Autoantibodies against DNA topoisomerase I promote renal allograft rejection by increasing alloreactive T cell responses

医学 免疫学 自身抗体 自身免疫 抗原 移植 同种免疫 表位 抗体 内科学
作者
Victoria Gorbacheva,Ran Fan,Satoshi Miyairi,Robert L. Fairchild,William M. Baldwin,Anna Valujskikh
出处
期刊:American Journal of Transplantation [Elsevier BV]
卷期号:23 (9): 1307-1318 被引量:1
标识
DOI:10.1016/j.ajt.2023.03.027
摘要

Abstract

Antibodies reactive to self-antigens are an important component of posttransplant immune responses. The generation requirements and functions of autoantibodies, as well as the mechanisms of their influence on alloimmune responses, still remain to be determined. Our study investigated the contribution of autoimmunity during rejection of renal allografts. We have previously characterized a mouse model in which the acute rejection of a life-supporting kidney allograft is mediated by antibodies. At rejection, recipient sera screening against >4000 potential autoantigens revealed DNA topoisomerase I peptide 205-219 (TI-I205-219) as the most prominent epitope. Subsequent analysis showed TI-I205-219-reactive autoantibodies are induced in nonsensitized recipients of major histocompatibility complex–mismatched kidney allografts in a T cell–dependent manner. Immunization with TI-I205-219 broke self-tolerance, elicited TI-I205-219 immunoglobin G autoantibodies, and resulted in acute rejection of allogeneic but not syngeneic renal transplants. The graft loss was associated with increased priming of donor-reactive T cells but not with donor-specific alloantibodies elevation. Similarly, passive transfer of anti-TI-I205-219 sera following transplantation increased donor-reactive T cell activation with minimal effects on donor-specific alloantibody levels. The results identify DNA topoisomerase I as a novel self-antigen in transplant settings and demonstrate that autoantibodies enhance activation of donor-reactive T cells following renal transplantation.
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