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Philip F Halloran - One of the best experts on this subject based on the ideXlab platform.
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new concepts in chronic antibody mediated Kidney Allograft Rejection prevention and treatment
Current Opinion in Organ Transplantation, 2021Co-Authors: Katharina A Mayer, Philip F Halloran, Farsad Eskandary, Konstantin Doberer, Georg A. BöhmigAbstract:PURPOSE OF REVIEW Chronic antibody-mediated Rejection (AMR) is a cardinal cause of transplant failure, with currently no proven effective prevention or treatment. The present review will focus on new therapeutic concepts currently under clinical evaluation. RECENT FINDINGS One interesting treatment approach may be interference with interleukin-6 (IL-6) signaling to modulate B-cell immunity and donor-specific antibody (DSA) production. Currently, a large phase III randomized controlled trial is underway to clarify the safety and efficacy of clazakizumab, a high-affinity anti-IL-6 antibody, in chronic AMR. A prevention/treatment strategy may be costimulation blockade using belatacept to interfere with germinal center responses and DSA formation. In a recent uncontrolled study, belatacept conversion was shown to stabilize renal function and dampen AMR activity. Moreover, preliminary clinical results suggest efficacy of CD38 antibodies to deplete plasma and natural killer cells to treat AMR, with anecdotal reports demonstrating at least transient resolution of active Rejection. SUMMARY There are promising concepts on the horizon for the prevention and treatment of chronic AMR. The design of adequately powered placebo-controlled trials to clarify the safety and efficacy of such new therapies, however, remains a big challenge, and will rely on the definition of precise surrogate endpoints predicting long-term Allograft survival. Mapping the natural history of AMR would greatly help the understanding of who would derive benefits from treatment.
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the therapeutic challenge of late antibody mediated Kidney Allograft Rejection
Transplant International, 2019Co-Authors: Georg A. Böhmig, Farsad Eskandary, Konstantin Doberer, Philip F HalloranAbstract:Late antibody-mediated Rejection (ABMR) is a cardinal cause of Kidney Allograft failure, manifesting as a continuous and, in contrast with early Rejection, often clinically silent alloimmune process. While significant progress has been made towards an improved understanding of its molecular mechanisms and the definition of diagnostic criteria, there is still no approved effective treatment. In recent small randomized controlled trials, therapeutic strategies with promising results in observational studies, such as proteasome inhibitor bortezomib, anti-C5 antibody eculizumab, or high dose intravenous immunoglobulin plus rituximab, had no significant impact in late and/or chronic ABMR. Such disappointing results reinforce a need of new innovative treatment strategies. Potential candidates may be the interference with interleukin-6 to modulate B cell alloimmunity, or innovative compounds that specifically target antibody-producing plasma cells, such as antibodies against CD38. Given the phenotypic heterogeneity of ABMR, the design of adequate systematic trials to assess the safety and efficiency of such therapies, however, is challenging. Several trials are currently being conducted, and new developments will hopefully provide us with effective ways to counteract the deleterious impact of antibody-mediated graft injury. Meanwhile, the weight of evidence would suggest that, when approaching using existing treatments for established antibody-mediated Rejection, "less may be more".
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or50 complement binding donor specific anti hla antibodies induce a specific histo molecular Kidney Allograft Rejection phenotype
Human Immunology, 2017Co-Authors: Carmen Lefaucheur, Philip F Halloran, B Sis, Denis Viglietti, Massimo Mangiola, Olivier Aubert, Denis Glotz, Christophe Legendre, Alexandre Loupy, Adriana ZeeviAbstract:Aim Complement-binding donor-specific anti-HLA antibodies (DSA) have been associated with impaired Kidney transplant outcome. We investigated whether they induce a specific Kidney Allograft Rejection phenotype. Methods We prospectively enrolled 931 Kidney recipients transplanted between 2011 and 2014, with systematic screening for circulating DSA in the first year post-transplantation. We assessed DSA specificity, mean fluorescence intensity (MFI), C1q-binding capacity and IgG1-4 subclasses using Luminex SAB. All patients underwent Allograft biopsy at the time post-transplant DSA detection. The Allograft Rejection phenotypes were assessed by histopathology, immunochemistry and Allograft gene expression (microarray). A model of fully MHC-mismatched male CBA (H-2 k) Kidneys transplanted into B6.RAG1−/− (H-2b) immunodeficient mice with adoptive transfer of complement and non-complement-activating DSA was studied. Results We identified 157 (17%) patients with circulating anti-HLA DSA detected in the first year after transplantation, 44 (28%) with complement-binding DSA, and 113 (72%) with non-complement-binding DSA. Patients with complement-binding DSA showed higher MFI levels (9483±747 vs. 2978±278; P P P P P P P Conclusions Circulating complement-binding anti-HLA DSA induce a specific histo-molecular phenotype of Kidney Allograft Rejection.
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the early course of Kidney Allograft Rejection defining the time when Rejection begins
American Journal of Transplantation, 2009Co-Authors: Gunilla Einecke, Konrad S Famulski, Michael Mengel, Luis G Hidalgo, K Allanach, Philip F HalloranAbstract:We studied the early events in mouse Kidney Allografts and isografts to define when allorecognition begins and when alloimmune tissue injury begins. Allografts but not isografts showed T-cell infiltration in perivascular areas from day 1, but tubulitis and arteritis did not develop until day 7. Flow cytometry confirmed the early allospecific CD3+CD8+ T-cell infiltrate. At day 1, both Allografts and isografts showed extensive transcriptome changes, reflecting the response to surgery, but only Allografts showed expression of interferon-gamma (IFN-γ)-inducible transcripts and T-cell-associated transcripts. Although the number of CD68+ myeloid cell numbers did not increase in day 1 isografts or Allografts, mRNA expression for myeloid markers was increased in isografts and Allografts, suggesting activation of resident cells of the macrophage-dendritic cell series (MMDCs) in response to injury, followed by increased CD68+ cell numbers from day 2. By day 3, an interstitial T-cell and MMDC infiltrate was established in Allografts, corresponding with the emergence of allospecific tissue injury, as reflected by decreased parenchymal transcripts. Thus, in renal Allografts, allorecognition by T cells occurs in perivascular sites by day 1, but alloimmune parenchymal damage begins at day 3, coinciding with the emergence of the interstitial T-cell–MMDC infiltrate.
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expression of ctl associated transcripts precedes the development of tubulitis in t cell mediated Kidney graft Rejection
American Journal of Transplantation, 2005Co-Authors: Gunilla Einecke, Anette Melk, Vido Ramassar, Chris R Bleackley, Konrad S Famulski, Philip F HalloranAbstract:The usual phenotype of clinical Kidney Allograft Rejection is infiltration by lymphocytes and macrophages and evolution of histologic Banff lesions, particularly tubulitis, which indicate parenchymal injury. Using Affymetrix microarrays, we evaluated the relationship between the evolution of pathologic lesions and the transcriptome. We studied CBA/J into C57Bl/6 mouse Kidney Allografts in which one host Kidney is left in place to permit observation of lesion development. Histology was dominated by early infiltration by mononuclear cells from day 3 and slower evolution of tubulitis after day 7. We defined a set of cytotoxic T lymphocyte-associated transcripts (CATs) on the basis of expression in purified cytotoxic T lymphocytes (CTL) and in a mixed lymphocyte culture, and absence in normal Kidney. CATs were detectable by day 3 and highly expressed by day 5 in rejecting Kidneys, with a median signal 14% of that in CTL, compared to 4% in isografts and normal Kidneys, and persisted through day 42. Lack of mature B cells had little effect on CAT expression, confirming that CATs reflect T-cell-mediated Rejection. Expression of CATs was established before diagnostic lesions and remained remarkably consistent through day 42 despite massive alterations in the pathology, and probably reflects T cells recruited to the graft.
Georg A. Böhmig - One of the best experts on this subject based on the ideXlab platform.
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new concepts in chronic antibody mediated Kidney Allograft Rejection prevention and treatment
Current Opinion in Organ Transplantation, 2021Co-Authors: Katharina A Mayer, Philip F Halloran, Farsad Eskandary, Konstantin Doberer, Georg A. BöhmigAbstract:PURPOSE OF REVIEW Chronic antibody-mediated Rejection (AMR) is a cardinal cause of transplant failure, with currently no proven effective prevention or treatment. The present review will focus on new therapeutic concepts currently under clinical evaluation. RECENT FINDINGS One interesting treatment approach may be interference with interleukin-6 (IL-6) signaling to modulate B-cell immunity and donor-specific antibody (DSA) production. Currently, a large phase III randomized controlled trial is underway to clarify the safety and efficacy of clazakizumab, a high-affinity anti-IL-6 antibody, in chronic AMR. A prevention/treatment strategy may be costimulation blockade using belatacept to interfere with germinal center responses and DSA formation. In a recent uncontrolled study, belatacept conversion was shown to stabilize renal function and dampen AMR activity. Moreover, preliminary clinical results suggest efficacy of CD38 antibodies to deplete plasma and natural killer cells to treat AMR, with anecdotal reports demonstrating at least transient resolution of active Rejection. SUMMARY There are promising concepts on the horizon for the prevention and treatment of chronic AMR. The design of adequately powered placebo-controlled trials to clarify the safety and efficacy of such new therapies, however, remains a big challenge, and will rely on the definition of precise surrogate endpoints predicting long-term Allograft survival. Mapping the natural history of AMR would greatly help the understanding of who would derive benefits from treatment.
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the therapeutic challenge of late antibody mediated Kidney Allograft Rejection
Transplant International, 2019Co-Authors: Georg A. Böhmig, Farsad Eskandary, Konstantin Doberer, Philip F HalloranAbstract:Late antibody-mediated Rejection (ABMR) is a cardinal cause of Kidney Allograft failure, manifesting as a continuous and, in contrast with early Rejection, often clinically silent alloimmune process. While significant progress has been made towards an improved understanding of its molecular mechanisms and the definition of diagnostic criteria, there is still no approved effective treatment. In recent small randomized controlled trials, therapeutic strategies with promising results in observational studies, such as proteasome inhibitor bortezomib, anti-C5 antibody eculizumab, or high dose intravenous immunoglobulin plus rituximab, had no significant impact in late and/or chronic ABMR. Such disappointing results reinforce a need of new innovative treatment strategies. Potential candidates may be the interference with interleukin-6 to modulate B cell alloimmunity, or innovative compounds that specifically target antibody-producing plasma cells, such as antibodies against CD38. Given the phenotypic heterogeneity of ABMR, the design of adequate systematic trials to assess the safety and efficiency of such therapies, however, is challenging. Several trials are currently being conducted, and new developments will hopefully provide us with effective ways to counteract the deleterious impact of antibody-mediated graft injury. Meanwhile, the weight of evidence would suggest that, when approaching using existing treatments for established antibody-mediated Rejection, "less may be more".
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Immunoadsorption in severe C4d-positive acute Kidney Allograft Rejection: a randomized controlled trial.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2006Co-Authors: Georg A. Böhmig, Markus Wahrmann, H. Regele, Markus Exner, B. Robl, Kurt Derfler, T. Soliman, P. Bauer, Marcus Müllner, W. DrumlAbstract:Antibody-mediated Rejection (AMR) frequently causes refractory graft dysfunction. This randomized controlled trial was designed to evaluate whether immunoadsorption (IA) is effective in the treatment of severe C4d-positive AMR. Ten out of 756 Kidney Allograft recipients were included. Patients were randomly assigned to IA with protein A (N = 5) or no such treatment (N = 5) with the option of IA rescue after 3 weeks. Enrolled recipients were subjected to tacrolimus conversion and, if indicated, 'anti-cellular' treatment. All IA-treated patients responded to treatment. One death unrelated to IA occurred after successful reversal of Rejection. Four control subjects remained dialysis-dependent. With the exception of one patient who developed graft necrosis, non-responders were subjected to rescue IA, however, without success. Because of a high graft loss rate in the control group the study was terminated after a first interim analysis. Even though limited by small patient numbers, this trial suggests efficiency of IA in reversing severe AMR.
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Diagnosis and treatment of antibody-mediated Kidney Allograft Rejection
Transplant International, 2003Co-Authors: Georg A. Böhmig, Heinz RegeleAbstract:Evidence of a significant pathogenetic role of donor-reactive antibodies (DRA) in Kidney Allograft Rejection is accumulating. At least, partially owing to the recent discovery of the complement split product C4d as a valuable Rejection marker, antibody-mediated Rejection (AMR) has regained increasing attention. We review here the value of various diagnostic criteria, including immunohistochemistry (C4d staining), histomorphology and posttransplant serology, for the diagnosis of AMR. Furthermore, the mechanisms underlying alloantibody/complement-mediated Allograft injury are discussed in detail. Finally, a thorough discussion of recently proposed “anti-humoral” therapeutic strategies is provided.
Farsad Eskandary - One of the best experts on this subject based on the ideXlab platform.
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new concepts in chronic antibody mediated Kidney Allograft Rejection prevention and treatment
Current Opinion in Organ Transplantation, 2021Co-Authors: Katharina A Mayer, Philip F Halloran, Farsad Eskandary, Konstantin Doberer, Georg A. BöhmigAbstract:PURPOSE OF REVIEW Chronic antibody-mediated Rejection (AMR) is a cardinal cause of transplant failure, with currently no proven effective prevention or treatment. The present review will focus on new therapeutic concepts currently under clinical evaluation. RECENT FINDINGS One interesting treatment approach may be interference with interleukin-6 (IL-6) signaling to modulate B-cell immunity and donor-specific antibody (DSA) production. Currently, a large phase III randomized controlled trial is underway to clarify the safety and efficacy of clazakizumab, a high-affinity anti-IL-6 antibody, in chronic AMR. A prevention/treatment strategy may be costimulation blockade using belatacept to interfere with germinal center responses and DSA formation. In a recent uncontrolled study, belatacept conversion was shown to stabilize renal function and dampen AMR activity. Moreover, preliminary clinical results suggest efficacy of CD38 antibodies to deplete plasma and natural killer cells to treat AMR, with anecdotal reports demonstrating at least transient resolution of active Rejection. SUMMARY There are promising concepts on the horizon for the prevention and treatment of chronic AMR. The design of adequately powered placebo-controlled trials to clarify the safety and efficacy of such new therapies, however, remains a big challenge, and will rely on the definition of precise surrogate endpoints predicting long-term Allograft survival. Mapping the natural history of AMR would greatly help the understanding of who would derive benefits from treatment.
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cd38 antibody daratumumab for the treatment of chronic active antibody mediated Kidney Allograft Rejection
Transplantation, 2020Co-Authors: Konstantin Doberer, Farsad Eskandary, Katharina A Mayer, Johannes Klager, Guido A Gualdoni, Evan A Farkash, Hermine Agis, Thomas Reiter, Roman Reindlschwaighofer, Markus WahrmannAbstract:BACKGROUND Late antibody-mediated Rejection (AMR) is a major cause of transplant failure. Potential therapeutic targets are plasma cells and natural killer (NK) cells, both expressing high levels of CD38. METHODS Here, we report the use of CD38 monoclonal antibody daratumumab (9-mo course) in a Kidney Allograft recipient diagnosed with smoldering myeloma and anti-HLA class II donor-specific antibody-positive chronic active AMR 13 years after transplantation. Patient monitoring included serial HLA single-antigen testing, peripheral blood immune cell phenotyping, as well as follow-up Allograft and bone marrow biopsies at 3 and 9 months, including analyses of Rejection-related gene expression patterns. RESULTS Daratumumab led to persistent CD138+ cell depletion in the bone marrow and blood and substantially decreased NK cells counts in blood and graft tissue. At the same time, donor-specific antibody in serum disappeared, and in vitro alloantibody production by CD138+ cells enriched from bone marrow aspirates was abrogated. A 3-month follow-up biopsy revealed a complete resolution of microcirculation inflammation (g+ptc: 3 to 0) and molecular AMR activity (AMR score: 0.79 to <0.2). The same biopsy showed (subclinical) tubulointerstitial inflammation, which prompted steroid treatment. Over an observation period of 12 months, graft function stabilized. CONCLUSIONS Targeting CD38 for plasma cell and NK cell depletion may be an effective strategy to counteract AMR. Our results may encourage the design of future trials to clarify the role of this innovative treatment concept in organ transplantation.
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the therapeutic challenge of late antibody mediated Kidney Allograft Rejection
Transplant International, 2019Co-Authors: Georg A. Böhmig, Farsad Eskandary, Konstantin Doberer, Philip F HalloranAbstract:Late antibody-mediated Rejection (ABMR) is a cardinal cause of Kidney Allograft failure, manifesting as a continuous and, in contrast with early Rejection, often clinically silent alloimmune process. While significant progress has been made towards an improved understanding of its molecular mechanisms and the definition of diagnostic criteria, there is still no approved effective treatment. In recent small randomized controlled trials, therapeutic strategies with promising results in observational studies, such as proteasome inhibitor bortezomib, anti-C5 antibody eculizumab, or high dose intravenous immunoglobulin plus rituximab, had no significant impact in late and/or chronic ABMR. Such disappointing results reinforce a need of new innovative treatment strategies. Potential candidates may be the interference with interleukin-6 to modulate B cell alloimmunity, or innovative compounds that specifically target antibody-producing plasma cells, such as antibodies against CD38. Given the phenotypic heterogeneity of ABMR, the design of adequate systematic trials to assess the safety and efficiency of such therapies, however, is challenging. Several trials are currently being conducted, and new developments will hopefully provide us with effective ways to counteract the deleterious impact of antibody-mediated graft injury. Meanwhile, the weight of evidence would suggest that, when approaching using existing treatments for established antibody-mediated Rejection, "less may be more".
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anti c1s monoclonal antibody bivv009 in late antibody mediated Kidney Allograft Rejection results from a first in patient phase 1 trial
American Journal of Transplantation, 2018Co-Authors: Farsad Eskandary, Markus Wahrmann, Heinz Regele, Bernd Jilma, Jakob Muhlbacher, Nicolas Kozakowski, Christa Firbas, Sandip Panicker, Graham Parry, Jim GilbertAbstract:The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated Rejection (ABMR). Selective CP blockade may be a promising strategy to counteract Rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of four weekly doses (60 mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable Kidney transplant recipients (median of 4.3 years post-transplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During seven weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of eight C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another two recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or Kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials. gov NCT#02502903 This article is protected by copyright. All rights reserved.
Konstantin Doberer - One of the best experts on this subject based on the ideXlab platform.
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new concepts in chronic antibody mediated Kidney Allograft Rejection prevention and treatment
Current Opinion in Organ Transplantation, 2021Co-Authors: Katharina A Mayer, Philip F Halloran, Farsad Eskandary, Konstantin Doberer, Georg A. BöhmigAbstract:PURPOSE OF REVIEW Chronic antibody-mediated Rejection (AMR) is a cardinal cause of transplant failure, with currently no proven effective prevention or treatment. The present review will focus on new therapeutic concepts currently under clinical evaluation. RECENT FINDINGS One interesting treatment approach may be interference with interleukin-6 (IL-6) signaling to modulate B-cell immunity and donor-specific antibody (DSA) production. Currently, a large phase III randomized controlled trial is underway to clarify the safety and efficacy of clazakizumab, a high-affinity anti-IL-6 antibody, in chronic AMR. A prevention/treatment strategy may be costimulation blockade using belatacept to interfere with germinal center responses and DSA formation. In a recent uncontrolled study, belatacept conversion was shown to stabilize renal function and dampen AMR activity. Moreover, preliminary clinical results suggest efficacy of CD38 antibodies to deplete plasma and natural killer cells to treat AMR, with anecdotal reports demonstrating at least transient resolution of active Rejection. SUMMARY There are promising concepts on the horizon for the prevention and treatment of chronic AMR. The design of adequately powered placebo-controlled trials to clarify the safety and efficacy of such new therapies, however, remains a big challenge, and will rely on the definition of precise surrogate endpoints predicting long-term Allograft survival. Mapping the natural history of AMR would greatly help the understanding of who would derive benefits from treatment.
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cd38 antibody daratumumab for the treatment of chronic active antibody mediated Kidney Allograft Rejection
Transplantation, 2020Co-Authors: Konstantin Doberer, Farsad Eskandary, Katharina A Mayer, Johannes Klager, Guido A Gualdoni, Evan A Farkash, Hermine Agis, Thomas Reiter, Roman Reindlschwaighofer, Markus WahrmannAbstract:BACKGROUND Late antibody-mediated Rejection (AMR) is a major cause of transplant failure. Potential therapeutic targets are plasma cells and natural killer (NK) cells, both expressing high levels of CD38. METHODS Here, we report the use of CD38 monoclonal antibody daratumumab (9-mo course) in a Kidney Allograft recipient diagnosed with smoldering myeloma and anti-HLA class II donor-specific antibody-positive chronic active AMR 13 years after transplantation. Patient monitoring included serial HLA single-antigen testing, peripheral blood immune cell phenotyping, as well as follow-up Allograft and bone marrow biopsies at 3 and 9 months, including analyses of Rejection-related gene expression patterns. RESULTS Daratumumab led to persistent CD138+ cell depletion in the bone marrow and blood and substantially decreased NK cells counts in blood and graft tissue. At the same time, donor-specific antibody in serum disappeared, and in vitro alloantibody production by CD138+ cells enriched from bone marrow aspirates was abrogated. A 3-month follow-up biopsy revealed a complete resolution of microcirculation inflammation (g+ptc: 3 to 0) and molecular AMR activity (AMR score: 0.79 to <0.2). The same biopsy showed (subclinical) tubulointerstitial inflammation, which prompted steroid treatment. Over an observation period of 12 months, graft function stabilized. CONCLUSIONS Targeting CD38 for plasma cell and NK cell depletion may be an effective strategy to counteract AMR. Our results may encourage the design of future trials to clarify the role of this innovative treatment concept in organ transplantation.
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the therapeutic challenge of late antibody mediated Kidney Allograft Rejection
Transplant International, 2019Co-Authors: Georg A. Böhmig, Farsad Eskandary, Konstantin Doberer, Philip F HalloranAbstract:Late antibody-mediated Rejection (ABMR) is a cardinal cause of Kidney Allograft failure, manifesting as a continuous and, in contrast with early Rejection, often clinically silent alloimmune process. While significant progress has been made towards an improved understanding of its molecular mechanisms and the definition of diagnostic criteria, there is still no approved effective treatment. In recent small randomized controlled trials, therapeutic strategies with promising results in observational studies, such as proteasome inhibitor bortezomib, anti-C5 antibody eculizumab, or high dose intravenous immunoglobulin plus rituximab, had no significant impact in late and/or chronic ABMR. Such disappointing results reinforce a need of new innovative treatment strategies. Potential candidates may be the interference with interleukin-6 to modulate B cell alloimmunity, or innovative compounds that specifically target antibody-producing plasma cells, such as antibodies against CD38. Given the phenotypic heterogeneity of ABMR, the design of adequate systematic trials to assess the safety and efficiency of such therapies, however, is challenging. Several trials are currently being conducted, and new developments will hopefully provide us with effective ways to counteract the deleterious impact of antibody-mediated graft injury. Meanwhile, the weight of evidence would suggest that, when approaching using existing treatments for established antibody-mediated Rejection, "less may be more".
Robert L. Fairchild - One of the best experts on this subject based on the ideXlab platform.
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recipient myeloperoxidase producing cells regulate antibody mediated acute versus chronic Kidney Allograft Rejection
JCI insight, 2021Co-Authors: Satoshi Miyairi, Kazunari Tanabe, Nina Dvorina, Anna Valujskikh, Takafumi Yagisawa, Daisuke Ueda, Daigo Okada, Karen Keslar, Stanley L Hazen, Robert L. FairchildAbstract:Antibody-mediated Rejection (ABMR) continues to be a major problem undermining the success of Kidney transplantation. Acute antibody-mediated Rejection (ABMR) of Kidney grafts is characterized by neutrophil and monocyte margination in the tubular capillaries and by graft transcripts indicating NK cell activation, but the myeloid cell mechanisms required for acute ABMR have remained unclear. Dysregulated donor-specific antibody (DSA) responses with high antibody titers are induced in B6.CCR5-/- mice transplanted with complete MHC mismatched A/J Kidneys and are required for Rejection of the grafts. This study tested the role of recipient myeloid cell production of myeloperoxidase (MPO) on the cellular and molecular components of acute ABMR. Despite induction of equivalent DSA titers, B6.CCR5-/- recipients rejected A/J Kidneys between days 18-25 with acute ABMR whereas B6.CCR5-/-MPO-/- recipients rejected the grafts between days 46-54 with histopathological features of chronic graft injury. On day 15, myeloid cells infiltrating grafts from B6.CCR5-/- and B6.CCR5-/-MPO-/- recipients expressed marked phenotypic and functional transcript differences that correlated with development of acute vs. chronic Allograft injury, respectively. Near the time of peak DSA titers, NK cell activation to proliferate and express CD107a was markedly decreased within Allografts in B6.CCR5-/-MPO-/- recipients. Despite high titers of DSA, depletion of neutrophils reproduced the inhibition of NK cell activation and decreased macrophage infiltration but increased monocytes producing MPO. Overall, recipient myeloid cells producing MPO regulate graft-infiltrating monocyte/macrophage function and NK cell activation that are required for DSA-mediated acute Kidney Allograft injury and their absence switches DSA-mediated acute pathology and graft outcomes to chronic ABMR.
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in the absence of natural killer cell activation donor specific antibody mediates chronic but not acute Kidney Allograft Rejection
Kidney International, 2019Co-Authors: Takafumi Yagisawa, Toshiaki Tanaka, Kazunari Tanabe, Nina Dvorina, Anna Valujskikh, Satoshi Miyairi, Wayne M Yokoyama, Robert L. FairchildAbstract:Antibody mediated Rejection (ABMR) is a major barrier to long-term Kidney graft survival. Dysregulated donor-specific antibody (DSA) responses are induced in CCR5-deficient mice transplanted with complete major histocompatibility complex (MHC)-mismatched Kidney Allografts, and natural killer (NK) cells play a critical role in graft injury and Rejection. We investigated the consequence of high DSA titers on Kidney graft outcomes in the presence or absence of NK cell activation within the graft. Equivalent serum DSA titers were induced in CCR5-deficient B6 recipients of complete MHC mismatched A/J Allografts and semi-allogeneic (A/J x B6) F1 Kidney grafts, peaking by day 14 post-transplant. A/J Allografts were rejected between days 16-28, whereas B6 isografts and semi-allogeneic grafts survived past day 65. On day 7 post-transplant, NK cell infiltration into A/J Allografts was composed of distinct populations expressing high and low levels of the surface antigen NK1.1, with NK1.1low cells reflecting the highest level of activation. These NK cell populations increased with time post-transplant. In contrast, NK cell infiltration into semi-allogeneic grafts on day 7 was composed entirely of NK1.1high cells that decreased thereafter. On day 65 post-transplant the semi-allogeneic grafts had severe interstitial fibrosis, glomerulopathy, and arteriopathy, accompanied by expression of pro-fibrogenic genes. These results suggest that NK cells synergize with DSA to cause acute Kidney Allograft Rejection, whereas high DSA titers in the absence of NK cell activation cannot provoke acute ABMR but instead induce the indolent development of interstitial fibrosis and glomerular injury that leads to late graft failure.
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natural killer cells play a critical role in mediating inflammation and graft failure during antibody mediated Rejection of Kidney Allografts
Kidney International, 2016Co-Authors: Naoki Kohei, William M Baldwin, Toshiaki Tanaka, Kazunari Tanabe, Naoya Masumori, Nina Dvorina, Anna Valujskikh, Robert L. FairchildAbstract:While the incidence of antibody-mediated Kidney graft Rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of Kidney Allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated Kidney Allograft Rejection in these recipients. Wild-type C57BL/6, B6.CCR5 -/- , and B6.CD8 -/- /CCR5 -/- mice were transplanted with complete MHC-mismatched A/J Kidney grafts, and intragraft inflammatory components were followed to Rejection. B6.CCR5 -/- and B6.CD8 -/- /CCR5 -/- recipients rejected Kidney Allografts by day 35, whereas 65% of Allografts in wild-type recipients survived past day 80 post-transplant. Rejected Allografts in wild-type C57BL/6, B6.CCR5 -/- , and B6.CD8 -/- /CCR5 -/- recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in Allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8 -/- /CCR5 -/- recipients reduced this expression to background levels and promoted the long-term survival of 40% of the Kidney Allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated Kidney Allograft injury and in Rejection of the grafts.
