*Purpose: Multiple clinical and pre-clinical studies describe correlations between pre-existing or de novo autoimmune responses and poor transplant outcome. We have previously reported that following renal transplantation, mouse recipients containing donor-reactive memory CD4 T cells rapidly develop donor specific alloantibody (DSA) causing acute antibody-mediated rejection (AMR). Inhibition of DSA production prevented acute AMR but the allografts in these recipients developed signs of chronic tissue injury at later time points. The goal of this study was to test whether donor-reactive memory T cells also induce generation of autoantibodies and investigate the relevance of these autoantibodies to renal tissue injury.

*Methods: C57BL/6 (B6, H-2^b) recipients containing donor-reactive memory T cells were transplanted with BALB/c (H-2^d) renal allografts. Recipient sera were collected at d. 7 posttransplant and screened for reactivity to potential autoantigen epitopes using PEPperCHIP Autoimmune Epitope Microarray. Peptide TI-I_205-219 representing an identified DNA topoisomerase I (TI-I) 205-219 epitope was custom-synthesized. B6 mice immunized with TI-I_205-219 (3 biweekly injections of 100μg TI-I_205-219/CFA s.c.) were tested in a model of bilateral renal warm ischemia or used as recipients of BALB/c renal allografts.

*Results: DNA topoisomerase I peptide TI-I_205-219 was identified as the most prominent epitope in sensitized renal allograft recipients. Anti-TI-I_205-219 antibodies were induced after transplantation of BALB/c kidney allografts into non-sensitized B6.WT but not B6.TCRβ-/- recipients indicating that T cell help is required for autoantibody production. Furthermore, the level of anti-TI-I_205-219 autoantibodies was further increased in sensitized recipients.Immunization with TI-I_205-219 resulted in the generation of TI-I_205-219 IgG autoantibody and markedly exacerbated renal pathology after 25 min of bilateral warm kidney ischemia followed by reperfusion. TI-I_205-219/CFA immunization resulted in rapid rejection in 10/12 kidney allograft recipients (MST of 13.5 d) whereas only 2/6 CFA-immunized controls rejected by d. 16 posttransplant. 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.

*Conclusions: Our data identify DNA topoisomerase I as a novel self-antigen target and suggest complex interplay between auto- and alloreactive T cells and antibodies in the context of kidney transplantation.

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