Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients

Patel, J.; Coutance, Guillaume; Loupy, Alexandre; Dilibero, Deanna; Hamilton, Michèle A.; Kittleson, M.; Kransdorf, E.; Azarbal, Babak; Seguchi, Osamu; Zhang, Xiaohai; Chang, D.; Geft, D.; Czer, L.; Varnous, Shaïda; Kobashigawa, J.A.

doi:10.1111/ajt.16420

Cited by 45 publications

(32 citation statements)

References 32 publications

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“…In the field of transplantation, the effects of C1-q-positive DSAs on the development of AMR and the incidence of glomerulopathy, as well as the prognosis of transplantation outcomes, have been reported administration of the humanized anti-C5 monoclonal antibody eculizumab, a C5 inhibitor, inhibits the cleavage of C5 to C5a and C5b and the formation of the membrane attack complex C5b-9, and this drug is effective against acute AMR, as indicated by its effective improvement of histopathology in lung transplantation (76)(77)(78)(79). In immunologically high-risk cases, the incidence of biopsy-proven AMR following heart or kidney transplantation was significantly lower than that achieved using conventional antibody reduction therapy (80)(81)(82)(83).…”

Section: Development In Amr Control Agents Targeting Complement Systemmentioning

confidence: 99%

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Matsuda¹,

Watanabe²,

Li³

2021

Front. Immunol.

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Both acute and chronic antibody-mediated allograft rejection (AMR), which are directly mediated by B cells, remain difficult to treat. Long-lived plasma cells (LLPCs) in bone marrow (BM) play a crucial role in the production of the antibodies that induce AMR. However, LLPCs survive through a T cell-independent mechanism and resist conventional immunosuppressive therapy. Desensitization therapy is therefore performed, although it is accompanied by severe side effects and the pathological condition may be at an irreversible stage when these antibodies, which induce AMR development, are detected in the serum. In other words, AMR control requires the development of a diagnostic method that predicts its onset before LLPC differentiation and enables therapeutic intervention and the establishment of humoral immune monitoring methods providing more detailed information, including individual differences in the susceptibility to immunosuppressive agents and the pathological conditions. In this study, we reviewed recent studies related to the direct or indirect involvement of immunocompetent cells in the differentiation of naïve-B cells into LLPCs, the limitations of conventional methods, and the possible development of novel control methods in the context of AMR. This information will significantly contribute to the development of clinical applications for AMR and improve the prognosis of patients who undergo organ transplantation.

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Section: Development In Amr Control Agents Targeting Complement Systemmentioning

confidence: 99%

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Matsuda¹,

Watanabe²,

Li³

2021

Front. Immunol.

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“…The specific strategy (intravenous immune globulin and rituximab and/or plasmapheresis and bortezomib) depends on the degree of antibody sensitization 40 and patients with a positive flow crossmatch at the time of transplantation receive eculizumab. 41 Sensitization is to be expected in ACHD patients given prior cardiac surgeries with attendant blood transfusions and homograft implantation, and the increased risk of rejection compared to similarly sensitized non-ACHD patients offers a signal, in this small sample, that ACHD patients may be at higher rejection risk. 7,42,43 Nonetheless, it is reassuring that despite the marginal increase in treated rejection among ACHD patients, there was no difference in mortality, cardiac allograft vasculopathy, or rehospitalization at 1-year post-HTx.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of ACHD does not impact the choice of desensitization protocol in sensitized heart transplant candidates at our center. The specific strategy (intravenous immune globulin and rituximab and/or plasmapheresis and bortezomib) depends on the degree of antibody sensitization 40 and patients with a positive flow crossmatch at the time of transplantation receive eculizumab 41 . Sensitization is to be expected in ACHD patients given prior cardiac surgeries with attendant blood transfusions and homograft implantation, and the increased risk of rejection compared to similarly sensitized non‐ACHD patients offers a signal, in this small sample, that ACHD patients may be at higher rejection risk 7,42,43 .…”

Section: Discussionmentioning

confidence: 99%

Advanced heart failure and heart transplantation in adult congenital heart disease in the current era

Rosa

Singer-Englar

Tompkins

et al. 2021

Clinical Transplantation

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Background: Adults with congenital heart disease (ACHD) may undergo heart transplantation (HTx) despite increased risk of poor short-term outcomes due to factors including surgical complexity and antibody sensitization. We assessed the clinical characteristics and outcomes of patients with ACHD in the current era referred for HTx at a single high-volume transplant center. Methods:From 2010 to 2020, 37 ACHD patients were evaluated for HTx. ACHD HTx recipients were compared to non-ACHD HTx recipients matched for age, sex, listing status, and prior cardiac surgery.Results: Of the 37 patients with ACHD, eight (21.6%) were declined for HTx. Of 29 ACHD patients listed, 19 (65.5%) underwent HTx. Compared with non-ACHD HTx controls, the ACHD HTx recipients had more treated cellular (21.1% vs. 15.8%, P = .010) and antibody-mediated (15.8% vs. 10.5%, P = .033) rejection. There was no difference in hospital readmission or allograft vasculopathy at 1 year. There was a nonsignificant higher 1-year mortality in ACHD HTx recipients (21.1% vs. 7.9%, P = .21). Conclusion:At a high-volume transplant center, ACHD patients undergoing HTx appear to have a marginally higher risk of rejection, but no significant increase in 1year mortality. With careful selection and management, HTx for patients with ACHD may be feasible in the current era.

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“…An alternative approach is to block the downstream effects of pathogenic HLA antibodies. The complement inhibitor eculizumab has been studied in kidney transplant recipients and more recently in heart transplantation with favorable short-term outcomes ( 131 , 132 ). The strength of this approach is that it permits transplantation across DSA and a positive flow-crossmatch without hyperacute rejection.…”

Section: Current Approaches To Desensitization In Heart Transplantationmentioning

confidence: 99%

Current Desensitization Strategies in Heart Transplantation

Habal

2021

Front. Immunol.

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Heart transplant candidates sensitized to HLA antigens wait longer for transplant, are at increased risk of dying while waiting, and may not be listed at all. The increasing prevalence of HLA sensitization and limitations of current desensitization strategies underscore the urgent need for a more effective approach. In addition to pregnancy, prior transplant, and transfusions, patients with end-stage heart failure are burdened with unique factors placing them at risk for HLA sensitization. These include homograft material used for congenital heart disease repair and left ventricular assist devices (LVADs). Moreover, these risks are often stacked, forming a seemingly insurmountable barrier in some cases. While desensitization protocols are typically implemented uniformly, irrespective of the mode of sensitization, the heterogeneity in success and post-transplant outcomes argues for a more tailored approach. Achieving this will require progress in our understanding of the immunobiology underlying the innate and adaptive immune response to these varied allosensitizing exposures. Further attention to B cell activation, memory, and plasma cell differentiation is required to establish methods that durably abrogate the anti-HLA antibody response before and after transplant. The contribution of non-HLA antibodies to the net state of sensitization and the potential implications for graft longevity also remain to be comprehensively defined. The aim of this review is to first bring forth select issues unique to the sensitized heart transplant candidate. The current literature on desensitization in heart transplantation will then be summarized providing context within the immune response. Building on this, newer approaches with therapeutic potential will be discussed emphasizing the importance of not only addressing the short-term pathogenic consequences of circulating HLA antibodies, but also the need to modulate alloimmune memory.

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Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients

Cited by 45 publications

References 32 publications

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Advanced heart failure and heart transplantation in adult congenital heart disease in the current era

Current Desensitization Strategies in Heart Transplantation

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