W230 - On the Clonal Evolution of Pathogenic and Non-pathogenic Donor-specific B Cell Responses to Kidney Transplantation in Human recipients

Matthew Cusick, PhD – Pathology – University of Michigan; Evan Farkash, MD, PhD – Pathology – University of Michigan; Jeffrey Chicca – Research Associate, Surgery, University of Michigan; Mona Doshi, MD – Professor, Internal Medicine, University of Michigan; Mayara Garcia de Mattos BArbosa; Jeffrey Platt, MD – Professor, Surgery, University of Michigan

Abstract Text: Donor-specific (DS) B cell responses generate antibodies that sometimes cause rejection of organ transplants but at other times not. We ought to determine how donor-specific B cells weigh on the outcomes of clinical transplants.
We used intact cells to isolate avidly donor-specific, self-specific and third party-specific B cells from clinical kidney transplant recipients, and sequenced their Ig V regions.
Nearly all recipients had appreciable numbers of B cells that avidly bound donor cells at 37oC during the first several months after transplantation.
DS IgVH sequences revealed several clonal evolution patterns. In some recipients, DS B cells exhibited promiscuous specificity (avid binding both to donor cells and to autologous cells) before or shortly after transplantation evolving later to high specificity (absence of dual recognition). In others, donor-specific B cell clones were not promiscuous initially, but promiscuous recognition emerged at 1 year.
DS B cells encoded predominantly germline IgVH predominantly germline and polyreactive antibodies during periods of stable function. New highly mutated clones encoding Ig of high affinity, high specificity and pathogenicity expanded before or at the time of rejection.
We concluded that DS B cell responses that avidly bind autologous cells are not pathogenic and may confer benefit since recipients with these responses exhibit stable graft function. Our results also suggest that expansion of non-promiscuous DS B cells with highly mutated IgV regions (likely reflecting T cell-dependent responses) is associated with and may cause rejection. Whether outcomes reflect antibodies or other functions of the B cells remains unknown.