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Diebold M, Mayer KA, Hidalgo L, Kozakowski N, Budde K, Böhmig GA. Chronic Rejection After Kidney Transplantation. Transplantation 2025; 109:610-621. [PMID: 39192468 PMCID: PMC11927446 DOI: 10.1097/tp.0000000000005187] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024]
Abstract
In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Luis Hidalgo
- HLA Laboratory, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | | | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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2
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Chou-Wu E, Niemann M, Youngs D, Gimferrer I. De Novo donor-specific anti-HLA antibody risk stratification in kidney transplantation using a combination of B cell and T cell molecular mismatch assessment. Front Immunol 2025; 16:1508796. [PMID: 40070832 PMCID: PMC11893832 DOI: 10.3389/fimmu.2025.1508796] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 02/04/2025] [Indexed: 03/14/2025] Open
Abstract
Introduction The presence of de novo donor-specific antibody (dnDSA) has detrimental effect on allograft outcomes in kidney transplantation. As humoral responses in transplantation are elicited targeting non-self-epitopes on donor HLA proteins, assessing HLA mismatches at the molecular level provides a refined means for immunological risk stratification. Methods In the present study, we utilized three HLA molecular mismatch assessment algorithms, Snow, HLAMatchmaker, and PIRCHE-II, to evaluate the independent and synergistic association of B cell and T cell epitope mismatches with dnDSA development in a cohort of 843 kidney transplant recipients. Results Our results demonstrated that B cell and T cell epitope mismatches at HLA Class I and DRB1/DQB1 loci are remarkably increased in dnDSA-positive recipients, even after normalization by allele mismatch numbers in individual study subjects. Furthermore, elevated Snow, verified eplet mismatches, and PIRCHE-II scores are significantly associated with dnDSA occurrence individually and in combination. Conclusion Our findings highlight the value of utilizing B cell and T cell epitope mismatch evaluation in living donor selection and immunological risk stratification to improve transplant outcomes.
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Affiliation(s)
- Elaine Chou-Wu
- Immunogenetics/HLA Laboratory, Bloodworks Northwest, Seattle, WA, United States
| | | | - Danny Youngs
- Immunogenetics/HLA Laboratory, Bloodworks Northwest, Seattle, WA, United States
| | - Idoia Gimferrer
- Immunogenetics/HLA Laboratory, Bloodworks Northwest, Seattle, WA, United States
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3
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Zhanzak Z, Johnson AC, Foster P, Cardenas MA, Morris AB, Zhang J, Karadkhele G, Badell IR, Morris AA, Au-Yeung BB, Roversi FM, Silva JAF, Breeden C, Hadley A, Zhang W, Larsen CP, Kissick HT. Identification of indirect CD4 + T cell epitopes associated with transplant rejection provides a target for donor-specific tolerance induction. Immunity 2025; 58:448-464.e6. [PMID: 39889703 DOI: 10.1016/j.immuni.2025.01.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 09/24/2024] [Accepted: 01/10/2025] [Indexed: 02/03/2025]
Abstract
Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSAs) posing the highest rejection risk. Here, we investigated the role of indirect CD4+ T cell epitopes-donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II-in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides. Antigen mapping of indirect CD4+ T cell epitopes in a mouse model of fully MHC mismatched skin graft transplantation (BALB/c to C57BL/6) identified a similar epitope (amino acids 287-301) derived from the donor H2-Kd. Tetramer-binding Kd287+ CD4+ T cells were detected during rejection and their transfer into T cell-deficient mice induced DSA. Systemic delivery of high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287+ CD4+ T cells and DSA formation. Thus, targeting a narrow range of donor antigens may prevent DSA formation and improve transplant outcomes.
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Affiliation(s)
- Zhuldyz Zhanzak
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Aileen C Johnson
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Petra Foster
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Maria A Cardenas
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Anna B Morris
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Joan Zhang
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Geeta Karadkhele
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - I Raul Badell
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Alanna A Morris
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Byron B Au-Yeung
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Division of Immunology, Department of Medicine, Lowance Center for Human Immunology, Emory University School of Medicine Atlanta, GA, USA
| | - Fernanda M Roversi
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Juliete A F Silva
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Cynthia Breeden
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Annette Hadley
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Weiwen Zhang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Christian P Larsen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute of Emory University, Atlanta, GA, USA.
| | - Haydn T Kissick
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute of Emory University, Atlanta, GA, USA; Emory Vaccine Center, Emory University, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
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4
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San Segundo D, Comins-Boo A, López-Hoyos M. Anti-Human Leukocyte Antigen Antibody Detection from Terasaki's Humoral Theory to Delisting Strategies in 2024. Int J Mol Sci 2025; 26:630. [PMID: 39859344 PMCID: PMC11766285 DOI: 10.3390/ijms26020630] [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: 12/05/2024] [Revised: 01/03/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The human leukocyte antigen (HLA) system plays a critical role in transplant immunology, influencing outcomes through various immune-mediated rejection mechanisms. Hyperacute rejection is driven by preformed donor-specific antibodies (DSAs) targeting HLAs, leading to complement activation and graft loss within hours to days. Acute rejection typically occurs within six months post-transplantation, involving cellular and humoral responses, including the formation of de novo DSAs. Chronic rejection, a key factor in long-term graft failure, often involves class II DSAs and complex interactions between the innate and adaptive immune systems. Advancements in HLA antibody detection, particularly single antigen bead (SAB) assays, have improved the sensitivity and characterization of DSAs. However, these assays face challenges like false positives from denatured antigens and false negatives due to low antibody titers or complement competition. Furthermore, molecular mismatch (MM) analysis has emerged as a potential tool for refining donor-recipient compatibility but faces some issues such as a lack of standardization. Highly sensitized patients with calculated panel-reactive antibodies (cPRA) of 100% face barriers to transplantation. Strategies like serum dilution, novel therapies (e.g., Imlifidase), and delisting approaches could refine immunological risk assessment and delisting strategies are essential to expand transplant opportunities for these patients.
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Affiliation(s)
- David San Segundo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Alejandra Comins-Boo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Marcos López-Hoyos
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
- Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain
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5
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Gorbacheva V, Fan R, Gaudette B, Baldwin WM, Fairchild RL, Valujskikh A. Marginal zone B cells are required for optimal humoral responses to allograft. Am J Transplant 2025; 25:48-59. [PMID: 39278625 PMCID: PMC11734443 DOI: 10.1016/j.ajt.2024.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 08/09/2024] [Accepted: 09/05/2024] [Indexed: 09/18/2024]
Abstract
Antibody-mediated rejection (AMR) is among the leading causes of graft failure in solid organ transplantation. However, AMR treatment options are limited by an incomplete understanding of the mechanisms underlying de novo donor-specific antibody (DSA) generation. The development of pathogenic isotype-switched DSA in response to transplanted allografts is typically attributed to follicular B cells undergoing germinal center reaction whereas the contribution of other B cell subsets has not been previously addressed. The current study investigated the role of recipient marginal zone B cells (MZ B cells) in DSA responses using mouse models of heart and renal allotransplantation. MZ B cells rapidly differentiate into antibody-secreting cells in response to allotransplantation. Despite the selective depletion of follicular B cells in heart allograft recipients, MZ B cells are sufficient for T-dependent IgM and early IgG DSA production. Furthermore, the presence of intact MZ B cell subset is required to support the generation of pathogenic isotype-switched DSA in renal allograft recipients containing donor-reactive memory helper T cells. These findings are the first demonstration of the role of MZ B cells in humoral alloimmune responses following solid organ transplantation and identify MZ B cells as a potential therapeutic target for minimizing de novo DSA production and AMR in transplant recipients.
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Affiliation(s)
- Victoria Gorbacheva
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Ran Fan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Brian Gaudette
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - William M Baldwin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Robert L Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Anna Valujskikh
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
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6
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Rasyid N, Duarsa GWK, Tirtayasa PMW, Situmorang GR, Rodjani A. Association Between De Novo C1q-Binding Donor-Specific Anti-HLA Antibodies and Clinical Outcomes After Kidney Transplantation: A Meta-Analysis. Transplant Proc 2024; 56:1976-1983. [PMID: 36792484 DOI: 10.1016/j.transproceed.2022.10.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/18/2022] [Indexed: 02/15/2023]
Abstract
BACKGROUND Donor-specific antibodies (DSAs) are recognized as an important factor of kidney allograft loss as a subsequent event of antibody-mediated rejection (AMR). The clinical relevance of de novo DSAs (dnDSAs) after kidney transplant, particularly in their ability to bind C1q, has been widely investigated to various extents among studies. A recent study was performed to examine the association between C1q-binding dnDSAs and succeeding clinical events after kidney transplant. METHODS A meta-analysis of studies published before April 2021 was conducted from PubMed, Science Direct, and Cochrane databases. Publications on dnDSA after kidney transplant focusing on differentiation between C1q-binding and non-C1q-binding were included. The outcomes analyzed were AMR rate and allograft loss. Studies using preformed DSA were excluded. The pooled risk ratio and 95% confidence interval (CI) were analyzed using Mantzel-Haenzel method, and the I2 value was used to determine the heterogeneity of the studies. Data analysis was conducted using Review Manager 5.3. RESULTS A total of 535 patients from 13 studies who developed dnDSA after kidney transplant were analyzed. Among these, 239 (44.7%) had C1q-binding and 296 (55.3%) had non-C1q-binding dnDSA. Acute AMR was found in 59.2% (97/164) of the C1q-binding group and in 28.8% (49/170) of the non-C1q-binding group (risk ratio [RR], 0.58 [95% CI, 0.39-0.85], P = .006, I2 = 58%). Chronic AMR was found in 50% (19/38) of the C1q-binding group and in 16.9% (11/65) of the non-C1q-binding group (RR, 0.39 [95% CI, 0.21-0.71], P = .002, I2 = 0%). Allograft loss was found in 62.2% (74/119) of the C1q-binding group and in 34.1% (60/176) of the non-C1q-binding group (RR, 0.57 [95% CI, 0.38-0.85], P = .006, I2 = 61%). CONCLUSIONS This meta-analysis demonstrates that patients who developed C1q-binding dnDSA display an increased risk of AMR and allograft loss compared with those with non-C1q-binding dnDSA. Therefore, C1q-binding dnDSAs are associated with inferior outcomes after kidney transplant.
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Affiliation(s)
- Nur Rasyid
- Department of Urology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | | | | | | | - Arry Rodjani
- Department of Urology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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7
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Cui Y, Hackett RG, Ascue J, Muralidaran V, Patil D, Kang J, Kaufman SS, Khan K, Kroemer A. Innate and Adaptive Immune Responses in Intestinal Transplant Rejection: Through the Lens of Inflammatory Bowel and Intestinal Graft-Versus-Host Diseases. Gastroenterol Clin North Am 2024; 53:359-382. [PMID: 39068000 DOI: 10.1016/j.gtc.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Intestinal transplantation is a life-saving procedure utilized for patients failing total parenteral nutrition. However, intestinal transplantattion remains plagued with low survival rates and high risk of allograft rejection. The authors explore roles of innate (macrophages, natural killer cells, innate lymphoid cells) and adaptive immune cells (Th1, Th2, Th17, Tregs) in inflammatory responses, particularly inflammatory bowel disease and graft versus host disease, and correlate these findings to intestinal allograft rejection, highlighting which effectors exacerbate or suppress intestinal rejection. Better understanding of this immunology can open further investigation into potential biomolecular targets to develop improved therapeutic treatment options and immunomonitoring techniques to combat allograft rejection and enhance patient lives.
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Affiliation(s)
- Yuki Cui
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Ryan G Hackett
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jhalen Ascue
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Vinona Muralidaran
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Digvijay Patil
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA
| | - Stuart S Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA.
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8
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Sangermano M, Negrisolo S, Antoniello B, Vadori M, Cozzi E, Benetti E. Use of Tocilizumab in the treatment of chronic active antibody-mediated rejection in pediatric kidney transplant recipients. Hum Immunol 2024; 85:111088. [PMID: 39146803 DOI: 10.1016/j.humimm.2024.111088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/29/2024] [Accepted: 08/07/2024] [Indexed: 08/17/2024]
Abstract
Chronic active antibody-mediated rejection is one of the leading causes of graft failure and traditional therapies have unclear efficacy. Recent studies suggested that Tocilizumab could stabilize renal function and improve microvascular inflammation. Here we report the outcomes of Tocilizumab therapy in 6 pediatric kidney transplant recipients with biopsy-proven chronic active antibody-mediated rejection resistant to standard treatments. All patients received monthly Tocilizumab infusions for 6 months and were monitored for renal function (creatinine, estimated glomerular filtration rate (eGFR), proteinuria) and Human Leukocyte Antigens (HLA) and non-HLA antibodies at baseline and 3 and 6 months after Tocilizumab initiation. For each patient, a follow-up biopsy was scheduled at the end of the treatment. Renal function did not show stabilization or improvement (mean eGFR 37 ml/min/1.73 m2 pre-Tocilizumab and 27 ml/min/1.73 m2 3 months after-Tocilizumab) and proteinuria remained stable. Moreover, Tocilizumab had no impact on HLA and non-HLA antibodies. Graft loss was observed in 3 patients (50 %) and 4 patients who underwent post-treatment biopsy showed a worsening in overall chronicity scores. In our pediatric series, rescue therapy with Tocilizumab did not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection.
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Affiliation(s)
- Maria Sangermano
- Pediatric Nephrology, Department of Women's and Children's Health, Padua University Hospital, Padua, Italy
| | - Susanna Negrisolo
- Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women's and Children's Health, Padua University Hospital, Padua, Italy
| | - Benedetta Antoniello
- Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women's and Children's Health, Padua University Hospital, Padua, Italy
| | - Marta Vadori
- Transplant Immunology Unit, Department of CardioThoraco-Vascular Sciences and Public Health, Padua University Hospital, Padua, Italy
| | - Emanuele Cozzi
- Transplant Immunology Unit, Department of CardioThoraco-Vascular Sciences and Public Health, Padua University Hospital, Padua, Italy
| | - Elisa Benetti
- Pediatric Nephrology, Department of Women's and Children's Health, Padua University Hospital, Padua, Italy; Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women's and Children's Health, Padua University Hospital, Padua, Italy.
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9
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Friedmann J, Schuster A, Reichelt-Wurm S, Banas B, Bergler T, Steines L. Serum IL-6 predicts risk of kidney transplant failure independently of immunological risk. Transpl Immunol 2024; 84:102043. [PMID: 38548029 DOI: 10.1016/j.trim.2024.102043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 03/23/2024] [Accepted: 03/25/2024] [Indexed: 04/07/2024]
Abstract
Interleukin-6 (IL-6) is an important immune mediator and a target for novel antibody therapies. In this study, we aimed to determine whether serum IL-6 levels are associated with immunological risk, allograft rejection and outcomes in kidney transplant (Ktx) patients. We retrospectively analyzed the data of 104 patients who underwent Ktx at our center between 2011 and 2015. The patients were divided into high- and low-risk groups (n = 52 per group) based on panel reactive antibody (PRA) percentage ≥ 35%, the existence of pre-Ktx donor-specific antibodies (DSA), or a previous transplant. IL-6 concentrations were measured before and at 3 months, 12 months, and 3 years after Ktx. Serum IL-6 levels tended to be higher in high-risk patients than in low-risk patients prior to Ktx and at 12 months after Ktx; however, the difference did not reach statistical significance (pre-Ktx, high-risk: 1.995 ± 2.79 pg/ml vs. low-risk: 1.43 ± 1.76 pg/ml, p = 0.051; 12 mo. high-risk: 1.16 ± 1.87 pg/ml vs. low-risk: 0.78 ± 1.13 pg/ml, p = 0.067). IL-6 levels were correlated with the types (no rejection, T cell mediated rejection (TCMR), antibody-mediated rejection (ABMR), or both) and time (<1 year vs. >1 year after Ktx) of rejection, as well as patient and graft survival. Patients with both TCMR and ABMR had significantly higher IL-6 levels at 3 months (14.1 ± 25.2 pg/ml) than patients with ABMR (3.4 ± 4.8 pg/ml, p = 0.017), with TCMR (1.7 ± 1.3 pg/ml, p < 0.001), and without rejection (1.7 ± 1.4 pg/ml, p < 0.001). Three years after Ktx, patients with AMBR had significantly higher IL-6 levels (5.30 ± 7.66 pg/ml) than patients with TCMR (1.81 ± 1.61 pg/ml, p = 0.009) and patients without rejection (1.19 ± 0.95 pg/ml; p = 0.001). Moreover, three years after Ktx IL-6 levels were significantly higher in patients with late rejections (3.5 ± 5.4 pg/ml) than those without rejections (1.2 ± 1.0 pg/ml) (p = 0.006). The risk of death-censored graft failure was significantly increased in patients with elevated IL-6 levels at 12 months (IL-6 level > 1.396 pg/ml, HR 4.61, p = 0.007) and 3 years (IL-6 level > 1.976 pg/ml, HR 6.75, p = 0.003), but elevated IL-6 levels were not associated with a higher risk of death. Overall, our study highlights IL-6 as a risk factor for allograft failure and confirms that IL-6 levels are higher in patients developing ABMR compared to TCMR alone or no rejection.
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Affiliation(s)
- Julius Friedmann
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Antonia Schuster
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | | | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Tobias Bergler
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany; Department of Nephrology, Hospital Ingolstadt, Ingolstadt, Germany
| | - Louisa Steines
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
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10
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Auner S, Hillebrand C, Boehm PM, Boecker J, Koren D, Schwarz S, Kovacs Z, Murakoezy G, Fischer G, Aigner C, Hoetzenecker K, Jaksch P, Benazzo A. Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation. Transpl Int 2024; 37:12774. [PMID: 38779355 PMCID: PMC11110840 DOI: 10.3389/ti.2024.12774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/15/2024] [Indexed: 05/25/2024]
Abstract
Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host's humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.
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Affiliation(s)
- S. Auner
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - C. Hillebrand
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - P. M. Boehm
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - J. Boecker
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - D. Koren
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - S. Schwarz
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Z. Kovacs
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - G. Murakoezy
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - G. Fischer
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - C. Aigner
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - K. Hoetzenecker
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - P. Jaksch
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - A. Benazzo
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
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11
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Salhi S, Congy-Jolivet N, Hebral AL, Esposito L, Vieu G, Milhès J, Kamar N, Del Bello A. Utility of Routine Post Kidney Transplant Anti-HLA Antibody Screening. Kidney Int Rep 2024; 9:1343-1353. [PMID: 38707794 PMCID: PMC11068955 DOI: 10.1016/j.ekir.2024.02.1394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/28/2024] [Accepted: 02/12/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction De novo donor-specific antibody (dnDSA) is a strong biomarker associated with the development of antibody-mediated rejection (AMR) and graft loss after kidney transplantation. This procedure is expensive; however, systematic annual screening was recommended by some national organ transplant agencies or societies even though its clinical utility was not clearly established. Methods To address this question, we retrospectively assessed the incidence of dnDSA according to the test justification (clinically indicated or systematic) in a cohort of low-immunological risk patients, defined by being nonhuman leukocyte antigen (non-HLA)-sensitized and having no previous kidney transplants. Results A total of 1072 patients, for whom 4611 anti-HLA tests were performed, were included in the study. During the follow-up period of 8 (interquartile range, IQR: 5-11) years, 77 recipients developed dnDSA (prevalence of 7.2%). Thirty-five of these dnDSAs (45.5%) were detected during the first year posttransplantation. In 95% of patients with dnDSA, an immunizing event was identified in their medical records. dnDSA was detected in 46 of 4267 systematic screening tests (1.08%) performed. Active and chronic AMR were frequently observed in biopsies performed after systematic DSA testing (17.9% and 15.4%, respectively). Conclusion Our results suggest that the detection by systematic screening of dnDSA in low-immunological risk kidney transplant patients without sensitizing events is a rare event, especially after 1 year. Moreover, in real life, systematic annual screening for dnDSA, seems having a limited impact to detect AMR at an earlier stage compared to patients in whom dnDSA was detected after a clinically indicated test.
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Affiliation(s)
- Sofiane Salhi
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
- Faculté de santé, Université Paul Sabatier, Toulouse, France
| | - Nicolas Congy-Jolivet
- Faculté de santé, Université Paul Sabatier, Toulouse, France
- Molecular Immunogenetics Laboratory, EA 3034, Faculté de Médecine Purpan, IFR150 (INSERM), France
- Department of Immunology, CHU de Toulouse, Hôpital de Rangueil, CHU de Toulouse, France
| | - Anne-Laure Hebral
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Laure Esposito
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Guillaume Vieu
- Etablissement Francais du Sang, CHU de Purpan, Toulouse, France
| | - Jean Milhès
- Faculté de santé, Université Paul Sabatier, Toulouse, France
- Molecular Immunogenetics Laboratory, EA 3034, Faculté de Médecine Purpan, IFR150 (INSERM), France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
- Faculté de santé, Université Paul Sabatier, Toulouse, France
- INSERM U1043, IFR–BMT, CHU Purpan, Toulouse, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
- Faculté de santé, Université Paul Sabatier, Toulouse, France
- INSERM U1297, IFR–BMT, CHU Rangueil, Toulouse, France
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12
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Jiang S, Su H. Exploration of the shared gene signatures and biological mechanisms between ischemia-reperfusion injury and antibody-mediated rejection in renal transplantation. Transpl Immunol 2024; 83:102001. [PMID: 38266883 DOI: 10.1016/j.trim.2024.102001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 12/22/2023] [Accepted: 01/20/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND Antibody-mediated rejection (ABMR) plays a crucial role in graft loss during allogeneic renal transplantation. In renal transplantation, ischemia-reperfusion injury (IRI) is unavoidable, serves as a major contributor to acute rejection, and is linked to graft loss. However, the mechanisms underlying IRI and ABMR are unclear. Therefore, this study aimed to investigate the shared genetic characteristics and biological mechanisms between IRI and ABMR. METHODS Gene expressions for IRI (GSE43974) and ABMR (GSE129166 and GSE36059) were retrieved from the Gene Expression Omnibus database. The shared differentially expressed genes (DEGs) of IRI and ABMR were identified, and subsequent functional enrichment analysis was performed. Immune cell infiltration in ABMR and its relationship with the shared DEGs were investigated using the CIBERSORT method. Random forest analysis, a protein-protein interaction network, and Cytoscape were used to screen hub genes, which were subsequently subjected to gene set enrichment analysis, miRNA prediction, and transcription factors analysis. The survival analysis was performed through Kaplan-Meier curves. Finally, drug compound prediction was performed on the shared DEGs using the Drug Signature Database. RESULTS Overall, 27 shared DEGs were identified between the renal IRI and ABMR groups. Among these, 24 genes exhibited increased co-expression, whereas none showed decreased co-expression. The shared DEGs were primarily enriched in the inflammation signaling pathways. Notably, CD4 memory T cells were identified as potential critical mediators of IRI, leading to ABMR. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), interferon regulatory factor 1 (IRF1), and early growth response 2 (EGR2) were identified as key components in the potential mechanism that link IRI and ABMR. Patients undergoing renal transplantation with higher expression levels of TNFAIP3, IRF1, and EGR2 exhibited decreased survival rates compared to those with lower expression levels. CONCLUSION Inflammation is a key mechanism that links IRI and ABMR, with a potential role played by CD4 memory T cells. Furthermore, TNFAIP3, IRF1, and EGR2 are implicated in the underlying mechanism between IRI and ABMR.
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Affiliation(s)
- Shan Jiang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hua Su
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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13
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Banno T, Hirai T, Oki R, Yagisawa T, Unagami K, Kanzawa T, Omoto K, Shimizu T, Ishida H, Takagi T. Higher Donor Age and Severe Microvascular Inflammation Are Risk Factors for Chronic Rejection After Treatment of Active Antibody-Mediated Rejection. Transpl Int 2024; 37:11960. [PMID: 38371907 PMCID: PMC10869508 DOI: 10.3389/ti.2024.11960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 01/10/2024] [Indexed: 02/20/2024]
Abstract
Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1 year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59 years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI.
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Affiliation(s)
- Taro Banno
- Department of Urology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Toshihito Hirai
- Department of Urology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Rikako Oki
- Department of Organ Transplant Medicine, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Takafumi Yagisawa
- Department of Urology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Kohei Unagami
- Department of Organ Transplant Medicine, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Taichi Kanzawa
- Department of Urology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Kazuya Omoto
- Department of Urology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Tomokazu Shimizu
- Department of Organ Transplant Medicine, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Hideki Ishida
- Department of Organ Transplant Medicine, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
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14
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Mengrelis K, Muckenhuber M, Wekerle T. Chimerism-based Tolerance Induction in Clinical Transplantation: Its Foundations and Mechanisms. Transplantation 2023; 107:2473-2485. [PMID: 37046378 DOI: 10.1097/tp.0000000000004589] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
Hematopoietic chimerism remains the most promising strategy to bring transplantation tolerance into clinical routine. The concept of chimerism-based tolerance aims to extend the recipient's mechanisms of self-tolerance (ie, clonal deletion, anergy, and regulation) to include the tolerization of donor antigens that are introduced through the cotransplantation of donor hematopoietic cells. For this to be successful, donor hematopoietic cells need to engraft in the recipient at least temporarily. Three pioneering clinical trials inducing chimerism-based tolerance in kidney transplantation have been published to date. Within this review, we discuss the mechanisms of tolerance that are associated with the specific therapeutic protocols of each trial. Recent data highlight the importance of regulation as a mechanism that maintains tolerance. Insufficient regulatory mechanisms are also a likely explanation for situations of tolerance failure despite persisting donor chimerism. After decades of preclinical development of chimerism protocols, mechanistic data from clinical trials have recently become increasingly important. Better understanding of the required mechanisms for tolerance to be induced in humans will be a key to design more reliable and less invasive chimerism protocols in the future.
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Affiliation(s)
- Konstantinos Mengrelis
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
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15
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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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16
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Zeng S, Crichton ES, Ford ML, Badell IR. Memory T follicular helper cells drive donor-specific antibodies independent of memory B cells and primary germinal center and alloantibody formation. Am J Transplant 2023; 23:1511-1525. [PMID: 37302575 PMCID: PMC11228286 DOI: 10.1016/j.ajt.2023.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/01/2023] [Accepted: 06/06/2023] [Indexed: 06/13/2023]
Abstract
Human leukocyte antigen antibodies are important immunologic mediators of renal allograft loss and are difficult to control. The inability to permanently eliminate donor-specific antibodies (DSA) is partly due to an incomplete understanding of the cellular mechanisms driving alloantibody formation, recurrence, and maintenance. Memory T follicular helper (mTfh) cells rapidly interact with memory B cells upon antigen re-exposure for anamnestic humoral responses, but little is known about Tfh memory in transplantation. We hypothesized that alloreactive mTfh cells form after transplantation and play a critical role in DSA formation following alloantigen re-encounter. To test this hypothesis, we utilized murine skin allograft models to identify and characterize Tfh memory and interrogate its ability to mediate alloantibody responses. We identified alloreactive Tfh memory as a mediator of accelerated humoral alloresponses independent of memory B cells and primary germinal center, or DSA, formation. Furthermore, we demonstrate that mTfh-driven alloantibody formation is susceptible to CD28 costimulation blockade. These findings provide novel insight into a pathologic role for memory Tfh in alloantibody responses and strongly support shifting therapeutic focus from the singular targeting of B cell lineage cells and alloantibodies themselves to multimodal strategies that include inhibition of mTfh cells to treat DSA.
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Affiliation(s)
- Shan Zeng
- Emory Transplant Center, Atlanta, Georgia, USA
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17
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Malhotra D, Jethwani P. Preventing Rejection of the Kidney Transplant. J Clin Med 2023; 12:5938. [PMID: 37762879 PMCID: PMC10532029 DOI: 10.3390/jcm12185938] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
With increasing knowledge of immunologic factors and with the advent of potent immunosuppressive agents, the last several decades have seen significantly improved kidney allograft survival. However, despite overall improved short to medium-term allograft survival, long-term allograft outcomes remain unsatisfactory. A large body of literature implicates acute and chronic rejection as independent risk factors for graft loss. In this article, we review measures taken at various stages in the kidney transplant process to minimize the risk of rejection. In the pre-transplant phase, it is imperative to minimize the risk of sensitization, aim for better HLA matching including eplet matching and use desensitization in carefully selected high-risk patients. The peri-transplant phase involves strategies to minimize cold ischemia times, individualize induction immunosuppression and make all efforts for better HLA matching. In the post-transplant phase, the focus should move towards individualizing maintenance immunosuppression and using innovative strategies to increase compliance. Acute rejection episodes are risk factors for significant graft injury and development of chronic rejection thus one should strive for early detection and aggressive treatment. Monitoring for DSA development, especially in high-risk populations, should be made part of transplant follow-up protocols. A host of new biomarkers are now commercially available, and these should be used for early detection of rejection, immunosuppression modulation, prevention of unnecessary biopsies and monitoring response to rejection treatment. There is a strong push needed for the development of new drugs, especially for the management of chronic or resistant rejections, to prolong graft survival. Prevention of rejection is key for the longevity of kidney allografts. This requires a multipronged approach and significant effort on the part of the recipients and transplant centers.
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Affiliation(s)
- Divyanshu Malhotra
- Johns Hopkins Medicine, Johns Hopkins Comprehensive Transplant Center, Baltimore, MD 21287, USA
| | - Priyanka Jethwani
- Methodist Transplant Institute, University of Tennessee Health Science Center, Knoxville, TN 37996, USA;
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18
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Sasaki H, Tanabe T, Tsuji T, Hotta K. Mechanism and treatment for chronic antibody-mediated rejection in kidney transplant recipients. Int J Urol 2023; 30:624-633. [PMID: 37306194 DOI: 10.1111/iju.15197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 04/11/2023] [Indexed: 06/13/2023]
Abstract
Chronic antibody-mediated rejection of kidney transplantation is a major cause of late-stage graft loss. Donor-specific antibodies are the main cause of antibody-mediated rejection; in particular, de novo donor-specific antibodies are a risk factor for chronic active antibody-mediated rejection. The level of de novo donor-specific antibodies tends to increase with time throughout long-term graft survival. Donor-specific antibodies induce humoral rejection through complement activation, which results in tissue injury and coagulation. Additionally, complement activation promotes the migration of inflammatory cells through the innate immune response, causing endothelial injury. This inflammatory response may cause persistent glomerulitis and peritubular capillaritis, leading to fixed pathological lesions that impair graft function. No treatment has been established for chronic antibody-mediated rejection, a condition in which antibody-mediated rejection becomes irreversible. Thus, antibody-mediated rejection must be detected and treated while it is still reversible. In this review, we discuss the development of de novo donor-specific antibodies and the mechanisms leading to chronic antibody-mediated rejection and summarize the current treatment options and the latest biomarkers for detecting chronic antibody-mediated rejection at an earlier stage.
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Affiliation(s)
- Hajime Sasaki
- Division of Renal Surgery and Transplantation, Department of Urology, Jichi Medical University Hospital, Shimotsuke, Japan
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Japan
| | - Tatsu Tanabe
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Japan
| | - Takahiro Tsuji
- Department of Pathology, Sapporo City General Hospital, Sapporo, Japan
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
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19
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Kim HW, Lee J, Heo SJ, Kim BS, Huh KH, Yang J. Comparison of high-dose IVIG and rituximab versus rituximab as a preemptive therapy for de novo donor-specific antibodies in kidney transplant patients. Sci Rep 2023; 13:7682. [PMID: 37169835 PMCID: PMC10175554 DOI: 10.1038/s41598-023-34804-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/08/2023] [Indexed: 05/13/2023] Open
Abstract
De novo donor-specific antibody (dnDSA) is associated with a higher risk of kidney graft failure. However, it is unknown whether preemptive treatment of subclinical dnDSA is beneficial. Here, we assessed the efficacy of high-dose intravenous immunoglobulin (IVIG) and rituximab combination therapy for subclinical dnDSA. An open-label randomized controlled clinical trial was conducted at two Korean institutions. Adult (aged ≥ 19 years) kidney transplant patients with subclinical class II dnDSA (mean fluorescence intensity ≥ 1000) were enrolled. Eligible participants were randomly assigned to receive rituximab or rituximab with IVIG at a 1:1 ratio. The primary endpoint was the change in dnDSA titer at 3 and 12 months after treatment. A total of 46 patients (24 for rituximab and 22 for rituximab with IVIG) were included in the analysis. The mean baseline estimated glomerular filtration rate was 66.7 ± 16.3 mL/min/1.73 m2. The titer decline of immune-dominant dnDSA at 12 months in both the preemptive groups was significant. However, there was no difference between the two groups at 12 months. Either kidney allograft function or proteinuria did not differ between the two groups. No antibody-mediated rejection occurred in either group. Preemptive treatment with high-dose IVIG combined with rituximab did not show a better dnDSA reduction compared with rituximab alone.Trial registration: IVIG/Rituximab versus Rituximab in Kidney Transplant With de Novo Donor-specific Antibodies (ClinicalTrials.gov Identifier: NCT04033276, first trial registration (26/07/2019).
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Affiliation(s)
- Hyung Woo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Juhan Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Seok-Jae Heo
- Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kyu Ha Huh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
| | - Jaeseok Yang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
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20
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Steinbach EJ, Barletta GM, Patel HP, Hooper DK, Garro R, Harshman LA. Donor specific antibody surveillance among pediatric kidney transplant programs: A report from the improving renal outcome collaborative. Pediatr Transplant 2023; 27:e14498. [PMID: 36898856 PMCID: PMC10305844 DOI: 10.1111/petr.14498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/23/2023] [Accepted: 02/22/2023] [Indexed: 03/12/2023]
Abstract
BACKGROUND Kidney transplantation (KT) is the preferred treatment for children with end-stage kidney disease. Recent advances in immunosuppression and advances in donor specific antibody (DSA) testing have resulted in prolonged allograft survival; however, standardized approaches for surveillance DSA monitoring and management of de novo (dn) DSA are widely variable among pediatric KT programs. METHODS Pediatric transplant nephrologists in the multi-center Improving Renal Outcomes Collaborative (IROC) participated in a voluntary, web-based survey between 2019 and 2020. Centers provided information pertaining to frequency and timing of routine DSA surveillance and theoretical management of dnDSA development in the setting of stable graft function. RESULTS 29/30 IROC centers responded to the survey. Among the participating centers, screening for DSA occurs, on average, every 3 months for the first 12 months post-transplant. Antibody mean fluorescent intensity and trend most frequently directed changes in patient management. Increased creatinine above baseline was reported by all centers as an indication for DSA assessment outside of routine surveillance testing. 24/29 centers would continue to monitor DSA and/or intensify immunosuppression after detection of antibodies in the setting of stable graft function. In addition to enhanced monitoring, 10/29 centers reported performing an allograft biopsy upon detection of dnDSA, even in the setting of stable graft function. CONCLUSIONS This descriptive report is the largest reported survey of pediatric transplant nephrologist practice patterns on this topic and provides a reference for monitoring dnDSA in the pediatric kidney transplant population.
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Affiliation(s)
- Emily J Steinbach
- Division of Nephrology, Dialysis, and Transplantation, University of Iowa Stead Family Children's Hospital, Iowa City, Iowa, USA
| | - Gina M Barletta
- Department of Pediatric Nephrology, Phoenix Children's Hospital, Phoenix, Arizona, USA
| | - Hiren P Patel
- Division of Nephrology and Hypertension, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - David K Hooper
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Rouba Garro
- Emory School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Lyndsay A Harshman
- Division of Nephrology, Dialysis, and Transplantation, University of Iowa Stead Family Children's Hospital, Iowa City, Iowa, USA
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21
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Griffin MD, Malone AF. Endothelial Expression of Class II MHC Proteins: A New Layer of Complexity in Kidney Transplantation. J Am Soc Nephrol 2023; 34:727-729. [PMID: 36958047 PMCID: PMC10125630 DOI: 10.1681/asn.0000000000000115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023] Open
Affiliation(s)
- Matthew D. Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
| | - Andrew F. Malone
- Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri
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22
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Reis Pereira P, Ribeiro B, Oliveira J, Santos S, Pedroso S, Tafulo S, Almeida M, Dias L, Martins LS, Malheiro J. Antibody-Mediated Rejection in Kidney Transplantation: A Retrospective Study on the Impact of Donor-Specific Antibodies and on the Timing of Diagnosis. Cureus 2022; 14:e30296. [DOI: 10.7759/cureus.30296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2022] [Indexed: 11/07/2022] Open
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23
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Chen X, Wang Y, Dong P, Wang J, Yu X, Yu B. Efficacy of Combined Desensitization Therapy Based on Protein A Immunoadsorption on Anti-human Leukocyte Antigen Antibodies in Sensitized Kidney Transplant Recipients: A Retrospective Study. Cureus 2022; 14:e28661. [PMID: 36196288 PMCID: PMC9525051 DOI: 10.7759/cureus.28661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2022] [Indexed: 11/07/2022] Open
Abstract
Background and objectives Protein A immunoadsorption (PA-IA) therapy is an immunoglobulin selective apheresis for pre-transplantation desensitization therapy and treatment of post-transplantation antibody-mediated rejection. There is no unified protocol for the timing of PA-IA therapy or its combination with other drug therapy. This study aimed to investigate and analyze the clearance effects of desensitization therapy on human leukocyte antigen (HLA) antibodies to provide a reference for the formulation of clinical desensitization therapy regimens. Materials and methods Overall, 27 kidney transplant recipients who received preoperative/postoperative desensitization therapy based on PA-IA therapy in combination with drug therapy were enrolled. The pre-treatment mean fluorescence intensity (MFI) of 1324 human leukocyte antigen (HLA) antibody specificities (MFI >2000) and the post-treatment MFI of the corresponding antibody specificities (after one, four, seven, and 10 sessions) were recorded to analyze the changes in antibody level reduction for the different antibody classes and MFI ranges. Results After 10 sessions of PA-IA therapy, the MFI of class I antibodies decreased from 8298.56 to 3196.15 (reduction of 66.80%), while the MFI of class II antibodies decreased from 13,521.09 to 2773.29 (reduction of 71.14%). The pre-treatment level of class II antibodies was significantly higher than that of class I antibodies (p<0.001), whereas the post-treatment levels of class I and II antibodies were comparable (p>0.05). The clearance effects of PA-IA therapy were greater for strongly positive (MFI>10,000) class II antibodies than for strongly positive class I antibodies, showing a reduction of 62.59% (25.17% to 91.04%) and 45.13% (32.70% to 73.94%), respectively (p=0.015). Conclusions We confirmed the removal efficacy of PA-IA for HLA antibodies. The removal efficacy of class II antibodies on PA-IA is not inferior to that of class I. Under an adequate number of treatment sessions, the clearance effect of PA-IA therapy for strongly positive class II antibodies may be greater than that for strongly positive class I antibodies.
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Chamoun B, Sánchez-Sancho P, Torres IB, Gabaldon A, Perelló M, Sellarés J, Moreso F, Serón D. Tocilizumab in the treatment of active chronic humoral rejection resistant to standard therapy. Nefrologia 2022; 42:578-584. [PMID: 36717307 DOI: 10.1016/j.nefroe.2021.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 06/18/2023] Open
Abstract
INTRODUCTION There is no consensus on the most appropriate treatment for chronic active antibody-mediated rejection (cAMR). Recent studies suggest that treatment with tocilizumab (TCZ) may stabilize graft function, decrease the intensity of donor-specific HLA antibodies (DSAs) and reduce inflammation of microcirculation. PATIENTS AND METHODS Observational study with renal allograft recipients diagnosed with cAMR (n = 5) who had not submitted a response to traditional treatment based on the combination of plasma replacements, immunoglobulins, and rituximab. Patients were told to be treated with TCZ as compassionate use in six doses per month (8 mg/kg/month). Renal function, proteinuria, and the intensity of DSAs were monitored during follow-up. RESULTS Five patients, average age 60 ± 13 years, three male and two retrasplants (cPRA average 55%) with preformed DSAs. Treatment with TCZ was initiated within 47 ± 52 days of biopsy. In two cases treatment was discontinued after the first dose, by severe bicitopenia with cytomegalovirus viremia and by graft failure, respectively. In the three patients who completed treatment, no stability of renal function (serum creatinine from 1.73 ± 0.70 to 2.04 ± 0.52 mg/dL, e-FGR 4 6 ± 15 to 36 ± 16 mL/min), showed increased proteinuria (3.2 ± 4.0 to 6.9 ± 11.0 g/g) and the intensity of DSAs maintain stable. No changes were observed in the degree of inflammation of microcirculation (g+pt 4.2 ± 0.8 vs. 4.3 ± 1.0) or in the degree of transplant glomerulopathy (cg 1.2 ± 0.4 vs. 1.8 ± 1.0). CONCLUSIONS TCZ therapy does not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection, does not improve the degree of inflammation of microcirculation and does not reduces the intensity of DSAs.
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Affiliation(s)
- Betty Chamoun
- Servicio de Nefrología, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain.
| | - Pablo Sánchez-Sancho
- Servicio de Farmacia, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Irina B Torres
- Servicio de Nefrología, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain.
| | - Alejandra Gabaldon
- Servicio de Patología, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Manel Perelló
- Servicio de Nefrología, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Joana Sellarés
- Servicio de Nefrología, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Francesc Moreso
- Servicio de Nefrología, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Daniel Serón
- Servicio de Nefrología, Hospital Universitari Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
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Chamoun B, Sánchez-Sancho P, Torres IB, Gabaldon A, Perelló M, Sellarés J, Moreso F, Serón D. Tocilizumab en el tratamiento del rechazo humoral crónico activo resistente a terapia estándar. Nefrologia 2022. [DOI: 10.1016/j.nefro.2021.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Role for exosomes with self-antigens and immune regulatory molecules in allo- and auto-immunity leading to chronic immune injury following murine kidney transplantation. Transpl Immunol 2022; 75:101702. [PMID: 36038048 DOI: 10.1016/j.trim.2022.101702] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Antibodies against donor human leukocyte antigen are a risk factor for chronic immune injury (CII) following renal transplantation; however, it is often not detectable. The main goal of this study is to gain new insights into the kinetics of exosome release and content in sensitized vs non-sensitized recipients. Towards this, we investigated the role for circulating exosomes with allo and self-antigens as well as immunoregulatory molecules in the development of CII and acute rejection. METHODS Using murine kidney allograft rejection models, we investigated the role of exosomes on immune responses leading to allo- and auto-immunity to self-antigens resulting in rejection. Exosomes were analyzed for kidney self-antigens (Collagen-IV, fibronectin, angiotensin II receptor type 1), and immune-regulatory molecules (PD-L1, CD73) using western blot. Antibodies to donor MHC in serum samples were detected by immunofluorescence, self-antigens by enzyme-linked immunosorbent assay and kidney tissue infiltrating cells were determined by immunohistochemistry. RESULTS BALB/c; H2d to C57BL/6; H2b renal transplantation (BALB/c), resulted in tubulitis and cellular infiltration by day 14, suggestive of acute inflammation, that was self-limiting with functioning graft. This contributed to CII on post-transplant day >100, which was preceded by induction of exosomes with donor and self-antigens leading to antibodies and immune-regulatory molecules. The absence of acute rejection in this allogenic transplant model is likely due to the induction of splenic and, graft-infiltrating CD4 + FoxP3+ T regulatory cells. In contrast, prior sensitization by skin graft followed by kidney transplantation induced antibodies to MHC and self-antigens leading to acute rejection. CONCLUSION We demonstrate a pivotal role for induction of exosomes with immune-regulatory molecules, allo- and auto-immunity to self-antigens leading to chronic immune injury following murine kidney transplantation.
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Lebraud E, Eloudzeri M, Rabant M, Lamarthée B, Anglicheau D. Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms. Front Immunol 2022; 13:864730. [PMID: 35392097 PMCID: PMC8980419 DOI: 10.3389/fimmu.2022.864730] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 02/22/2022] [Indexed: 12/26/2022] Open
Abstract
Antibody-mediated rejection (ABMR) is associated with poor transplant outcomes and was identified as a leading cause of graft failure after kidney transplantation. Although the hallmark histological features of ABMR (ABMRh), i.e., microvascular inflammation (MVI), usually correlate with the presence of anti-human leukocyte antigen donor-specific antibodies (HLA-DSAs), it is increasingly recognized that kidney transplant recipients can develop ABMRh in the absence of HLA-DSAs. In fact, 40-60% of patients with overt MVI have no circulating HLA-DSAs, suggesting that other mechanisms could be involved. In this review, we provide an update on the current understanding of the different pathogenic processes underpinning MVI. These processes include both antibody-independent and antibody-dependent mechanisms of endothelial injury and ensuing MVI. Specific emphasis is placed on non-HLA antibodies, for which we discuss the ontogeny, putative targets, and mechanisms underlying endothelial toxicity in connection with their clinical impact. A better understanding of these emerging mechanisms of allograft injury and all the effector cells involved in these processes may provide important insights that pave the way for innovative diagnostic tools and highly tailored therapeutic strategies.
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Affiliation(s)
- Emilie Lebraud
- Necker-Enfants Malades Institute, Inserm U1151, Université de Paris, Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP, Paris, France
| | - Maëva Eloudzeri
- Necker-Enfants Malades Institute, Inserm U1151, Université de Paris, Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP, Paris, France
| | - Marion Rabant
- Department of Renal Pathology, Necker Hospital, AP-HP, Paris, France
| | - Baptiste Lamarthée
- Université Bourgogne Franche-Comté, EFS BFC, Inserm UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Dijon, France
| | - Dany Anglicheau
- Necker-Enfants Malades Institute, Inserm U1151, Université de Paris, Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP, Paris, France
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28
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Kang ZY, Liu C, Liu W, Li DH. Effect of C1q-binding donor-specific anti-HLA antibodies on the clinical outcomes of patients after renal transplantation: A systematic review and meta-analysis. Transpl Immunol 2022; 72:101566. [DOI: 10.1016/j.trim.2022.101566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 12/01/2022]
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Unagami K, Ishida H, Furusawa M, Kitajima K, Hirai T, Kakuta Y, Toki D, Shimizu T, Omoto K, Okumi M, Nitta K, Tanabe K. Influence of a low-dose tacrolimus protocol on the appearance of de novo donor-specific antibodies during 7 years of follow-up after renal transplantation. Nephrol Dial Transplant 2021; 36:1120-1129. [PMID: 33280052 PMCID: PMC8160958 DOI: 10.1093/ndt/gfaa258] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs). METHODS A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not. RESULTS We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P < 0.001), were more likely to have preformed DSAs (48.2% versus 27.1%; P < 0.001) and showed poor allograft outcome. CONCLUSIONS There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4-6 ng/mL during the immunosuppression maintenance period.
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Affiliation(s)
- Kohei Unagami
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan.,Nephrology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Hideki Ishida
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan.,Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Miyuki Furusawa
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kumiko Kitajima
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Toshihito Hirai
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoichi Kakuta
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Daisuke Toki
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Tomokazu Shimizu
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuya Omoto
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kosaku Nitta
- Nephrology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
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Fylaktou A, Sampani E, Kasimatis E, Nikolaidou V, Dimitriadis C, Anastasiou A, Papachristou M, Chatzika G, Papagianni A. Prospective De Novo Donor-Specific Antibody Monitoring in Renal Transplant Patients. Transplant Proc 2021; 53:2765-2768. [PMID: 34598809 DOI: 10.1016/j.transproceed.2021.08.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/27/2021] [Accepted: 08/24/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection leading to kidney transplant failure. However, many transplant patients are stable with no signs of graft dysfunction at the time of dnDSA detection at screening test. METHODS We prospectively studied 26 kidney transplant patients for 3 years, with dnDSA detected using the Luminex single-antigen bead assay in a routine test. Proteinuria and estimated glomerular filtration rate were evaluated along with dnDSA monitoring at least annually. RESULTS Graft loss associated with dnDSA occurred in 8 (31%) patients, 14 ± 11 months after the initial detection of dnDSA. These patients had more frequently multiple dnDSA (P = .004) and remarkable proteinuria, more than 1 g daily (P < .001). The remaining 18 patients were followed for 38 ± 15 months and considered stable as there was no deterioration regarding estimated glomerular filtration rate and proteinuria. In 7 (39%) of these patients, dnDSA waned and were not detected anymore at follow-up. Antibodies against HLA class I had a significantly (P < .001) lower mean fluorescence intensity (MFI) (2603 ± 1098) compared with those against HLA class II (11,109 ± 6414). In regression analysis, they were predictive of dnDSA wane (P = .043; odds ratio, 0.18; 95% confidence interval, 0.04-0.94). Despite fluctuations during follow-up, there was no significant change in MFI for those who retained the dnDSA. CONCLUSIONS The presence of dnDSA is transient in a significant proportion of stable renal transplant patients, especially in those with antibodies against HLA class I and a low MFI. Multiple dnDSA and severe proteinuria adversely affect renal graft survival.
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Affiliation(s)
- Asimina Fylaktou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Erasmia Sampani
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece
| | - Efstratios Kasimatis
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece.
| | - Vasiliki Nikolaidou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Chrysostomos Dimitriadis
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece
| | - Aikaterini Anastasiou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Marianthi Papachristou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Georgia Chatzika
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Aikaterini Papagianni
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece
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Tang C, Unterrainer C, Fink A, Cinca S, Ruhenstroth A, Scherer S, Morath C, Zeier M, Mehrabi A, Süsal C, Tran TH. Analysis of de novo donor-specific HLA-DPB1 antibodies in kidney transplantation. HLA 2021; 98:423-430. [PMID: 34480415 DOI: 10.1111/tan.14422] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/17/2021] [Accepted: 09/01/2021] [Indexed: 11/30/2022]
Abstract
HLA matching and avoidance of unacceptable mismatches are important aspects in the selection of donors for solid organ transplantation. The impact of HLA-DPB1 incompatibility on the outcomes of kidney transplantation is not fully understood. We investigated a potential effect of mismatching for HLA-DPB1 at allele, eplet, or Terasaki epitope (TerEp) level on the formation of de novo donor-specific antibodies (dnDSA) and also asked whether polymorphisms associated with HLA-DPB1 expression level may influence dnDSA induction. Furthermore, we analyzed the correlation between graft survival and HLA-DPB1 mismatches defined by different approaches. A cohort of 366 patients who received a kidney transplant at the Heidelberg University Hospital, Germany, with availability of pre- and post-transplant HLA antibody results by single antigen testing as well as of donor and recipient HLA-DPB1 high-resolution typing were analyzed retrospectively. Susceptibility to increased HLA-DPB1 expression was predicted by the linked dimorphism rs9277534 A/G of the HLA-DPB1 gene. Neither HLA-DPB1 mismatches at allele, eplet or TerEp level nor exposure to donor's high HLA-DPB1 expression were significantly associated with the risk of developing dnDSA against HLA-DPB1. However, HLA-DPB1 eplet and TerEp mismatches had a significant negative impact on graft survival (p < 0.001 and p = 0.003, respectively). Matching for HLA-DPB1 at epitope instead of allele level appears to have potential to improve graft survival in kidney transplantation.
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Affiliation(s)
- Chen Tang
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Christian Unterrainer
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Annette Fink
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Sofia Cinca
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Andrea Ruhenstroth
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabine Scherer
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Christian Morath
- Division of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Martin Zeier
- Division of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Caner Süsal
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thuong Hien Tran
- Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
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Abstract
Defined as histologic evidence of rejection on a protocol biopsy in the absence of kidney dysfunction, subclinical rejection has garnered attention since the 1990s. The major focus of much of this research, however, has been subclinical T cell-mediated rejection (TCMR). Herein, we review the literature on subclinical antibody-mediated rejection (AMR), which may occur with either preexisting donor-specific antibodies (DSA) or upon the development of de novo DSA (dnDSA). In both situations, subsequent kidney function and graft survival are compromised. Thus, we recommend protocol biopsy routinely within the first year with preexisting DSA and at the initial detection of dnDSA. In those with positive biopsies, baseline immunosuppression should be maximized, any associated TCMR treated, and adherence stressed, but it remains uncertain if antibody-reduction treatment should be initiated. Less invasive testing of blood for donor DNA or gene profiling may have a role in follow-up of those with negative initial biopsies. If a protocol biopsy is positive in the absence of detectable HLA-DSA, it also remains to be determined whether non-HLA-DSA should be screened for either in particular or on a genome-wide basis and how these patients should be treated. Randomized controlled trials are clearly needed.
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Goesch TR, Wilson NA, Zeng W, Verhoven BM, Zhong W, Coumbe Gitter MM, Fahl WE. Suppression of Inflammation-Associated Kidney Damage Post-Transplant Using the New PrC-210 Free Radical Scavenger in Rats. Biomolecules 2021; 11:1054. [PMID: 34356678 PMCID: PMC8301928 DOI: 10.3390/biom11071054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/12/2021] [Accepted: 07/12/2021] [Indexed: 01/10/2023] Open
Abstract
Allograft kidney transplantation, which triggers host cellular- and antibody-mediated rejection of the kidney, is a major contributor to kidney damage during transplant. Here, we asked whether PrC-210 would suppress damage seen in allograft kidney transplant. Brown Norway (BN) rat kidneys were perfused in situ (UW Solution) with or without added 30 mM PrC-210, and then immediately transplanted into Lewis (LEW) rats. 20 h later, the transplanted BN kidneys and LEW rat plasma were analyzed. Kidney histology, and kidney/serum levels of several inflammation-associated cytokines, were measured to assess mismatch-related kidney pathology, and PrC-210 protective efficacy. Twenty hours after the allograft transplants: (i) significant histologic kidney tubule damage and mononuclear inflammatory cell infiltration were seen in allograft kidneys; (ii) kidney function metrics (creatinine and BUN) were significantly elevated; (iii) significant changes in key cytokines, i.e., TIMP-1, TNF-alpha and MIP-3A/CCL20, and kidney activated caspase levels were seen. In PrC-210-treated kidneys and recipient rats, (i) kidney histologic damage (Banff Scores) and mononuclear infiltration were reduced to untreated background levels; (ii) creatinine and BUN were significantly reduced; and (iii) activated caspase and cytokine changes were significantly reduced, some to background. In conclusion, the results suggest that PrC-210 could provide broadly applicable organ protection for many allograft transplantation conditions; it could protect transplanted kidneys during and after all stages of the transplantation process-from organ donation, through transportation, re-implantation and the post-operative inflammation-to minimize acute and chronic rejection.
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Affiliation(s)
| | - Nancy A. Wilson
- Department of Surgery, Division of Organ Transplant, University of Wisconsin-Madison, Madison, WI 53706, USA; (N.A.W.); (W.Z.); (B.M.V.); (W.Z.)
| | - Weifeng Zeng
- Department of Surgery, Division of Organ Transplant, University of Wisconsin-Madison, Madison, WI 53706, USA; (N.A.W.); (W.Z.); (B.M.V.); (W.Z.)
| | - Bret M. Verhoven
- Department of Surgery, Division of Organ Transplant, University of Wisconsin-Madison, Madison, WI 53706, USA; (N.A.W.); (W.Z.); (B.M.V.); (W.Z.)
| | - Weixiong Zhong
- Department of Surgery, Division of Organ Transplant, University of Wisconsin-Madison, Madison, WI 53706, USA; (N.A.W.); (W.Z.); (B.M.V.); (W.Z.)
| | - Maya M. Coumbe Gitter
- Department of Oncology, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, Madison, WI 53706, USA;
| | - William E. Fahl
- Obvia Pharmaceuticals Ltd., Madison, WI 53719, USA;
- Department of Oncology, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, Madison, WI 53706, USA;
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Liu W, Zhao J, Kang ZY, Xiao YL, Yang L, Liu C, Li DH. De novo donor-specific HLA antibodies reduce graft survival rates and increase the risk of kidney transplant rejection: A single-center retrospective study. Transpl Immunol 2021; 68:101430. [PMID: 34147608 DOI: 10.1016/j.trim.2021.101430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND We investigated the impact of de novo donor-specific anti-human leukocyte antigen antibodies (dnDSAs) on long-term death-censored graft survival and renal allograft rejection in kidney transplant recipients. METHODS The sample for this retrospective cohort study comprised 121 recipients of kidney transplants with negative complement-dependent cytotoxicity crossmatches to their deceased donors. Recipients were divided into two groups: dnDSAs+ (n = 31) and dnDSAs- (n = 90). We evaluated rejection and long-term graft survival rates in the recipients along with pathologic changes in the transplanted kidneys. RESULTS DnDSAs were identified in 31/121 patients (25.6%). The graft survival rate in the dnDSAs+ group was 87.1% (27/31) and that of the dnDSAs- group was 97.8% (88/90). The dnDSAs+ group had lower graft survival rates than patients without dnDSAs (p = 0.007). There was no difference in the graft survival rates between patients with high DSA mean fluorescence intensity (≥4000) and those with low intensity (<4000) (p = 0.669). There was also no difference in the graft survival rates of patients with HLA class I, II, and I + II dnDSAs (p = 0.571). The presence of dnDSA in serum was associated with a higher incidence of antibody- and T-cell-mediated rejection (p < 0.0001). Banff scores for arterial fibrointimal and arteriolar hyalin, thickening as well as C4d deposition differed for the dnDSAs+ and dnDSAs- groups (p < 0.05). CONCLUSION DnDSAs were found to be associated with decreased long-term graft survival rates and increased rejection rates, often accompanied by C4d deposition.
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Affiliation(s)
- Wei Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Jie Zhao
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zhong-Yu Kang
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Yan-Li Xiao
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Li Yang
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Chun Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Dai-Hong Li
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China.
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Steines L, Poth H, Schuster A, Amann K, Banas B, Bergler T. Disruption of Tfh:B Cell Interactions Prevents Antibody-Mediated Rejection in a Kidney Transplant Model in Rats: Impact of Calcineurin Inhibitor Dose. Front Immunol 2021; 12:657894. [PMID: 34135891 PMCID: PMC8201497 DOI: 10.3389/fimmu.2021.657894] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 04/23/2021] [Indexed: 12/16/2022] Open
Abstract
We aimed to investigate the mechanisms of humoral immune activation in ABMR using a MHC-mismatched rat kidney transplant model. We applied low dose cyclosporine A (loCNI) to allow donor-specific antibody (DSA) formation and rejection and high dose cyclosporine A (hiCNI) for non-rejection. DSA and leukocyte subsets were measured by flow cytometry. Germinal centers (GC), T follicular helper cells (Tfh), plasma cells and interleukin-21 (IL-21) expression were analyzed by immunofluorescence microscopy. Expression of important costimulatory molecules and cytokines was measured by qRT-PCR. Allograft rejection was evaluated by a nephropathologist. We found that DSA formation correlated with GC frequency and expansion, and that GC size was linked to the number of activated Tfh. In hiCNI, GC and activated Tfh were virtually absent, resulting in fewer plasma cells and no DSA or ABMR. Expression of B cell activating T cell cytokine IL-21 was substantially inhibited in hiCNI, but not in loCNI. In addition, hiCNI showed lower expression of ICOS ligand and IL-6, which stimulate Tfh differentiation and maintenance. Overall, Tfh:B cell crosstalk was controlled only by hiCNI treatment, preventing the development of DSA and ABMR. Additional strategies targeting Tfh:B cell interactions are needed for preventing alloantibody formation and ABMR.
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Affiliation(s)
- Louisa Steines
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Helen Poth
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Antonia Schuster
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Kerstin Amann
- Department of Nephropathology, University Hospital Erlangen, Erlangen, Germany
| | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Tobias Bergler
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
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36
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Challenges of Diagnosing Antibody-Mediated Rejection: The Role of Invasive and Non-Invasive Biomarkers. ACTA ACUST UNITED AC 2021; 57:medicina57050439. [PMID: 34063583 PMCID: PMC8147623 DOI: 10.3390/medicina57050439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 12/22/2022]
Abstract
Kidney transplantation is the best treatment modality for end-stage kidney disease, leading to improvement in a patient’s quality and quantity of life. With significant improvements in short-term outcomes, prolonging long-term allograft and patient survival remain ongoing challenges. The ability to monitor allograft function, immune tolerance and predict rejection accurately would enable personalization and better prognostication during post-transplant care. Though kidney biopsy remains the backbone of transplant diagnostics, emerging biomarkers can help detecting kidney allograft injury early enough to prevent permanent damage and detect injury before it is clinically apparent. In this review, we summarize the recent biomarkers that have shown promise in the prediction of acute rejection with a focus on antibody-mediated rejection in kidney transplantation.
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Andrade-Sierra J, Cueto-Manzano AM, Rojas-Campos E, Cardona-Muñoz E, Cerrillos-Gutiérrez JI, González-Espinoza E, Evangelista-Carrillo LA, Medina-Pérez M, Jalomo-Martínez B, Nieves Hernández J, Pazarín-Villaseñor L, Mendoza-Cerpa CA, Gómez-Navarro B, Miranda-Díaz AG. Donor-specific antibodies development in renal living-donor receptors: Effect of a single cohort. Int J Immunopathol Pharmacol 2021; 35:20587384211000545. [PMID: 33787382 PMCID: PMC8020398 DOI: 10.1177/20587384211000545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Minimization in immunosuppression could contribute to the appearance the donor-specific HLA antibodies (DSA) and graft failure. The objective was to compare the incidence of DSA in renal transplantation (RT) in recipients with immunosuppression with and without steroids. A prospective cohort from March 1st, 2013 to March 1st, 2014 and follow-up (1 year), ended in March 2015, was performed in living donor renal transplant (LDRT) recipients with immunosuppression and early steroid withdrawal (ESW) and compared with a control cohort (CC) of patients with steroid-sustained immunosuppression. All patients were negative cross-matched and for DSA pre-transplant. The regression model was used to associate the development of DSA antibodies and acute rejection (AR) in subjects with immunosuppressive regimens with and without steroids. Seventy-seven patients were included (30 ESW and 47 CC). The positivity of DSA class I (13% vs 2%; P < 0.05) and class II (17% vs 4%, P = 0.06) antibodies were higher in ESW versus CC. The ESW tended to predict DSA class II (RR 5.7; CI (0.93–34.5, P = 0.06). T-cell mediated rejection presented in 80% of patients with DSA class I (P = 0.07), and 86% with DSA II (P = 0.03), and was associated with DSA class II, (RR 7.23; CI (1.2–44), P = 0.03). ESW could favor the positivity of DSA. A most strictly monitoring the DSA is necessary for the early stages of the transplant to clarify the relationship between T-cell mediated rejection and DSA.
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Affiliation(s)
- Jorge Andrade-Sierra
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México.,Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, México
| | - Alfonso M Cueto-Manzano
- Medical Research Unit in Renal Diseases, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Enrique Rojas-Campos
- Medical Research Unit in Renal Diseases, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Ernesto Cardona-Muñoz
- Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, México
| | - José I Cerrillos-Gutiérrez
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Eduardo González-Espinoza
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Luis A Evangelista-Carrillo
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Miguel Medina-Pérez
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Basilio Jalomo-Martínez
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Juan Nieves Hernández
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Leonardo Pazarín-Villaseñor
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Claudia A Mendoza-Cerpa
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Benjamin Gómez-Navarro
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Alejandra G Miranda-Díaz
- Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, México
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Cioni M, Comoli P, Tagliamacco A, Innocente A, Basso S, Fontana I, Magnasco A, Trivelli A, Nocco A, Macchiagodena M, Catenacci L, Klersy C, Verrina E, Garibotto G, Ghiggeri GM, Cardillo M, Ginevri F, Nocera A. Post-transplant de novo non donor-specific HLA antibodies are not associated with poor graft outcome in non-sensitized pediatric recipients of kidney transplantation. Transpl Immunol 2021; 65:101375. [PMID: 33610675 DOI: 10.1016/j.trim.2021.101375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 10/22/2022]
Abstract
While de novo donor-specific HLA antibodies (dnDSAs) have a detrimental impact on kidney graft outcome, the clinical significance of de novo non donor-specific antibodies (dnNDSAs) is more controversial. We retrospectively evaluated for Ab development and characteristics of dnNDSAs serially collected post-transplant sera and, when available, graft biopsy eluates, from 144 non-sensitized, primary pediatric kidney recipients, consecutively transplanted at a single center between 2003 and 2017, using HLA class I and class II single-antigen flow-bead assays (SAB). The results were compared with clinical-pathologic data from HLA antibody negative and HLA dnDSA-positive patients. Forty-five out of 144 patients developed dnNDSAs (31%). Among the dnNDSA-positive patients, 86% displayed one or more class I/II antibodies recognizing antigens included in the CREG/shared epitope groups that also comprise the mismatched donor HLA antigens. Despite potential pathogenicity, as suggested by their occasional presence within the graft, dnNDSAs displayed significantly lower MFI, and limited complement binding and graft homing properties, when compared with dnDSAs. In parallel, the graft survival probability was significantly lower in patients with dnDSA than in those with dnNDSA or without HLA antibodies (p < 0.005). Indeed, the dnNDSA-positive patients remaining dnDSA-negative throughout the posttransplant period did not develop clinical antibody mediated rejection and graft loss, and maintained good graft function at a median follow-up of 9 years. The biological characteristics of dnNDSAs may account for the low graft damaging capability when compared to dnDSAs.
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Affiliation(s)
- Michela Cioni
- Laboratory of Molecular Nephrology, IRCCS Giannina Gaslini, Genova, Italy
| | - Patrizia Comoli
- Cell Factory and Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Augusto Tagliamacco
- Clinical Nephrology Unit and Transplant Coordination Unit, Policlinico San Martino, Genova, Italy
| | - Annalisa Innocente
- Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Sabrina Basso
- Cell Factory and Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Iris Fontana
- Vascular and Endovascular Unit and Kidney Transplant Surgery Unit, Ospedale Policlinico San Martino, Genova, Italy
| | - Alberto Magnasco
- Nephrology, Dialysis, Transplantation Unit, IRCCS Giannina Gaslini, Genova, Italy
| | - Antonella Trivelli
- Nephrology, Dialysis, Transplantation Unit, IRCCS Giannina Gaslini, Genova, Italy
| | - Angela Nocco
- Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Mario Macchiagodena
- Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Laura Catenacci
- Cell Factory and Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Catherine Klersy
- Biometry and Clinical Epidemiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Enrico Verrina
- Nephrology, Dialysis, Transplantation Unit, IRCCS Giannina Gaslini, Genova, Italy
| | - Giacomo Garibotto
- Clinical Nephrology Unit, University of Genova and Policlinico San Martino Genova, Italy
| | - Gian Marco Ghiggeri
- Nephrology, Dialysis, Transplantation Unit, IRCCS Giannina Gaslini, Genova, Italy
| | - Massimo Cardillo
- Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy; Italian National Transplant Centre, Italian National Institute of Health (ISS), Rome, Italy
| | - Fabrizio Ginevri
- Nephrology, Dialysis, Transplantation Unit, IRCCS Giannina Gaslini, Genova, Italy.
| | - Arcangelo Nocera
- Nephrology, Dialysis, Transplantation Unit, IRCCS Giannina Gaslini, Genova, Italy
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39
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O'Neill MA, Hidalgo LG. NK cells in antibody-mediated rejection - Key effector cells in microvascular graft damage. Int J Immunogenet 2021; 48:110-119. [PMID: 33586864 DOI: 10.1111/iji.12532] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/12/2021] [Accepted: 01/31/2021] [Indexed: 12/14/2022]
Abstract
Antibody-mediated rejection (ABMR) stands as the major limitation to long-term transplant outcome. The immunologic understanding of ABMR continues to progress and has identified natural killer (NK) cells as key effector cells promoting and coordinating the immune attack on the graft microvascular endothelium. This review discusses the current concepts outlining the different ways that allow for NK cell recognition of graft endothelial cells which includes antibody-dependent as well as independent processes.
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Affiliation(s)
- Megan A O'Neill
- Department of Surgery, University of Wisconsin School of Medicine and Public Health (UWSMPH), Madison, WI, USA
| | - Luis G Hidalgo
- Department of Surgery, University of Wisconsin School of Medicine and Public Health (UWSMPH), Madison, WI, USA
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40
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Kueht M, Jindra P, Stevenson HL, Galvan TN, Murthy B, Goss J, Anton J, Abbas R, Cusick MF. Intra-operative kinetics of anti-HLA antibody in simultaneous liver-kidney transplantation. Mol Genet Metab Rep 2021; 26:100705. [PMID: 33489761 PMCID: PMC7811052 DOI: 10.1016/j.ymgmr.2020.100705] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 12/27/2020] [Accepted: 12/28/2020] [Indexed: 11/05/2022] Open
Abstract
During simultaneous liver-kidney transplantation (SLK) in highly sensitized patients, donor specific anti-human leukocyte antigen antibodies (DSA, HLA) can be present prior to transplant leading to positive crossmatch, yet these recipients have relatively low incidences of acute rejection. The mechanisms and timing underlying immunologic changes that occur intra-operatively remain largely unknown. Therefore, we measured the intra- and peri-operative kinetics of anti-HLA antibodies in highly sensitized SLK recipients. In this study, pre- and post-operative blood samples were obtained from sensitized SLK candidates with documented DSA. Intra-operative samples were obtained from a sub-group of SLK recipients. Pretransplant anti-HLA antibody profiles were created and flow cytometry and anti-human globulin complement-dependent cytotoxic crossmatches were performed. Significant reductions in anti-HLA class I and II DSA were seen intra-operatively shortly after reperfusion of the liver allograft. This effect was most pronounced for anti-HLA class I DSA (mean change, −85%, p < 0.05); changes to anti-HLA class II DSA were less robust (mean change, −47%, p = 0.15). Importantly, non-DSA anti-HLA antibodies remained unchanged throughout the perioperative period, suggesting the mechanism(s) by which the liver lowers DSA levels are specific to the DSA. These data demonstrate the immunologic benefit of performing SLK is lasting and occurs very shortly after liver reperfusion.
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Affiliation(s)
- M Kueht
- Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, United States of America
| | - P Jindra
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, MS:BCM 504, Houston, TX 77030, United States of America
| | - H L Stevenson
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, United States of America
| | - T N Galvan
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, MS:BCM 504, Houston, TX 77030, United States of America
| | - B Murthy
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, MS:BCM 504, Houston, TX 77030, United States of America
| | - J Goss
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, MS:BCM 504, Houston, TX 77030, United States of America
| | - J Anton
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, MS:BCM 504, Houston, TX 77030, United States of America
| | - R Abbas
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, MS:BCM 504, Houston, TX 77030, United States of America
| | - M F Cusick
- Department of Pathology, University of Michigan Medicine, 2800 Plymouth Rd., Building 36, Ann Arbor, MI 48109, United States of America
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41
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Safety and Efficacy of a Steroid Avoidance Immunosuppression Regimen in Renal Transplant Patients With De Novo or Preformed Donor-Specific Antibodies: A Single-Center Study. Transplant Proc 2020; 53:950-961. [PMID: 33293041 DOI: 10.1016/j.transproceed.2020.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/18/2020] [Accepted: 10/20/2020] [Indexed: 11/23/2022]
Abstract
Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing. Cohorts included kidney transplant recipients with de novo DSAs (dnDSAs; n = 27), preformed DSAs (pfDSAs; n = 15), and no DSAs (nDSAs; n = 146). Median time to dnDSA development (classes I and II) was shorter (102 days) than in previous studies. Rejection of any type was associated with DSAs to class I HLA (P < .05) and class II HLA (P < .01) but not with graft loss. Although mean fluorescence intensity (MFI) independently showed no association with rejection, an MFI >5000 showed a trend toward more antibody-mediated rejection (P < .06), though graft loss was not independently associated. Banff chronic allograft nephropathy scores and a modified chronic injury score were increased in the dnDSA cohort at 6 months, but not at 2 years (P < .001 and P < .08, respectively). Our data suggest that dnDSAs and pfDSAs impact short-term rejection rates but do not negatively impact graft survival or histopathological outcomes at 2 years. Periodic protocol post-transplant DSA monitoring may preemptively identify patients who develop dnDSAs who are at a higher risk for rejection.
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42
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von Moos S, Cippà PE, van Breemen R, Mueller TF. HLA antibodies are associated with deterioration of kidney allograft function irrespective of donor specificity. Hum Immunol 2020; 82:19-24. [PMID: 33162184 DOI: 10.1016/j.humimm.2020.10.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 10/23/2020] [Accepted: 10/23/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND Donor-specific antibodies are associated with high immunological risk and poor allograft outcome. Risk and clinical relevance of non-donor-specific HLA antibodies is less clear. METHODS A retrospective single-center study was conducted in all patients receiving a first kidney transplant at the University hospital of Zürich between 01/2006 and 02/2015. Patients were stratified into 3 groups having either no HLA antibodies at all (NoAB), HLA antibodies with donor specificity (DSA) and HLA antibodies without donor specificity (NonDSA). Allograft outcome was assessed using the slope of the estimated glomerular filtration rate (eGFR slope) starting at 12 months after transplantation. RESULTS During a median follow-up of 1808 days HLA antibodies were detected in 106 of 238 eligible patients (44%). Out of these, 73 patients (69%) had DSA and 33 patients (31%) had NonDSA only. Medium-term allograft function, as determined by eGFR slope over three years, improved in patients with NoAB (months 12-48: +0.7 ml/min/1.73 m2) but deteriorated significantly in patients with both DSA (months 12-48: -1.5 ml/min per1.73 m2/year, p = 0.015) and NonDSA (months 12-48: -1.8 ml/min per1.73 m2/year, p = 0.03) as compared to the group with NoAB. CONCLUSION Both, donor-specific and non-donor-specific HLA antibodies are associated with medium-term kidney allograft dysfunction as compared to patients with no HLA antibodies.
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Affiliation(s)
- Seraina von Moos
- Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.
| | - Pietro E Cippà
- Division of Nephrology, Ente Ospedaliero Cantonale, Lugano, Switzerland.
| | - Rob van Breemen
- Division of Informatics, University Hospital Zürich, Zürich, Switzerland.
| | - Thomas F Mueller
- Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.
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Tafulo S, Malheiro J, Santos S, Dias L, Almeida M, Martins LS, Pedroso S, Mendes C, Lobato L, Castro-Henriques A. HLA class II eplet mismatch load improves prediction of dnDSA development after living donor kidney transplantation. Int J Immunogenet 2020; 48:1-7. [PMID: 33145950 DOI: 10.1111/iji.12519] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/26/2020] [Accepted: 10/13/2020] [Indexed: 12/01/2022]
Abstract
HLA donor-specific antibodies developed de novo after transplant remain a major cause of chronic allograft dysfunction. Our study main purpose was to determine whether HLA MM, assessed traditionally and by HLA total and AbVer eplet mismatch load (EptMM and EpvMM) assessed with HLAMatchMaker, had impact on dnDSA development after living donor kidney transplantation (LDKT). We retrospectively analysed a cohort of 96 LDKT between 2008 and 2017 performed in Hospital Santo António. Seven patients developed dnDSA-II and EpvMM and EptMM were greater in dnDSA-II group compared to the no dnDSA-II (18.0 ± 8.7 versus 9.9 ± 7.9, p = .041 and 41.3 ± 18.9 versus 23.1 ± 16.7, p = .018), which is not observed for AgMM (2.29 versus 1.56; p = .09). In a multivariate analysis, we found that preformed DSA (HR = 7.983; p = .023), living unrelated donors (HR = 8.052; p = .024) and retransplantation (HR = 14.393; p = .009) were predictors for dnDSA-II (AUC = 0.801; 0.622-0.981). HLA-II EpvMM (HR = 1.105; p = .028; AUC = 0.856) showed to be a superior predictor of dnDSA-II, when compared to AgMM (HR = 1.740; p = .113; AUC = 0.783), when adjusted for these clinical variables. Graft survival was significantly lower within dnDSA-II patient group (36% versus 88%, p < .001). HLA molecular mismatch analysis is extremely important to minimize risk for HLA-II dnDSA development improving outcome and increasing chance of retransplant lowering allosensitization.
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Affiliation(s)
- Sandra Tafulo
- Blood and Transplantation Center of Porto, Portuguese Institute for Blood and Transplantation, Porto, Portugal.,Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, Porto, Portugal
| | - Jorge Malheiro
- Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, Porto, Portugal.,Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Sofia Santos
- Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, Porto, Portugal.,Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Leonídio Dias
- Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Manuela Almeida
- Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, Porto, Portugal.,Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - La Salete Martins
- Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, Porto, Portugal.,Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Sofia Pedroso
- Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, Porto, Portugal.,Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Cecília Mendes
- Blood and Transplantation Center of Porto, Portuguese Institute for Blood and Transplantation, Porto, Portugal
| | - Luísa Lobato
- Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, Porto, Portugal.,Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - António Castro-Henriques
- Department of Nephrology, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
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44
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Immunological follow-up of patients with renal transplants: A proposal for clinical practice in Colombia. ACTA ACUST UNITED AC 2020; 40:479-486. [PMID: 33030826 PMCID: PMC7666855 DOI: 10.7705/biomedica.5092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Indexed: 11/21/2022]
Abstract
Graft damage is a process that starts at the moment of transplantation, due to comorbidities of receptor, donor status, ischemia time, ischemia-reperfusion phenomenon, among others, those induce metabolic and immune factors that ultimately trigger clinical manifestations of graft dysfunction. However, the preclinical progression between the time of transplantation and the appearance of signs and symptoms of graft damage can take weeks to years.
Therefore, the implementation of rational monitoring approaches during the post-transplantation period is critical and should include not only the clinical follow-up but also anticipate immunological graft damage. In the present essay, we propose an immunological monitoring algorithm for the post-renal transplantation period.
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45
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Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper. Transplantation 2020; 104:S1-S12. [DOI: 10.1097/tp.0000000000003270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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46
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Benazzo A, Worel N, Schwarz S, Just U, Nechay A, Lambers C, Böhmig G, Fischer G, Koren D, Muraközy G, Knobler R, Klepetko W, Hoetzenecker K, Jaksch P. Outcome of Extracorporeal Photopheresis as an Add-On Therapy for Antibody-Mediated Rejection in Lung Transplant Recipients. Transfus Med Hemother 2020; 47:205-213. [PMID: 32595425 DOI: 10.1159/000508170] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 03/26/2020] [Indexed: 01/02/2023] Open
Abstract
Introduction The diagnosis and treatment of antibody-mediated rejection (AMR) after lung transplantation has recently gained recognition within the transplant community. Extracorporeal photopheresis (ECP), currently used to treat chronic lung allograft dysfunction, modulates various pathways of the immune system known to be involved in AMR. We hypothesize that adding ECP to established AMR treatments could prevent the rebound of donor-specific antibodies (DSA). Objectives This study aimed to analyze the role of ECP as an add-on therapy to prevent the rebound of DSA. Methods Lung transplant recipients who received ECP as an add-on therapy for pulmonary AMR between January 2010 and January 2019 were included in this single-center retrospective analysis. Baseline demographics of the patients, as well as their immunological characteristics and long-term transplant outcomes, were analyzed. Results A total of 41 patients developed clinical AMR during the study period. Sixteen patients received ECP as an add-on therapy after first-line AMR treatment. Among the 16 patients, 2 (13%) had pretransplant DSA, both against human leukocyte antigen (HLA) class I (B38, B13, and C06). Fifteen patients (94%) developed de novo DSA (dnDSA), i.e., 10 (63%) against class I and 14 (88%) against class II. The median time to dnDSA after lung transplantation was 361 days (range 25-2,548). According to the most recent International Society of Heart and Lung Transplantation (ISHLT) consensus report, 2 (13%) patients had definite clinical AMR, 6 (38%) had probable AMR, and 7 (44%) had possible AMR. The median mean fluorescence intensity (MFI) of dnDSA at the time of clinical diagnosis was 4,220 (range 1,319-10,552) for anti-HLA class I and 10,953 (range 1,969-27,501) for anti-HLA class II antibodies. ECP was performed for a median of 14 cycles (range 1-64). MFI values of dnDSA against HLA classes I and II were significantly reduced over the treatment period (for anti-class I: 752; range 70-2,066; for anti-class II: 5,612; range 1,689-21,858). The 1-year survival rate was 55%. No adverse events related to ECP were reported in any of the patients. Conclusions ECP is associated with a reduction of dnDSA in lung transplant recipients affected by AMR. Prospective studies are warranted to confirm the beneficial effects of ECP in the setting of AMR.
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Affiliation(s)
- Alberto Benazzo
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Nina Worel
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Stefan Schwarz
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Ulrike Just
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Anna Nechay
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Christoph Lambers
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Georg Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Gottfried Fischer
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Daniela Koren
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Gabriela Muraközy
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Robert Knobler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Walter Klepetko
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Konrad Hoetzenecker
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Peter Jaksch
- Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
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Torres-Ruiz J, Villca-Gonzales R, Gómez-Martín D, Zentella-Dehesa A, Tapia-Rodríguez M, Uribe-Uribe NO, Morales-Buenrostro LE, Alberú J. A potential role of neutrophil extracellular traps (NETs) in kidney acute antibody mediated rejection. Transpl Immunol 2020; 60:101286. [PMID: 32156665 DOI: 10.1016/j.trim.2020.101286] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND The aim of this study was to evaluate neutrophil extracellular traps (NETs) in kidney transplant recipients (KTR) and their potential involvement in acute antibody-mediated rejection (AAMR). METHODS We studied 3 groups: KTR with AAMR (KTR-Cases, n = 14); KTR without any immunologic event (KTR-Controls, n = 14) and donors (n = 12). Spontaneous and lipopolysaccharide-induced NETosis were evaluated by immunofluorescence indirect (IFI) (NET/cells ratio). Plasmatic cH3-DNA complexes were evaluated by ELISA, (Optic Density Index - ODI). The expression of MPO and citrullinated histone 4 (cH4) was evaluated in renal biopsies. RESULTS We found an enhanced spontaneous NETosis in KTR regardless of whether they had rejection. The Nets/cells ratio in spontaneous NETosis was 0.203 (IQR 0.12-0.34) in Total-KTR and 0.094 (IQR 0.01-0.17) in donors, p = .011. Likewise, the ODI of cH3-DNA was 1.41 (IQR 0.94-1.72) in Total-KTR, and 0.95 (IQR 0.83-1.27) in donors, p = .019. KTR-Cases had the higher amount of NETs 1.70 (IQR 1.19-1.91). In two KTR-Cases, expression of MPO and cH4 was found in biopsies. CONCLUSIONS KTR show enhanced NETosis. This may indicate a permanent activation of neutrophils. Although more studies are needed, the higher amount of NETs and netting neutrophils in biopsies of KTR-Cases suggest a role of NETosis in AAMR.
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Affiliation(s)
- Jiram Torres-Ruiz
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; Emergency Medicine Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Roxana Villca-Gonzales
- Department of Nephrology, Hospital Regional Lic Adolfo Lopez Mateos, ISSSTE, Mexico City, Mexico
| | - Diana Gómez-Martín
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey 64710, N.L., Mexico
| | - Alejandro Zentella-Dehesa
- Department of Genomic Medicine and Environmental Toxicology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Miguel Tapia-Rodríguez
- Microscopy Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Norma O Uribe-Uribe
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Luis E Morales-Buenrostro
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
| | - Josefina Alberú
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey 64710, N.L., Mexico; Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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Inverse Association Between the Quantity of Human Peripheral Blood CXCR5+IFN-γ+CD8+ T Cells With De Novo DSA Production in the First Year After Kidney Transplant. Transplantation 2020; 104:2424-2434. [PMID: 32032292 DOI: 10.1097/tp.0000000000003151] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND We recently reported that a novel CXCR5IFN-γCD8 T-cell subset significantly inhibits posttransplant alloantibody production in a murine transplant model. These findings prompted the current study to investigate the association of human CD8 T cells with the same phenotype with the development of de novo donor-specific antibody (DSA) after kidney transplantation. METHODS In the current studies, we prospectively and serially analyzed peripheral blood CD8 and CD4 T-cell subsets and monitored for the development of de novo DSA in kidney transplant recipients during the first-year posttransplant. We report results on 95 first-time human kidney transplant recipients with 1-year follow-up. RESULTS Twenty-three recipients (24.2%) developed de novo DSA within 1-year posttransplant. Recipients who developed DSA had significantly lower quantities of peripheral CXCR5IFN-γCD8 T cells (P = 0.01) and significantly lower ratios of CXCR5IFN-γCD8 T cell to combined CD4 Th1/Th2 cell subsets (IFN-γCD4 and IL-4CD4 cells; P = 0.0001) compared to recipients who remained DSA-negative over the first-year posttransplant. CONCLUSIONS Our data raise the possibility that human CXCR5IFN-γCD8 T cells are a homolog to murine CXCR5IFN-γCD8 T cells (termed antibody-suppressor CD8 T cells) and that the quantity of CXCR5IFN-γCD8 T cells (or the ratio of CXCR5IFN-γCD8 T cells to Th1/Th2 CD4 T cells) may identify recipients at risk for development of DSA.
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Gorbacheva V, Fan R, Beavers A, Fairchild RL, Baldwin WM, Valujskikh A. Anti-donor MHC Class II Alloantibody Induces Glomerular Injury in Mouse Renal Allografts Subjected to Prolonged Cold Ischemia. J Am Soc Nephrol 2019; 30:2413-2425. [PMID: 31597715 DOI: 10.1681/asn.2018111169] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 09/07/2019] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The mechanisms underlying the effects of prolonged cold-ischemia storage on kidney allografts are poorly understood. METHODS To investigate effects of cold ischemia on donor-reactive immune responses and graft pathology, we used a mouse kidney transplantation model that subjected MHC-mismatched BALB/c kidney allografts to cold-ischemia storage for 0.5 or 6 hours before transplant into C57BL/6 mice. RESULTS At day 14 post-transplant, recipients of allografts subjected to 6 versus 0.5 hours of cold-ischemia storage had increased levels of anti-MHC class II (but not class I) donor-specific antibodies, increased donor-reactive T cells, and a significantly higher proportion of transplant glomeruli infiltrated with macrophages. By day 60 post-transplant, allografts with a 6 hour cold-ischemia time developed extensive glomerular injury compared with moderate pathology in allografts with 0.5 hour of cold-ischemia time. Pathology was associated with increased serum levels of anti-class 2 but not anti-class 1 donor-specific antibodies. Recipient B cell depletion abrogated early macrophage recruitment, suggesting augmented donor-specific antibodies, rather than T cells, increase glomerular pathology after prolonged cold ischemia. Lymphocyte sequestration with sphingosine-1-phosphate receptor 1 antagonist FTY720 specifically inhibited anti-MHC class II antibody production and abrogated macrophage infiltration into glomeruli. Adoptive transfer of sera containing anti-donor MHC class II antibodies or mAbs against donor MHC class II restored early glomerular macrophage infiltration in FTY720-treated recipients. CONCLUSIONS Post-transplant inflammation augments generation of donor-specific antibodies against MHC class II antigens. Resulting MHC class II-reactive donor-specific antibodies are essential mediators of kidney allograft glomerular injury caused by prolonged cold ischemia.
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Affiliation(s)
- Victoria Gorbacheva
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ran Fan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ashley Beavers
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Robert L Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - William M Baldwin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Anna Valujskikh
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
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Clinical Significance of Alloantibodies in Hand Transplantation: A Multicenter Study. Transplantation 2019; 103:2173-2182. [DOI: 10.1097/tp.0000000000002650] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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