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

Victoria Gorbacheva, Ran Fan, Satoshi Miyairi, Robert L. Fairchild, William M. Baldwin, Anna Valujskikh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1307-1318
Number of pages12
JournalAmerican Journal of Transplantation
Issue number9
StatePublished - Sep 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 American Society of Transplantation & American Society of Transplant Surgeons


  • alloreactive T cells
  • antibody-mediated rejection
  • autoantibody
  • kidney transplantation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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