauer R. Novel insights into non-HLA alloimmunity in kidney transplantation. Transpl Int 2019; 33:5-17. [PMID: 31650645 PMCID: PMC6972536 DOI: 10.1111/tri.13546] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 08/26/2019] [Accepted: 10/23/2019] [Indexed: 12/14/2022]
Abstract
Recognition of non‐self structures on donor cells represents the main immunological barrier in solid organ transplantation. The human leukocyte antigens (HLA) are considered the most important non‐self (allo)antigens in transplantation. Long‐term graft attrition is mainly caused by the formation of alloreactive antibodies that are directed against non‐self structures (i.e., epitopes) on cell surface proteins. Recently published data provided evidence for a similar importance of non‐HLA mismatches between donors and recipients in acute rejection as well as long‐term kidney allograft survival. These data suggest a broader concept of immunological non‐self that goes beyond HLA incompatibility and expands the current concept of polymorphic non‐self epitopes on cell surface molecules from HLA to non‐HLA targets. Amino acid substitutions caused by single nucleotide variants in protein‐coding genes or complete loss of gene expression represent the basis for polymorphic residues in both HLA and non‐HLA molecules. To better understand these novel insights in non‐HLA alloimmunity, we will first review basic principles of the alloimmune response with a focus on the HLA epitope concept in donor‐specific antibody formation before discussing key publications on non‐HLA antibodies.
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Affiliation(s)
- Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Guido A Gualdoni
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Laurent Mesnard
- Sorbonne Université, Urgences Néphrologiques et Transplantation Rénale, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Tenon, Paris, France
| | - Frans H J Claas
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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19
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Tarazón E, Corbacho-Alonso N, Barderas MG, Gil-Cayuela C, García-Manzanares M, Feijóo-Bandín S, Lago F, González-Juanatey JR, Martínez-Dolz L, Portolés M, Roselló-Lletí E. Plasma CD5L and non-invasive diagnosis of acute heart rejection. J Heart Lung Transplant 2019; 39:257-266. [PMID: 31883820 DOI: 10.1016/j.healun.2019.11.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Acute rejection is one of the most important direct contributors to mortality after heart transplantation. Advances in the development of novel non-invasive approaches for the early identification of allograft rejection are necessary. We conducted a non-targeted proteome characterization focused on identifying multiple plasmatic protein differences to evaluate their diagnostic accuracy for rejection episodes. METHODS We included consecutive plasma samples from transplant recipients undergoing routine endomyocardial biopsies. A liquid chromatography-tandem mass spectrometry analysis using isobaric tags (tandem mass tag 10-plex) was performed and concentrations of CD5L were validated using a specific sandwich enzyme-linked immunosorbent assay. RESULTS A total of 17 altered proteins were identified as potential markers for detecting heart transplant rejection, most involved in inflammation and immunity. CD5L, an apoptosis inhibitor expressed by macrophages, showed the best results in the proteomic analysis (n = 30). We confirm this finding in a larger patient cohort (n = 218), obtaining a great diagnostic capacity for clinically relevant rejection (≥Grade 2R: area under the curve = 0.892, p < 0.0001) and preserving the accuracy at mild rejection (Grade 1R: area under the curve = 0.774, p < 0.0001). CD5L was a strong independent predictor, with an odds ratio of 14.74 (p < 0.0001), for the presence of rejection. CONCLUSIONS Episodes of acute cardiac allograft rejection are related to significant changes in a key inhibitor of apoptosis in macrophages, CD5L. Because of its precision to detect acute cellular rejection, even at mild grade, we propose CD5L as a potential candidate to be included in the studies of molecule combination panel assays. This finding could contribute to improving the diagnostic and preventive methods for the surveillance of cardiac transplanted patients.
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Affiliation(s)
- Estefanía Tarazón
- Myocardial Dysfunction and Cardiac Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain; CIBERCV, Madrid, Spain.
| | - Nerea Corbacho-Alonso
- Department of Vascular Physiopathology, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
| | - María G Barderas
- Department of Vascular Physiopathology, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
| | - Carolina Gil-Cayuela
- Myocardial Dysfunction and Cardiac Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain; CIBERCV, Madrid, Spain
| | - María García-Manzanares
- Medicine and Animal Surgery, CEU Cardenal Herrera University, Alfara del Patriarca, Valencia, Spain
| | - Sandra Feijóo-Bandín
- CIBERCV, Madrid, Spain; Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain
| | - Francisca Lago
- CIBERCV, Madrid, Spain; Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain
| | - José Ramón González-Juanatey
- CIBERCV, Madrid, Spain; Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain
| | - Luis Martínez-Dolz
- Myocardial Dysfunction and Cardiac Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain; CIBERCV, Madrid, Spain; Heart Failure and Transplantation Unit, Cardiology Department, University and Polytechnic La Fe Hospital, Valencia, Spain
| | - Manuel Portolés
- Myocardial Dysfunction and Cardiac Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain; CIBERCV, Madrid, Spain
| | - Esther Roselló-Lletí
- Myocardial Dysfunction and Cardiac Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain; CIBERCV, Madrid, Spain
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20
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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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21
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Dieudé M, Cardinal H, Hébert MJ. Injury derived autoimmunity: Anti-perlecan/LG3 antibodies in transplantation. Hum Immunol 2019; 80:608-613. [PMID: 31029511 DOI: 10.1016/j.humimm.2019.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/08/2019] [Accepted: 04/13/2019] [Indexed: 01/02/2023]
Abstract
Ischemic, immunologic or pharmacological stressors can induce vascular injury and endothelial apoptosis in organ donors, in transplant candidates due to the impact of end stage organ failure on the vasculature, and in association with peri-transplantation events. Vascular injury may shape innate and adaptive immune responses, leading to dysregulation in the balance between tolerance and immunoreactivity to vascular-derived antigens. Mounting evidence shows that the early stages of apoptosis, characterized by the absence of membrane permeabilization, are prone to trigger various modes of intercellular communication allowing neoantigen production, exposure, or both. In this review, we present the evidence for the release of LG3, an immunogenic fragment of perlecan, as a consequence of caspase-3 dependent vascular apoptosis leading to the genesis of anti-LG3 autoantibodies and the consequences of these autoantibodies in native and transplanted kidneys.
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Affiliation(s)
- Mélanie Dieudé
- Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Canadian Donation and Transplantation Research Program, Canada; Université de Montréal, Canada.
| | - Héloïse Cardinal
- Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Canadian Donation and Transplantation Research Program, Canada; Université de Montréal, Canada.
| | - Marie-Josée Hébert
- Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Canadian Donation and Transplantation Research Program, Canada; Université de Montréal, Canada.
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22
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Anglicheau D, Delville M, Lamarthee B. Non anti-HLA antibodies and acute rejection: A critical viewpoint. Nephrol Ther 2019; 15 Suppl 1:S53-S59. [PMID: 30981396 DOI: 10.1016/j.nephro.2019.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/04/2019] [Indexed: 10/27/2022]
Abstract
In solid organ transplantation, the deleterious effect of antibodies directed against donor HLA antigens, whether preformed or de novo, is well established. Anti-HLA antibodies have been associated not only with the risk of antibody-mediated rejection but also with late graft dysfunction and are now considered to be the leading cause of allograft loss after renal transplantation. In addition to HLA antibodies, the possible involvement of non-HLA antibodies targeting donor endothelial cells has long been the subject of intense research. The purpose of this review is to discuss current knowledge and remaining issues related to the involvement of non-HLA antibodies in solid organ transplantation. More specifically, the clinical data underlying the hypothesis of the role of non-HLA antibodies will be discussed, as well as the different techniques for antibody detection, their clinical relevance and their antigenic targets.
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Affiliation(s)
- Dany Anglicheau
- Service de néphrologie et transplantation rénale adulte, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, U1151, 149, rue de Sèvres, 75015 Paris, France.
| | - Marianne Delville
- Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Service de biothérapie, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Inserm, U1163, 24, boulevard de Montparnasse, 75015 Paris, France
| | - Baptiste Lamarthee
- Service de néphrologie et transplantation rénale adulte, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, U1151, 149, rue de Sèvres, 75015 Paris, France
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23
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Cippà PE, Liu J, Sun B, Kumar S, Naesens M, McMahon AP. A late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation. Nat Commun 2019; 10:1157. [PMID: 30858375 PMCID: PMC6411919 DOI: 10.1038/s41467-019-09092-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 02/20/2019] [Indexed: 12/24/2022] Open
Abstract
The mechanisms initiating late immune responses to an allograft are poorly understood. Here we show, via transcriptome analysis of serial protocol biopsies from kidney transplants, that the initial responses to kidney injury correlate with a late B lymphocyte signature relating to renal dysfunction and fibrosis. With a potential link between dysfunctional repair and immunoreactivity, we investigate the immunological consequences of dysfunctional repair examining chronic disease in mouse kidneys 18 months after a bilateral ischemia/reperfusion injury event. In the absence of foreign antigens, a sustained immune response involving both innate and adaptive immune systems accompanies a transition to chronic kidney damage. At late stages, B lymphocytes exhibite an antigen-driven proliferation, selection and maturation into broadly-reacting antibody-secreting cells. These findings reveal a previously unappreciated role for dysfunctional tissue repair in local immunomodulation that may have particular relevance to transplant-associated immunobiology.
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Affiliation(s)
- Pietro E Cippà
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, 90033-9080, CA, USA.
- Division of Nephrology, Regional Hospital Lugano, Lugano, 6900, Switzerland.
| | - Jing Liu
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, 90033-9080, CA, USA
| | - Bo Sun
- Molecular and Computational Biology, University of Southern California, Los Angeles, 90089-2910, CA, USA
| | - Sanjeev Kumar
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, 90033-9080, CA, USA
| | - Maarten Naesens
- Department of Microbiology and Immunology, KU Leuven, Leuven, 3000, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, 3000, Belgium
| | - Andrew P McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, 90033-9080, CA, USA.
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24
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Delville M, Lamarthée B, Pagie S, See SB, Rabant M, Burger C, Gatault P, Giral M, Thaunat O, Arzouk N, Hertig A, Hazzan M, Matignon M, Mariat C, Caillard S, Kamar N, Sayegh J, Westeel PF, Garrouste C, Ladrière M, Vuiblet V, Rivalan J, Merville P, Bertrand D, Le Moine A, Duong Van Huyen JP, Cesbron A, Cagnard N, Alibeu O, Satchell SC, Legendre C, Zorn E, Taupin JL, Charreau B, Anglicheau D. Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens. J Am Soc Nephrol 2019; 30:692-709. [PMID: 30850439 DOI: 10.1681/asn.2018080868] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 01/31/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed. METHODS We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs. RESULTS We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals. CONCLUSIONS Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.
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Affiliation(s)
- Marianne Delville
- French National Institute of Health and Medical Research (INSERM) Unit 1163 and.,Department of Biotherapy, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,Paris Descartes, Sorbonne Paris Cité University, Paris, France
| | | | - Sylvain Pagie
- Center for Research in Transplantation and Immunology, French National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR) 1064, Institut Hospitalo-Universitaire (IHU) Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (CESTI), Laboratoire d'excellence (LabEx) Immunotherapy Graft Oncology (IGO), LabEx Transplantex, Nantes, France.,Nantes Universtity, Nantes, France
| | - Sarah B See
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York
| | - Marion Rabant
- Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Department of Renal Pathology, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Carole Burger
- Paris Descartes, Sorbonne Paris Cité University, Paris, France
| | - Philippe Gatault
- Service de Néphrologie-Hypertension, Transplantation et Dialyses, University Hospital, Tours, France.,Equipe d'Accueil EA4245, Transplantation, Immunologie et Inflammation (T2I), University of Tours, Tours, France
| | - Magali Giral
- Nantes University Hospital, Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes, France
| | - Olivier Thaunat
- Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology.,INSERM Unit 1111, Lyon, France.,Claude Berna Saint-Etienne University Hospital rd University (Lyon 1), Lyon, France
| | - Nadia Arzouk
- Department of Urology, Nephrology and Kidney transplantation, Pitié Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Alexandre Hertig
- Sorbonne University, Paris, France.,Urgences Néphrologiques et Transplantation Rénale, Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Paris, France
| | - Marc Hazzan
- Department of Nephrology, Lille University Hospital, Lille, France.,Lille University, Lille, France.,French National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR) 995, Lille, France
| | - Marie Matignon
- Department of Nephrology and Renal Transplantation, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Assistance Publique-Hôpitaux de Paris (AP-HP), Créteil, France.,Paris-Est-Créteil University (UPEC), Créteil, France.,Institut Mondor de Recherche Biomédicale (IMRB), Equipe 21, French National Institute of Health and Medical Research (INSERM) Unit 955, Créteil, France
| | - Christophe Mariat
- Department of Nephrology, Dialysis and Renal Transplantation, Saint-Etienne University Hospital, Saint-Etienne, France.,Jean Monnet University, Saint-Etienne, France
| | - Sophie Caillard
- Department of Nephrology and Transplantation, Strasbourg, France.,French National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR) S1109, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Rangueil University Hospital, Toulouse, France.,French National Institute of Health and Medical Research (INSERM) Unit 1043, Institut Fédératif de Recherche Biomédicale de Toulouse (IFR-BMT), Paul Sabatier University, Toulouse, France
| | - Johnny Sayegh
- Angers University, Angers, France.,Department of Nephrology, Dialysis and Kidney Transplantation, Angers University Hospital, Angers, France
| | | | - Cyril Garrouste
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Marc Ladrière
- Department of Nephrology and Kidney Transplantation, Nancy University Hospital, Nancy, France
| | - Vincent Vuiblet
- Department of Nephrology and Renal Transplantation, Reims University Hospital, Reims, France
| | - Joseph Rivalan
- Department of Nephrology, Pontchaillou University Hospital, Rennes, France
| | - Pierre Merville
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.,Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 5164 Immuno ConcEpT, , Bordeaux, France.,Bordeaux University, Bordeaux, France
| | - Dominique Bertrand
- Nephrology, Dialysis and Kidney Transplantation, Rouen University Hospital, Rouen, France
| | - Alain Le Moine
- Erasme Hospital, Nephrology Dialysis and Transplantation Department, Bruxelles, Belgium.,Université Libre de Bruxelles, Brussels, Belgium
| | - Jean-Paul Duong Van Huyen
- Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Department of Renal Pathology, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Anne Cesbron
- HLA Laboratory, Etablissement Français du Sang (EFS) Centre Pays de la Loire, Nantes, France
| | - Nicolas Cagnard
- Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Bioinformatics, Structure Fédérative de Recherche Necker, French National Institute of Health and Medical Research (INSERM) US24/ Centre National de la Recherche Scientifique (CNRS) UMS3633, Paris, France
| | - Olivier Alibeu
- Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, French National Institute of Health and Medical Research (INSERM) Unit 1163 and INSERM US24/ Centre National de la Recherche Scientifique (CNRS) UMS3633, Paris, France
| | - Simon C Satchell
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of Bristol, Great Britain
| | - Christophe Legendre
- Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Necker-Enfants Malades Institute, French National Institute of Health and Medical Research (INSERM) Unit 1151, Paris, France.,Department of Nephrology and Kidney Transplantation, RTRS Centaure; LabEx Transplantex, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York
| | - Jean-Luc Taupin
- Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,French National Institute of Health and Medical Research (INSERM) Unit 1160, LabEx Transplantex, Paris France; and.,University Paris Diderot, Paris, France
| | - Béatrice Charreau
- Center for Research in Transplantation and Immunology, French National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR) 1064, Institut Hospitalo-Universitaire (IHU) Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (CESTI), Laboratoire d'excellence (LabEx) Immunotherapy Graft Oncology (IGO), LabEx Transplantex, Nantes, France.,Nantes Universtity, Nantes, France
| | - Dany Anglicheau
- Paris Descartes, Sorbonne Paris Cité University, Paris, France; .,Necker-Enfants Malades Institute, French National Institute of Health and Medical Research (INSERM) Unit 1151, Paris, France.,Department of Nephrology and Kidney Transplantation, RTRS Centaure; LabEx Transplantex, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
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Reindl-Schwaighofer R, Heinzel A, Kainz A, van Setten J, Jelencsics K, Hu K, Loza BL, Kammer M, Heinze G, Hruba P, Koňaříková A, Viklicky O, Boehmig GA, Eskandary F, Fischer G, Claas F, Tan JC, Albert TJ, Patel J, Keating B, Oberbauer R. Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohort. Lancet 2019; 393:910-917. [PMID: 30773281 DOI: 10.1016/s0140-6736(18)32473-5] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 09/18/2018] [Accepted: 09/27/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND The introduction of HLA matching of donors and recipients was a breakthrough in kidney transplantation. However, half of all transplanted kidneys still fail within 15 years after transplantation. Epidemiological data suggest a fundamental role of non-HLA alloimmunity. METHODS We genotyped 477 pairs of deceased donors and first kidney transplant recipients with stable graft function at three months that were transplanted between Dec 1, 2005, and April 30, 2015. Genome-wide genetic mismatches in non-synonymous single nucleotide polymorphisms (nsSNPs) were calculated to identify incompatibilities in transmembrane and secreted proteins. We estimated the association between nsSNP mismatch and graft loss in a Cox proportional hazard model, adjusting for HLA mismatch and clinical covariates. Customised peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes in 25 patients with biopsy-confirmed chronic antibody-mediated rejection. FINDINGS 59 268 nsSNPs affecting a transmembrane or secreted protein were analysed. The median number of nsSNP mismatches in immune-accessible transmembrane and secreted proteins between donors and recipients was 1892 (IQR 1850-1936). The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLA eplet mismatch (HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, and HLA-DR). Each increase by a unit of one IQR had an HR of 1·68 (95% CI 1·17-2·41, p=0·005). 5-year death censored graft survival was 98% in the quartile with the lowest mismatch, 91% in the second quartile, 89% in the third quartile, and 82% in the highest quartile (p=0·003, log-rank test). Customised peptide arrays verified a donor-specific alloimmune response to genetically predicted mismatched epitopes. INTERPRETATION Genetic mismatch of non-HLA haplotypes coding for transmembrane or secreted proteins is associated with an increased risk of functional graft loss independently of HLA incompatibility. As in HLA alloimmunity, donor-specific alloantibodies can be identified against genotype derived non-HLA epitopes. FUNDING Austrian Science Fund, WWTF (Vienna Science and Technology Fund), and Ministry of Health of the Czech Republic.
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Affiliation(s)
| | - Andreas Heinzel
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Alexander Kainz
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Jessica van Setten
- Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands
| | - Kira Jelencsics
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Karin Hu
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Bao-Li Loza
- Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael Kammer
- Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Georg Heinze
- Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alena Koňaříková
- Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ondrej Viklicky
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Georg A Boehmig
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Farsad Eskandary
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Gottfried Fischer
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Frans Claas
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands
| | | | | | | | - Brendan Keating
- Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Rainer Oberbauer
- Department of Nephrology, Medical University of Vienna, Vienna, Austria.
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26
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Qureshi MS, Alsughayyir J, Chhabra M, Ali JM, Goddard MJ, Devine CA, Conlon TM, Linterman MA, Motallebzadeh R, Pettigrew GJ. Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy. J Autoimmun 2019; 98:44-58. [DOI: 10.1016/j.jaut.2018.11.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 11/27/2018] [Accepted: 11/30/2018] [Indexed: 12/18/2022]
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27
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Padet L, Dieudé M, Karakeussian‐Rimbaud A, Yang B, Turgeon J, Cailhier J, Cardinal H, Hébert M. New insights into immune mechanisms of antiperlecan/LG3 antibody production: Importance of T cells and innate B1 cells. Am J Transplant 2019; 19:699-712. [PMID: 30129231 PMCID: PMC6519043 DOI: 10.1111/ajt.15082] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/25/2018] [Accepted: 07/29/2018] [Indexed: 01/25/2023]
Abstract
Autoantibodies against perlecan/LG3 (anti-LG3) have been associated with increased risks of delayed graft function, acute rejection, and reduced long-term survival. High titers of anti-LG3 antibodies have been found in de novo renal transplants recipients in the absence of allosensitizing or autoimmune conditions. Here, we seek to understand the pathways controlling anti-LG3 production prior to transplantation. Mice immunized with recombinant LG3 produce concomitantly IgM and IgG anti-LG3 antibodies suggesting a memory response. ELISpot confirmed the presence of LG3-specific memory B cells in nonimmunized mice. Purification of B1 and B2 subtypes identified peritoneal B1 cells as the major source of memory B cells reactive to LG3. Although nonimmunized CD4-deficient mice were found to express LG3-specific memory B cells, depletion of CD4+ T cells in wild type mice during immunization significantly decreased anti-LG3 production. These results demonstrate that B cell memory to LG3 is T cell independent but that production of anti-LG3 antibodies requires T cell help. Further supporting an important role for T cells in controlling anti-LG3 levels, we found that human renal transplant recipients show a significant decrease in anti-LG3 titers upon the initiation of CNI-based immunosuppression. Collectively, these results identify T cell targeting interventions as a means of reducing anti-LG3 levels in renal transplant patients.
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Affiliation(s)
- Lauriane Padet
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada,Université de MontréalMontrealQuebecCanada
| | - Mélanie Dieudé
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada
| | - Annie Karakeussian‐Rimbaud
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada
| | - Bing Yang
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada,Université de MontréalMontrealQuebecCanada
| | - Julie Turgeon
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada
| | - Jean‐François Cailhier
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada
| | - Héloïse Cardinal
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada
| | - Marie‐Josée Hébert
- Research CentreCentre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada,Canadian National Transplant Research ProgramEdmontonAlbertaCanada,Université de MontréalMontrealQuebecCanada
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28
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Oleinika K, Mauri C, Salama AD. Effector and regulatory B cells in immune-mediated kidney disease. Nat Rev Nephrol 2018; 15:11-26. [DOI: 10.1038/s41581-018-0074-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abstract
INTRODUCTION High-content protein microarrays in principle enable the functional interrogation of the human proteome in a broad range of applications, including biomarker discovery, profiling of immune responses, identification of enzyme substrates, and quantifying protein-small molecule, protein-protein and protein-DNA/RNA interactions. As with other microarrays, the underlying proteomic platforms are under active technological development and a range of different protein microarrays are now commercially available. However, deciphering the differences between these platforms to identify the most suitable protein microarray for the specific research question is not always straightforward. Areas covered: This review provides an overview of the technological basis, applications and limitations of some of the most commonly used full-length, recombinant protein and protein fragment microarray platforms, including ProtoArray Human Protein Microarrays, HuProt Human Proteome Microarrays, Human Protein Atlas Protein Fragment Arrays, Nucleic Acid Programmable Arrays and Immunome Protein Arrays. Expert commentary: The choice of appropriate protein microarray platform depends on the specific biological application in hand, with both more focused, lower density and higher density arrays having distinct advantages. Full-length protein arrays offer advantages in biomarker discovery profiling applications, although care is required in ensuring that the protein production and array fabrication methodology is compatible with the required downstream functionality.
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Affiliation(s)
- Jessica G Duarte
- a Cancer Immunobiology Laboratory, Olivia Newton-John Cancer Research Institute/School of Cancer Medicine , La Trobe University , Heidelberg , Australia
| | - Jonathan M Blackburn
- b Institute of Infectious Disease and Molecular Medicine & Department of Integrative Biomedical Sciences, Faculty of Health Sciences , University of Cape Town , Observatory, South Africa
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30
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Da Gama Duarte J, Parakh S, Andrews MC, Woods K, Pasam A, Tutuka C, Ostrouska S, Blackburn JM, Behren A, Cebon J. Autoantibodies May Predict Immune-Related Toxicity: Results from a Phase I Study of Intralesional Bacillus Calmette-Guérin followed by Ipilimumab in Patients with Advanced Metastatic Melanoma. Front Immunol 2018; 9:411. [PMID: 29552014 PMCID: PMC5840202 DOI: 10.3389/fimmu.2018.00411] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 02/14/2018] [Indexed: 11/13/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. The first ICI to demonstrate clinical benefit, ipilimumab, targets cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4); however, the long-term overall survival is just 22%. More than 40 years ago intralesional (IL) bacillus Calmette-Guérin (BCG), a living attenuated strain of Mycobacterium bovis, was found to induce tumor regression by stimulating cell-mediated immunity following a localized and self-limiting infection. We evaluated these two immune stimulants in combination with melanoma with the aim of developing a more effective immunotherapy and to assess toxicity. In this phase I study, patients with histologically confirmed stage III/IV metastatic melanoma received IL BCG injection followed by up to four cycles of intravenous ipilimumab (anti-CTLA-4) (ClinicalTrials.gov number NCT01838200). The trial was discontinued following treatment of the first five patients as the two patients receiving the escalation dose of BCG developed high-grade immune-related adverse events (irAEs) typical of ipilimumab monotherapy. These irAEs were characterized in both patients by profound increases in the repertoire of autoantibodies directed against both self- and cancer antigens. Interestingly, the induced autoantibodies were detected at time points that preceded the development of symptomatic toxicity. There was no overlap in the antigen specificity between patients and no evidence of clinical responses. Efforts to increase response rates through the use of novel immunotherapeutic combinations may be associated with higher rates of irAEs, thus the imperative to identify biomarkers of toxicity remains strong. While the small patient numbers in this trial do not allow for any conclusive evidence of predictive biomarkers, the observed changes warrant further examination of autoantibody repertoires in larger patient cohorts at risk of developing irAEs during their course of treatment. In summary, dose escalation of IL BCG followed by ipilimumab therapy was not well tolerated in advanced melanoma patients and showed no evidence of clinical benefit. Measuring autoantibody responses may provide early means for identifying patients at risk from developing severe irAEs during cancer immunotherapy.
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Affiliation(s)
- Jessica Da Gama Duarte
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia
| | - Sagun Parakh
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia
| | - Miles C Andrews
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia.,MD Anderson Cancer Center, University of Texas, Houston, TX, United States
| | - Katherine Woods
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia
| | - Anupama Pasam
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia
| | - Candani Tutuka
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia
| | - Simone Ostrouska
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
| | - Jonathan M Blackburn
- Department of Integrative Biomedical Sciences and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.,Sengenics Corporation, Singapore, Singapore
| | - Andreas Behren
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia
| | - Jonathan Cebon
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.,Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia
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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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32
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Gates KV, Pereira NL, Griffiths LG. Cardiac Non-Human Leukocyte Antigen Identification: Techniques and Troubles. Front Immunol 2017; 8:1332. [PMID: 29093713 PMCID: PMC5651233 DOI: 10.3389/fimmu.2017.01332] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/02/2017] [Indexed: 12/20/2022] Open
Abstract
Historically efforts have focused on the human leukocyte antigen (HLA) as the major cause for acute and chronic rejection following cardiac transplantation. However, rising evidence indicates that non-HLA antibodies can be both primary initiators and modifiers of antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV). The purpose of this review is to assess currently available technologies for non-HLA identification and leveraging such responses toward antibody quantification. Several techniques have been used to identify antigenic determinants of recipient graft-specific non-HLA humoral immune responses, but each comes with its own set of benefits and caveats. Improving our ability to detect non-HLA humoral immune response will aid in our understanding of the underlying antigenic determinants of AMR and CAV, as well as improve patient outcomes.
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Affiliation(s)
- Katherine V Gates
- Department of Veterinary Medicine and Epidemiology, University of California, Davis, Davis, CA, United States.,Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
| | - Naveen L Pereira
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
| | - Leigh G Griffiths
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
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Reindl-Schwaighofer R, Heinzel A, Signorini L, Thaunat O, Oberbauer R. Mechanisms underlying human genetic diversity: consequence for antigraft antibody responses. Transpl Int 2017; 31:239-250. [DOI: 10.1111/tri.13059] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 07/28/2017] [Accepted: 08/30/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis; Department of Internal Medicine III; Medical University of Vienna; Vienna Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis; Department of Internal Medicine III; Medical University of Vienna; Vienna Austria
| | - Lorenzo Signorini
- Renal and Dialysis Unit; Department of Medicine; University of Verona; Verona Italy
| | - Olivier Thaunat
- Hospices Civils de Lyon; Hôpital Edouard Herriot; Service de Transplantation; Néphrologie et Immunologie Clinique; INSERM U1111; Université Lyon-I; Lyon France
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis; Department of Internal Medicine III; Medical University of Vienna; Vienna Austria
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Luque S, Lúcia M, Bestard O. Refinement of humoral immune monitoring in kidney transplantation: the role of “hidden” alloreactive memory B cells. Transpl Int 2017; 30:955-968. [DOI: 10.1111/tri.13014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/07/2017] [Accepted: 07/20/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Sergi Luque
- Experimental Nephrology Laboratory; IDIBELL; Barcelona Spain
| | - Marc Lúcia
- Experimental Nephrology Laboratory; IDIBELL; Barcelona Spain
- Transplant Immunology; Stanford School of Medicine; Stanford CA USA
| | - Oriol Bestard
- Experimental Nephrology Laboratory; IDIBELL; Barcelona Spain
- Kidney Transplant Unit; Nephrology Department; Bellvitge University Hospital; Barcelona University; Barcelona Spain
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Cernoch M, Viklicky O. Complement in Kidney Transplantation. Front Med (Lausanne) 2017; 4:66. [PMID: 28611987 PMCID: PMC5447724 DOI: 10.3389/fmed.2017.00066] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 05/09/2017] [Indexed: 12/12/2022] Open
Abstract
The complement system is considered to be an important part of innate immune system with a significant role in inflammation processes. The activation can occur through classical, alternative, or lectin pathway, resulting in the creation of anaphylatoxins C3a and C5a, possessing a vast spectrum of immune functions, and the assembly of terminal complement cascade, capable of direct cell lysis. The activation processes are tightly regulated; inappropriate activation of the complement cascade plays a significant role in many renal diseases including organ transplantation. Moreover, complement cascade is activated during ischemia/reperfusion injury processes and influences delayed graft function of kidney allografts. Interestingly, complement system has been found to play a role in both acute cellular and antibody-mediated rejections and thrombotic microangiopathy. Therefore, complement system may represent an interesting therapeutical target in kidney transplant pathologies.
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Affiliation(s)
- Marek Cernoch
- Transplant Laboratory, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Ondrej Viklicky
- Transplant Laboratory, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czechia.,Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czechia
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Sullivan JA, Jankowska-Gan E, Hegde S, Pestrak MA, Agashe VV, Park AC, Brown ME, Kernien JF, Wilkes DS, Kaufman DB, Greenspan DS, Burlingham WJ. Th17 Responses to Collagen Type V, kα1-Tubulin, and Vimentin Are Present Early in Human Development and Persist Throughout Life. Am J Transplant 2017; 17:944-956. [PMID: 27801552 PMCID: PMC5626015 DOI: 10.1111/ajt.14097] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 09/29/2016] [Accepted: 10/14/2016] [Indexed: 01/25/2023]
Abstract
T helper 17 (Th17)-dependent autoimmune responses can develop after heart or lung transplantation and are associated with fibro-obliterative forms of chronic rejection; however, the specific self-antigens involved are typically different from those associated with autoimmune disease. To investigate the basis of these responses, we investigated whether removal of regulatory T cells or blockade of function reveals a similar autoantigen bias. We found that Th17 cells specific for collagen type V (Col V), kα1-tubulin, and vimentin were present in healthy adult peripheral blood mononuclear cells, cord blood, and fetal thymus. Using synthetic peptides and recombinant fragments of the Col V triple helical region (α1[V]), we compared Th17 cells from healthy donors with Th17 cells from Col V-reactive heart and lung patients. Although the latter responded well to α1(V) fragments and peptides in an HLA-DR-restricted fashion, Th17 cells from healthy persons responded in an HLA-DR-restricted fashion to fragments but not to peptides. Col V, kα1-tubulin, and vimentin are preferred targets of a highly conserved, hitherto unknown, preexisting Th17 response that is MHC class II restricted. These data suggest that autoimmunity after heart and lung transplantation may result from dysregulation of an intrinsic mechanism controlling airway and vascular homeostasis.
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Affiliation(s)
- Jeremy A Sullivan
- Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792,To whom correspondence should be addressed: 600 Highland Avenue, Room G4/702, Madison, WI 53792. Tel: (608) 263-0119 Fax: (608)262-6280,
| | - Ewa Jankowska-Gan
- Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792
| | - Subramanya Hegde
- Current Address: Abbvie Bio-Research Center, 100 Research Dr., Worcester, MA 01605
| | - Matthew A Pestrak
- Current Address: Department of Surgery, Ohio State University, 410 W 10th Ave, Columbus, OH 43210
| | - Vrushali V Agashe
- Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792
| | - Arick C Park
- Department of Cell & Regenerative Biology, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792
| | - Matthew E Brown
- Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792
| | - John F Kernien
- Department of Cell & Regenerative Biology, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792
| | - David S Wilkes
- Department of Medicine, University of Indiana, 340 W 10th St Suite 6200 Indianapolis, IN 46202
| | - Dixon B Kaufman
- Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792
| | - Daniel S Greenspan
- Department of Cell & Regenerative Biology, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792
| | - William J Burlingham
- Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792,To whom correspondence should be addressed: 600 Highland Avenue, Room G4/702, Madison, WI 53792. Tel: (608) 263-0119 Fax: (608)262-6280,
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Analysis of Sera of Recipients with Allograft Rejection Indicates That Keratin 1 Is the Target of Anti-Endothelial Antibodies. J Immunol Res 2017; 2017:8679841. [PMID: 28265584 PMCID: PMC5318619 DOI: 10.1155/2017/8679841] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 01/04/2017] [Indexed: 11/24/2022] Open
Abstract
Anti-endothelial cell antibodies (AECAs) are usually directed against the surface antigens on the vascular endothelial cells. Clinical studies suggest a pathogenic role for nonhuman leukocyte antigen in antibody-mediated rejection; however, the antigens on the donor vascular endothelium that serve as the first-line targets for an immune response during allograft rejection have not been fully identified. Here, we used immunoprecipitation and mass spectrometry to identify antigens from the sera of kidney transplant recipients who were experiencing antibody-mediated rejection. Keratin 1 (KRT1) was identified as a novel antigenic target expressed on endothelial cells. To validate our finding, we produced recombinant proteins representing the three most common alleles of KRT1. The serum used for immunoprecipitation showed a strong reaction to KRT1 recombinants in western blot and ELISA. In the kidney transplant cohort, more AECA-positive recipients than AECA-negative recipients had KRT1 antibodies (32.2% versus 11.9%, p = 0.002). Sera from 255 renal recipients were tested by ELISA. Of the 77 recipients with deteriorating graft function (serum creatinine > 120 μmol/L), 23 had anti-KRT1 antibodies. KRT1-IgG positivity was, therefore, associated with a higher risk of kidney transplant rejection (29.9% (23/77) versus 16.9% (30/178), p = 0.0187). A better understanding of this antigenic target will improve long-term allograft survival.
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Chruscinski A, Huang FYY, Ulndreaj A, Chua C, Fehlings M, Rao V, Ross HJ, Levy GA. Generation of Two-color Antigen Microarrays for the Simultaneous Detection of IgG and IgM Autoantibodies. J Vis Exp 2016. [PMID: 27685156 DOI: 10.3791/54543] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Autoantibodies, which are antibodies against self-antigens, are present in many disease states and can serve as markers for disease activity. The levels of autoantibodies to specific antigens are typically detected with the enzyme-linked immunosorbent assay (ELISA) technique. However, screening for multiple autoantibodies with ELISA can be time-consuming and requires a large quantity of patient sample. The antigen microarray technique is an alternative method that can be used to screen for autoantibodies in a multiplex fashion. In this technique, antigens are arrayed onto specially coated microscope slides with a robotic microarrayer. The slides are probed with patient serum samples and subsequently fluorescent-labeled secondary antibodies are added to detect binding of serum autoantibodies to the antigens. The autoantibody reactivities are revealed and quantified by scanning the slides with a scanner that can detect fluorescent signals. Here we describe methods to generate custom antigen microarrays. Our current arrays are printed with 9 solid pins and can include up to 162 antigens spotted in duplicate. The arrays can be easily customized by changing the antigens in the source plate that is used by the microarrayer. We have developed a two-color secondary antibody detection scheme that can distinguish IgG and IgM reactivities on the same slide surface. The detection system has been optimized to study binding of human and murine autoantibodies.
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Affiliation(s)
| | | | | | - Conan Chua
- Multi-Organ Transplant Program, University Health Network
| | | | - Vivek Rao
- Division of Cardiac Surgery, University Health Network
| | - Heather J Ross
- Multi-Organ Transplant Program, University Health Network
| | - Gary A Levy
- Multi-Organ Transplant Program, University Health Network
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Pathogenesis of non-HLA antibodies in solid organ transplantation: Where do we stand? Hum Immunol 2016; 77:1055-1062. [PMID: 27237040 DOI: 10.1016/j.humimm.2016.05.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 04/29/2016] [Accepted: 05/23/2016] [Indexed: 11/20/2022]
Abstract
Antibody-mediated rejection (ABMR) is associated with poor transplant outcome. Pathogenic alloantibodies are usually directed against human leukocyte antigens (HLAs). Histological findings suggestive of ABMR usually demonstrate an anti-HLA donor-specific antibody (DSA)-mediated injury, while a small subset of patients develop acute dysfunction with histological lesions suggestive of ABMR in the absence of anti-HLA DSAs. Although this non-HLA ABMR is not well recognized by current diagnostic classifications, it is associated with graft dysfunction and allograft loss. These clinical descriptions suggest a pathogenic role for non-HLA anti-endothelial cell antibodies. Diverse antigenic targets have been described during the last decade. This review discusses recent findings in the field and addresses the clinical relevance of anti-endothelial cell antibodies (AECAs).
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40
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Dragun D, Catar R, Philippe A. Non-HLA antibodies against endothelial targets bridging allo- and autoimmunity. Kidney Int 2016; 90:280-288. [PMID: 27188505 DOI: 10.1016/j.kint.2016.03.019] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/12/2016] [Accepted: 03/17/2016] [Indexed: 12/17/2022]
Abstract
Detrimental actions of donor-specific antibodies (DSAs) directed against both major histocompatibility antigens (human leukocyte antigen [HLA]) and specific non-HLA antigens expressed on the allograft endothelium are a flourishing research area in kidney transplantation. Newly developed solid-phase assays enabling detection of functional non-HLA antibodies targeting G protein-coupled receptors such as angiotensin type I receptor and endothelin type A receptor were instrumental in providing long-awaited confirmation of their broad clinical relevance. Numerous recent clinical studies implicate angiotensin type I receptor and endothelin type A receptor antibodies as prognostic biomarkers for earlier occurrence and severity of acute and chronic immunologic complications in solid organ transplantation, stem cell transplantation, and systemic autoimmune vascular disease. Angiotensin type 1 receptor and endothelin type A receptor antibodies exert their pathophysiologic effects alone and in synergy with HLA-DSA. Recently identified antiperlecan antibodies are also implicated in accelerated allograft vascular pathology. In parallel, protein array technology platforms enabled recognition of new endothelial surface antigens implicated in endothelial cell activation. Upon target antigen recognition, non-HLA antibodies act as powerful inducers of phenotypic perturbations in endothelial cells via activation of distinct intracellular cell-signaling cascades. Comprehensive diagnostic assessment strategies focusing on both HLA-DSA and non-HLA antibody responses could substantially improve immunologic risk stratification before transplantation, help to better define subphenotypes of antibody-mediated rejection, and lead to timely initiation of targeted therapies. Better understanding of similarities and dissimilarities in HLA-DSA and distinct non-HLA antibody-related mechanisms of endothelial damage should facilitate discovery of common downstream signaling targets and pave the way for the development of endothelium-centered therapeutic strategies to accompany intensified immunosuppression and/or mechanical removal of antibodies.
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Affiliation(s)
- Duska Dragun
- Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany.
| | - Rusan Catar
- Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany
| | - Aurélie Philippe
- Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany
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Julliard W, Owens LA, O'Driscoll CA, Fechner JH, Mezrich JD. Environmental Exposures-The Missing Link in Immune Responses After Transplantation. Am J Transplant 2016; 16:1358-64. [PMID: 26696401 PMCID: PMC4844852 DOI: 10.1111/ajt.13660] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 12/01/2015] [Accepted: 12/02/2015] [Indexed: 01/25/2023]
Abstract
In transplantation, immunosuppression has been directed at controlling acute responses, but treatment of chronic rejection has been ineffective. It is possible that factors that have previously been unaccounted for, such as exposure to inhaled pollution, ultraviolet light, or loss of the normal equilibrium between the gut immune system and the outside environment may be responsible for shifting immune responses to an effector/inflammatory phenotype, which leads to loss of self-tolerance and graft acceptance, and a shift towards autoimmunity and chronic rejection. Cells of the immune system are in a constant balance of effector response, regulation, and quiescence. Endogenous and exogenous signals can shift this balance through the aryl hydrocarbon receptor, which serves as a thermostat to modulate the response one way or the other, both at mucosal surfaces of interface organs to the outside environment, and in the internal milieu. Better understanding of this balance will identify a target for maintenance of self-tolerance and continued graft acceptance in patients who have achieved a "steady state" after transplantation.
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Affiliation(s)
- W Julliard
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - L A Owens
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - C A O'Driscoll
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J H Fechner
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J D Mezrich
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
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Evidence to Support a Contribution of Polyreactive Antibodies to HLA Serum Reactivity. Transplantation 2016; 100:217-26. [PMID: 26285015 DOI: 10.1097/tp.0000000000000840] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Assessing the serum reactivity to HLA is essential for the evaluation of transplant candidates and the follow-up of allograft recipients. In this study, we look for evidence at the clonal level that polyreactive antibodies cross-reactive to apoptotic cells and multiple autoantigens can also react to HLA and contribute to the overall serum reactivity. METHODS We immortalized B cell clones from the blood of 2 kidney transplant recipients and characterized their reactivity to self-antigens, apoptotic cells as well as native, denatured, and cryptic HLA determinants using enzyme-linked immunosorbent assay (ELISA), immunofluorescence, flow cytometry and Luminex assays. We also assessed the reactivity of 300 pretransplant serum specimens to HLA and apoptotic cells. RESULTS We report here 4 distinct B cell clones cross-reactive to self and HLA class I. All 4 clones reacted to numerous HLA class I alleles but did not appear to target canonical "shared" epitopes. In parallel experiments, we observed a strong correlation between IgG reactivity to HLA and apoptotic cells in pretransplant serum samples collected from 300 kidney transplant recipients. Further analysis revealed that samples with higher reactivity to apoptotic cells displayed significantly higher class I percent panel-reactive antibodies compared to samples with low reactivity to apoptotic cells. CONCLUSIONS We provide here (1) proof of principle at the clonal level that human polyreactive antibodies can cross-react to HLA, multiple self-antigens and apoptotic cells and (2) supportive evidence that polyreactive antibodies contribute to overall HLA reactivity in the serum of patients awaiting kidney transplant.
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Chruscinski A, Huang FYY, Nguyen A, Lioe J, Tumiati LC, Kozuszko S, Tinckam KJ, Rao V, Dunn SE, Persinger MA, Levy GA, Ross HJ. Generation of Antigen Microarrays to Screen for Autoantibodies in Heart Failure and Heart Transplantation. PLoS One 2016; 11:e0151224. [PMID: 26967734 PMCID: PMC4788148 DOI: 10.1371/journal.pone.0151224] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 02/23/2016] [Indexed: 11/19/2022] Open
Abstract
Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR.
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Affiliation(s)
- Andrzej Chruscinski
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada
- * E-mail:
| | - Flora Y. Y. Huang
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Albert Nguyen
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Jocelyn Lioe
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Laura C. Tumiati
- Division of Cardiac Surgery, University Health Network, Toronto, Ontario, Canada
| | - Stella Kozuszko
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Kathryn J. Tinckam
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Vivek Rao
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Cardiac Surgery, University Health Network, Toronto, Ontario, Canada
| | - Shannon E. Dunn
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Research Institute, Toronto, Ontario, Canada
- Women’s College Research Institute, Toronto, Ontario, Canada
| | - Michael A. Persinger
- Behavioral Neuroscience, Biomolecular Sciences and Human Studies Programs, Laurentian University, Sudbury, Ontario, Canada
| | - Gary A. Levy
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Heather J. Ross
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada
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Abstract
B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation.
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Affiliation(s)
| | - Fadi G Lakkis
- Departments of Medicine (Renal-Electrolyte), Surgery, and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and
| | - Geetha Chalasani
- Departments of Medicine (Renal-Electrolyte), Surgery, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and Renal Section, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania
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Dieudé M, Bell C, Turgeon J, Beillevaire D, Pomerleau L, Yang B, Hamelin K, Qi S, Pallet N, Béland C, Dhahri W, Cailhier JF, Rousseau M, Duchez AC, Lévesque T, Lau A, Rondeau C, Gingras D, Muruve D, Rivard A, Cardinal H, Perreault C, Desjardins M, Boilard É, Thibault P, Hébert MJ. The 20
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proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Transl Med 2015; 7:318ra200. [DOI: 10.1126/scitranslmed.aac9816] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Tse GH, Johnston CJC, Kluth D, Gray M, Gray D, Hughes J, Marson LP. Intrarenal B Cell Cytokines Promote Transplant Fibrosis and Tubular Atrophy. Am J Transplant 2015; 15:3067-80. [PMID: 26211786 DOI: 10.1111/ajt.13393] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 04/28/2015] [Accepted: 05/23/2015] [Indexed: 01/25/2023]
Abstract
Renal transplantation is the optimum treatment for end-stage renal failure. B cells have been identified in chronic allograft damage (CAD) and associated with the development of tertiary lymphoid tissue within the human renal allograft. We performed renal transplantation in mice to model CAD and identified B cells forming tertiary lymphoid tissue with germinal centers. Intra-allograft B220(+) B cells comprised of IgM(high) CD23(-) B cells, IgM(lo) CD23(+) B cells, and IgM(lo) CD23(-) B cells with elevated expression of CD86. Depletion of B cells with anti-CD20 was associated with an improvement in CAD but only when administered after transplantation and not before. Isolated intra-allograft B cells were cultured and shown to synthesize multiple cytokines, the most abundant of these were GRO-α (CXCL1), RANTES (CCL5), IL-6 and MCP-1 (CCL2). Tubular loss was observed with T cell accumulation within the allograft and development of interstitial fibrosis, whilst type III collagen deposition was observed in areas of F4/80(+) macrophages and PDGFR-β(+) and transgelin(+) fibroblasts, all of which were reduced by B cell depletion. We have shown that intra-allograft B cells are key mediators of CAD. B cells possibly contribute to CAD by intra-allograft secretion of cytokines and chemokines.
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Affiliation(s)
- G H Tse
- Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom
| | - C J C Johnston
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - D Kluth
- Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom
| | - M Gray
- Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom
| | - D Gray
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - J Hughes
- Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom
| | - L P Marson
- Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom
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48
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T follicular regulatory cells in the regulation of B cell responses. Trends Immunol 2015; 36:410-8. [PMID: 26091728 DOI: 10.1016/j.it.2015.05.005] [Citation(s) in RCA: 235] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 05/12/2015] [Accepted: 05/13/2015] [Indexed: 12/13/2022]
Abstract
High affinity antibodies result from interactions between B cells and T follicular helper (Tfh) cells in germinal centers (GCs). Recent studies have identified an effector subset of T regulatory cells termed T follicular regulatory (Tfr) cells that specifically controls GC responses by suppressing Tfh and B cells. The discovery of Tfr cells has shed new light on pathways regulating humoral immunity that enable potent and specific responses to pathogens while restricting autoimmunity. Here, we review the current understanding of the cellular and molecular mechanisms underlying the differentiation and function of Tfr cells. In this context we discuss recent insights into the role of Tfh cells in disease, how this knowledge may be translated therapeutically, and important areas of further research.
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Generation of Alloreactive-Anergized Tr1 Cells From Patients on Dialysis for the Induction of Renal Transplant Tolerance: Are We There Yet? Transplantation 2015; 99:1551-2. [PMID: 26018353 DOI: 10.1097/tp.0000000000000752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Gao B, Moore C, Porcheray F, Rong C, Abidoglu C, DeVito J, Paine R, Girouard TC, Saidman SL, Schoenfeld D, Levin B, Wong W, Elias N, Schuetz C, Rosales IA, Fu Y, Zorn E. Pretransplant IgG reactivity to apoptotic cells correlates with late kidney allograft loss. Am J Transplant 2014; 14:1581-91. [PMID: 24935695 PMCID: PMC4120834 DOI: 10.1111/ajt.12763] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 02/03/2014] [Accepted: 02/20/2014] [Indexed: 01/25/2023]
Abstract
Preexisting serum antibodies have long been associated with graft loss in transplant recipients. While most studies have focused on HLA-specific antibodies, the contribution of non-HLA-reactive antibodies has been largely overlooked. We have recently characterized mAbs secreted by B cell clones derived from kidney allograft recipients with rejection that bind to apoptotic cells. Here, we assessed the presence of such antibodies in pretransplant serum from 300 kidney transplant recipients and examined their contribution to the graft outcomes. Kaplan-Meier survival analysis revealed that patients with high pretransplant IgG reactivity to apoptotic cells had a significantly increased rate of late graft loss. The effect was only apparent after approximately 1 year posttransplant. Moreover, the association between pretransplant IgG reactivity to apoptotic cells and graft loss was still significant after excluding patients with high reactivity to HLA. This reactivity was almost exclusively mediated by IgG1 and IgG3 with complement fixing and activating properties. Overall, our findings support the view that IgG reactive to apoptotic cells contribute to presensitization. Taking these antibodies into consideration alongside anti-HLA antibodies during candidate evaluation would likely improve the transplant risk assessment.
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Affiliation(s)
- Baoshan Gao
- Transplant Center, The First Hospital of Jilin University, Changchun, China,Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Carolina Moore
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Fabrice Porcheray
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Chunshu Rong
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA,The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Cem Abidoglu
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Julie DeVito
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Rosemary Paine
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Timothy C. Girouard
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Susan L. Saidman
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David Schoenfeld
- Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA
| | - Bruce Levin
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Waichi Wong
- Division of Nephrology, New York Presbyterian Hospital, Columbia University Medical Center, New York, NY, USA
| | - Nahel Elias
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Christian Schuetz
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yaowen Fu
- Transplant Center, The First Hospital of Jilin University, Changchun, China
| | - Emmanuel Zorn
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA,Corresponding author: Emmanuel Zorn, Massachusetts General Hospital, Transplant Center, Thier 807, 55 Fruit Street, Boston, MA 02114, , Tel: (617) 643-3675, Fax: (617) 724-3471
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