*Purpose: Loss of autoreactive B cell tolerance and production of non-HLA autoantibodies have been observed in patients undergoing chronic rejection, however, how autoreactive B cells lose their tolerance and the role of autoreactive antibodies remains an enigma. Recent observations from our laboratory that autoreactive B cells with a transcriptome profile of innate B cells accumulate in transplanted kidneys diagnosed with antibody-mediated rejection, led us to hypothesize that loss of tolerance is occurring in the inflamed kidney and that autoantibodies are contributing to graft rejection. In this study, we have developed a chronic rejecting mouse kidney transplant model to test these hypotheses

*Methods: C57BL/6 female mice were subjected to left nephrectomy and received kidneys from B6.H-2bm12 mice (difference of 3 amino acids in the peptide-binding groove of MHC class II I-A). All mice were sacrificed by D60 post-transplant and sera were collected every 2 weeks for 8 weeks. Donor-specific antibody responses were assayed using flow cytometry by adding sera to Bm12 splenocytes and detecting bound alloantibody with anti-mouse IgG mAb. Autoantibodies were detected by Hep-2 antibody detection kit.

*Results: Autoantibodies were detected in mice sera post-transplantation, but not bm12-specific antibodies. Unexpectedly, autoantibody amount fluctuated rapidly over the 8-week time period, and that the specificity of the autoantibody also changed. In some individuals, autoantibody specificity changed from nucleolar to nuclear to cytoplasmic, or from cytoplasmic to nucleus.

*Conclusions: Taken together, this model demonstrates a loss of autoreactive B cell tolerance and accumulation of autoantibodies that is highly dynamic in its accumulation and specificity. We plan to use this transplant model to further investigate the role of autoantibodies in kidney transplant rejection and how autoreactive B cells escape tolerance to differentiate into autoantibody-producing cells.

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