Association of Kidney Graft Loss With De Novo Produced Donor-Specific and Non-Donor-Specific HLA Antibodies Detected by Single Antigen Testing

Süsal, Caner; Wettstein, Dániel; Döhler, Bernd; Morath, Christian; Ruhenstroth, Andrea; Scherer, Sabine; Tran, Thuong Hien; Gombos, Petra; Schemmer, Peter; Wagner, Éric; Fehr, Thomas; Živčić-Ćosić, Stela; Balen, Sanja; Weimer, Rolf; Slavčev, Antonij; Bösmüller, Claudia; Norman, Douglas J.; Zeier, Martin; Opelz, Gerhard

doi:10.1097/tp.0000000000000672

Cited by 81 publications

(75 citation statements)

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“…Patients with high mean fluorescence intensity (MFI) DSA of greater than 3000 are automatically tested since March 2016 for the presence of complement C1q component-binding DSA. We also consider posttransplant appearance of C1q-DSA a major risk factor for AMR-mediated graft loss during the further course (see below) [2–4]. …”

Section: Heidelberg Algorithm For Transplantation Of Presensitizedmentioning

confidence: 99%

“…In the CTS serum study, we investigated a possible association of de novo development and persistence or loss of preexisting DSA with graft failure in 83 patients with failed kidney transplants and in 83 control patients without graft loss who were matched for eight different parameters, including the time after transplantation [4]. We chose this study design, because DSA determinations are costly and graft loss has increasingly become a rare event, and we wanted to include as many patients with graft loss into the analysis as possible.…”

Section: Association Of Posttransplant Dsa With Graft Lossmentioning

confidence: 99%

“…When the C1q-binding ability of de novo or persistent DSA was analyzed in sera of patients with and without graft loss, none of the nonrejectors demonstrated C1q positivity, whereas 43% of patients with graft loss showed C1q-positive antibodies, although not necessarily donor-specific ( p < 0.001). Overall, our data from this study indicated that the posttransplant presence of persisting or de novo HLA antibodies, especially if strong and C1q-binding, is associated with graft loss, even if the antibodies are not specific for mismatched donor HLA [4]. …”

Section: Association Of Posttransplant Dsa With Graft Lossmentioning

confidence: 99%

“…Many patients were transplanted in the past in the presence of preexisting DSA; not all of them lost their grafts, even if the DSA was strong and complement-activating [1–3]. Pretransplant DSA disappear in many patients without any clinical consequence directly after transplantation, whereas in others, even weak pretransplant DSA persist and do harm in the subsequent course [3, 4]. …”

Section: Introductionmentioning

confidence: 99%

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Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study

Süsal

Fichtner

Tönshoff

et al. 2017

Journal of Immunology Research

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Herein, we summarize our recent findings from the international Collaborative Transplant Study (CTS) and Heidelberg Transplant Center regarding the role of HLA antibodies in kidney transplantation and their application into the clinical routine. Based on the antibody findings from the CTS serum study, an algorithm was developed in 2006 for the transplantation of high-risk sensitized patients at the Heidelberg Transplant Center which includes seven different pre- and posttransplant measures. Using this algorithm, the number of transplantations could be increased in high-risk presensitized patients and the previously existing impact of antibodies on graft survival could greatly be diminished but not totally eliminated. More recent findings led to the hypothesis that T cell help from a preactivated immune system supports the harmful effects of pretransplant donor-specific HLA antibodies that otherwise disappear in many cases after transplantation without any consequence.

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Section: Heidelberg Algorithm For Transplantation Of Presensitizedmentioning

confidence: 99%

Section: Association Of Posttransplant Dsa With Graft Lossmentioning

confidence: 99%

Section: Association Of Posttransplant Dsa With Graft Lossmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study

Süsal

Fichtner

Tönshoff

et al. 2017

Journal of Immunology Research

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“…In addition, compatible MHC molecules (e.g., HLA-Ib antigens) overexpressed upon inflammation may elicit antibodies and contribute to the pool of NDSA. Both DSA and NDSA are capable of binding and/or aggregating on the vascular endothelial lining, attracting complement components (C1q, C4d) which form complexes that cause vascular blockage leading to minimal graft function, rejection, and graft loss [11, 12]. The allograft recipients may also develop Abs against nonclassical HLA (HLA-E, HLA-F, and HLA-G) [13] and non-MHC autoantigens (e.g., AT1R, vimentin, collagen, myosins) that may or may not be released from the allograft.…”

Section: Introductionmentioning

confidence: 99%

HLA Class Ia and Ib Polyreactive Anti-HLA-E IgG2a Monoclonal Antibodies (TFL-006 and TFL-007) Suppress Anti-HLA IgG Production by CD19+ B Cells and Proliferation of CD4+ T Cells While Upregulating Tregs

Ravindranath

2017

Journal of Immunology Research

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The anti-HLA-E IgG2a mAbs, TFL-006 and TFL-007, reacted with all HLA-I antigens, similar to the therapeutic preparations of IVIg. Indeed, IVIg lost its HLA reactivity, when its HLA-E reactivity was adsorbed out. US-FDA approved IVIg to reduce antibodies in autoimmune diseases. But the mechanism underlying IVIg-mediated antibody reduction could not be ascertained due to the presence of other polyclonal antibodies. In spite of it, the cost prohibitive high or low IVIg is administered to patients waiting for donor organ and for allograft recipients for lowering antiallograft antibodies. A mAb that could mimic IVIg in lowering Abs, with defined mechanism of action, would be highly beneficial for patients. Demonstrably, the anti-HLA-E mAbs mimicked several functions of IVIg relevant to suppressing the antiallograft Abs. The mAbs suppressed activated T cells and anti-HLA antibody production by activated B cells, which were dose-wise superior to IVIg. The anti-HLA-E mAb expanded CD4+, CD25+, and Foxp3+ Tregs, which are known to suppress T and B cells involved in antibody production. These defined functions of the anti-HLA-E IgG2a mAbs at a level superior to IVIg encourage developing their humanized version to lower antibodies in allograft recipients, to promote graft survival, and to control autoimmune diseases.

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Immune monitoring in renal transplantation: The search for biomarkers

2016

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It is now widely accepted that in order to improve long-term graft function and survival, a more personalized immunosuppressive treatment of transplant patients according to the individual anti-donor immune response status is needed. This applies to the identification of potentially "high-risk" patients likely to develop acute rejection episodes or display an accelerated decline of graft function, patients who might need immunosuppression intensification, and operationally tolerant patients suitable for immunosuppression minimization or weaning off. Such a patient stratification would benefit from biomarkers, which enable categorization into low and high risk or, ideally, identification of operational tolerant patients. Here, we report on recent developments regarding identification and performance analysis of noninvasive biomarkers such as mRNA and miRNA expression profiles, chemokines, or changes in immune cell subsets in either blood or urine of renal transplant patients. We will also discuss which future steps are needed to accelerate their clinical implementation. Keywords:Biomarker r Immunosuppression r Rejection r Renal transplantation r Tolerance Introduction: A need for immune monitoring in transplantationWith 1-year allograft survival reaching 90% and yet allograft halflife still being only approximately 10 years, renal transplantation is now facing new challenges; namely to improve long-term allograft outcomes [1,2]. Although physiological and age-related decline of graft function is irremediable and recurrence of initial renal disease difficult to prevent, uncontrolled immunological attack by the recipient's cells is the main contributor to late graft loss and should be therefore improved.Correspondence: Dr. Birgit Sawitzki e-mail: birgit.sawitzki@charite.deThe immune response toward allografts, like responses against other foreign antigens, involves the activation of antigen-reactive T cells and B cells. The main antigens priming the response against the transplanted organ are the donor, and thus foreign, MHC antigens, which elicit differentiation of, e.g. cytotoxic T cells and production of anti-MHC antibodies, also termed donor-specific antibodies (DSA). In conjunction with the activation of cells from the innate immune system or soluble factors such as complement, rejection can lead to the destruction of the transplanted organ (reviewed here: [3]). This rejection mechanism can be classified either as T-cell-mediated rejection (TCMR) when infiltration * These authors contributed equally to this work. Eur. J. Immunol. 2016. 46: 2695-2704 by the cellular compartment (i.e. T cells) predominates in renal graft biopsies, or as antibody-mediated rejection (ABMR) when the humoral response predominates, as observed in allograft glomerulopathy, and/or complement deposits in biopsy examination with serum-circulating DSA, as defined according the Banff classification [4]. In either case, impairment of renal allograft function (e.g. rise in serum creatinine) must be observed in order to diagnose a clinical r...

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Association of Kidney Graft Loss With De Novo Produced Donor-Specific and Non-Donor-Specific HLA Antibodies Detected by Single Antigen Testing

Abstract: Our data show that the posttransplant presence of persisting or de novo HLA antibodies, especially if C1q binding, is associated with graft loss, even if the antibodies are not specific for mismatched donor HLA.

Cited by 81 publications

References 20 publications

Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study

Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study

HLA Class Ia and Ib Polyreactive Anti-HLA-E IgG2a Monoclonal Antibodies (TFL-006 and TFL-007) Suppress Anti-HLA IgG Production by CD19+ B Cells and Proliferation of CD4+ T Cells While Upregulating Tregs

Immune monitoring in renal transplantation: The search for biomarkers

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