*Purpose: Immune responses to self antigens develop following organ transplantation. Multiple studies describe correlations between pre-existing or de novo autoimmune responses and poor transplant outcome. We previously identified DNA topoisomerase I peptide TI-I_205-219 as one of the most prominent epitopes for autoantibody generation in mouse renal allograft recipients. Anti-TI-I_205-219 IgG antibodies are induced in T cell dependent manner after transplantation of BALB/c kidney allografts into non-sensitized B6 recipients. Recipient sensitization further increases the level of anti-TI-I_205-219 autoantibodies. The goal of the current study was to investigate the contribution of anti-TI-I_205-219 autoantibodies to renal tissue injury in a mouse model of bilateral renal warm ischemia and kidney transplantation.

*Methods: B6 mice were immunized with TI-I_205-219 (3 biweekly injections of 100ug TI-I_205-219/CFA s.c.) and either subjected to 25 min bilateral renal warm ischemia followed by reperfusion or used as recipients of BALB/c renal allografts. In additional experiments sera collected from TI-I_205-219 or control CFA immunized mice were adoptively transferred into B6 recipients of BALB/c renal allografts on d2 and d4 posttransplant.

*Results: Immunization with TI-I_205-219 resulted in the generation of anti-TI-I_205-219 IgG autoantibody. Induced autoimmune response markedly enhanced neutrophil infiltration into the kidney following bilateral warm ischemia and reperfusion. Previous TI-I_205-219 immunization resulted in rapid rejection in 10/12 kidney allograft recipients (MST of 12.5 d) whereas only 2/6 CFA-immunized controls rejected by d.16 posttransplant (MST >60 d). Notably, acute rejection of renal allografts was predominantly observed in the recipients with high pretransplant levels of anti-TI-I_205-219 autoantibodies. TI-I_205-219/CFA immunization increased frequencies of donor BALB/c-reactive T cells but not serum class I and class II DSA levels at the time of rejection. Similarly, sera transfer from TI-I_205-219/CFA immunized mice into B6 recipients of renal BALB/c allografts was sufficient to increase the priming of donor-reactive T cell secreting IFNg. In addition, the transfer of anti- TI-I_205-219 but not control sera increased C4d deposition and platelets aggregation in the graft consistent with antibody-mediated tissue injury.

*Conclusions: Our data identify DNA topoisomerase I as a novel self-antigen target in renal transplant recipients and demonstrate the ability of anti-TI-I autoantibodies to enhance pathogenic alloresponses

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