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

Antibodies reactive to self-antigens are an important component of post-transplant 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 > 4,000 potential autoantigens revealed DNA topoisomerase I peptide 205-219 (TI-I) as the most prominent epitope. Subsequent analysis showed TI-I-reactive autoantibodies are induced in non-sensitized recipients of MHC-mismatched kidney allografts in a T cell dependent manner. Immunization with TI-I broke self-tolerance, elicited TI-I IgG 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 (DSA) elevation. Similarly, passive transfer of anti-TI-I sera following transplantation increased donor-reactive T cell activation with minimal effects on DSA levels. These results identify DNA topoisomerase I as a novel self-antigen in transplant settings, and demonstrate that these autoantibodies enhance activation of donor-reactive T cells following renal transplantation.