Reversing pregnancy-induced B cell sensitization to facilitate the induction of transplant tolerance in postpartum recipients.

Pregnancy can result in the development of antibodies to fetal human leukocyte antigens, and this humoral sensitization contributes to reduced access to transplantation. Although desensitization protocols have enabled more sensitized patients to undergo transplantation, their efficacy is variable due in part to the persistence of donor-specific memory B cells. Better constraint of memory B cells through the induction of a B cell-intrinsic tolerant state may result in improved humoral desensitization. This study uses mouse models of semiallogeneic pregnancy to show that, in the absence of fetus-specific antibodies, pregnancy-sensitized B cells can acquire a tolerant state that manifests as the inability to differentiate into germinal center B cells. Adoptive transfer of serum containing fetus-specific antibodies prevented tolerance induction and reversed established B cell tolerance. Strikingly, B cells sensitized through skin rejection did not acquire this tolerant state even when donor-specific antibodies were absent. Furthermore, antepartum CTLA-4Ig treatment prevented humoral sensitization, induced B cell tolerance, and preserved the ability of postpartum dams to accept F1 grafts with transient anti-CD154 treatment. Together, these findings reveal the distinct plasticity of pregnancy-induced memory B cells that may be leveraged toward new strategies to improve access to transplantation and outcomes in postpartum women.