Reversing pregnancy induced humoral sensitization to facilitate transplantation tolerance

Abstract

Purpose: Pregnancy induces split tolerance with tolerization of fetus-specific effector T cells, but sensitization of B cells contributing to sex disparity in access to transplantation for multiparous women. We previously showed that, following mating with Balb/c males, post-partum sIgKO mice (mIgM-/-AID-/-) that cannot produce secreted antibodies were tolerized by aCD154 and accepted F1 heart grafts (TolRx); this was not achieved with WT mice. Here, we tested, 1) if B cells from these sIgKO mice acquired cell intrinsic hypofunction? 2) if post-partum serum inhibited the acquisition and reversed intrinsic hypofunction in post-partum B cells? Methods: Post-partum sIgKO mice were subjected to TolRx ± transfused post-partum serum. After 30 days, B cells were transferred to MD4 hosts and challenged with F1 splenocytes ± post-partum serum. F1-specific germinal center B cells were quantified on D-14. Results: 1) Post-partum B cells subject to TolRx did not differentiate into germinal center B cells in MD4 mice, in contrast to non -tolerized post-partum B cells that did. 2) Post-partum serum transfused during TolRx or into MD4 mice inhibited the induction and reversed hypofunction in post-partum B cells. Conclusion: Pregnancy-sensitized B cells develop a state of intrinsic hypofunction when tolerance was induced with aCD154 to F1 HTx but was antagonized by fetus-specific antibodies.