Correlation between post transplant maternal microchimerism and tolerance across MHC barriers in mice.

Abstract

Exposure to non-inherited maternal antigens (NIMA) during fetal and neonatal life can result in lifelong maternal microchimerism (MMc) and tolerance to NIMA(+) allografts. We have previously shown that 40-50% of BDF1 female x B6 male offspring have multi-organ and multi-lineage MMc, while 70% have evidence of acquired maternal class I antigen in circulating PBMC and splenocytes. These features correlated with the presence of NIMA(d)-specific CD4(+) Treg cells, while offspring lacking MMc also lacked NIMA-specific Tregs. Furthermore, after a DBA/2 heart transplant, NIMA(d)-specific CD4(+) Treg cells rapidly mobilize to the allograft where they produce IL10 and TGFβ, suppressing early acute rejection, while mice deficient in MMc and NIMA(d)-specific Treg reject, allowing IFNγ-producing T effector cells to predominate in the grafts. We hypothesized that maternal cells occupy key sites of alloantigen presentation after transplant, sustaining pre-existing host Treg amidst a rising tide of donor alloantigen released from the graft. Using quantitative PCR to detect GFP transgeneic maternal cells, we found that transplant tolerance was associated with elevated MMc levels in blood, heart & lung, but surprisingly, not in liver. Rejection was associated with significantly lower levels of MMc in CD11b(+) (p = 0.0001) and CD11c(+) (p = 0.045) splenocytes, but not with differences in T cell MMc. Furthermore, compared with low pre-transplant baseline rate of maternal antigen acquisition, long-term graft survival was associated with an increased mean % of cells in blood [0.5% pre vs. 5.0% post] and spleen that were dimly positive for H-2K(d), indicative of de novo cell-surface alloantigen acquisition from the DBA/2 donor heart allograft. In contrast, NIMA-exposed mice that rejected their DBA/2 graft showed a transient increase in H-2K(d-dim) cells in blood during rejection (day 9-12) but a complete absence of donor MHC acquisition 100 days after transplant. As was the case prior to transplant, antigen acquisition was largely confined to MHC class II+ professional APC. When a NIMA-expressing organ allograft is accepted, MMc persists, mainly distributed into the antigen-presenting cell compartment, where the bulk of graft-derived alloantigen for "semi-direct" presentation is also present.