Pregnancy is recognized as a spontaneously acquired state of immunological tolerance by the mother to her semi-allogeneic fetus, but it is a major cause of allosensitization in candidates for organ transplantation. This sensitization, assessed by the presence of anti-HLA IgG, contributes to sex disparity in access to transplantation and increases the risk for rejection and graft loss. Understanding this dual tolerance/sensitization conundrum may lead to new strategies for equalizing access to transplantation among sexes and improving transplant outcomes in parous women. Here, we review the clinical evidence that pregnancy results in humoral sensitization and query whether T cell responses are sensitized. Furthermore, we summarize preclinical evidence on the effects of pregnancy on fetus-specific CD4+ conventional, regulatory, and CD8+ T cells, and humoral responses. We end with a discussion on the impact of the divergent effects that pregnancy has upon alloantigen re-encounter in the context of solid organ transplantation, and how these insights point to a therapeutic roadmap for controlling pregnancy-dependent allosensitization.

Background. Although donor-specific antibody pre- and posttransplantation is routinely assessed, accurate quantification of memory alloreactive B cells that mediate recall antibody response remains challenging. Major histocompatibility complex (MHC) tetramers have been used to identify alloreactive B cells in mice and humans, but the specificity of this approach has not been rigorously assessed. Methods. B-cell receptors from MHC tetramer-binding single B cells were expressed as mouse recombinant immunoglobulin G1 (rIgG1) monoclonal antibodies, and the specificity was assessed with a multiplex bead assay. Relative binding avidity of rIgG1 was measured by modified dilution series technique and surface plasmon resonance. Additionally, immunoglobulin heavy chain variable regions of 50 individual B-cell receptors were sequenced to analyze the rate of somatic hypermutation. Results. The multiplex bead assay confirmed that expressed rIgG1 monoclonal antibodies were preferentially bound to bait MHC class II I-Ed over control I-Ad and I-Ab tetramers. Furthermore, the dissociation constant 50 binding avidities of the rIgG1 ranged from 10 mM to 7 nM. The majority of tetramer-binding B cells were low avidity, and ~12.8% to 15.2% from naive and tolerant mice and 30.9% from acute rejecting mice were higher avidity (dissociation constant 50 <1 mM). Conclusions. Collectively, these studies demonstrate that donor MHC tetramers, under stringent binding conditions with decoy self-MHC tetramers, can specifically identify a broad repertoire of donor-specific B cells under conditions of rejection and tolerance.

FIGURE 1. Following mating of C57BL/6 females with OVA-transgenic males, successful pregnancy results in the secretion of sialylated OVA by trophoblast cells around mid-gestation. Circulating sialylated OVA binds to CD22 on follicular B cells, which then engages the Lyn tyrosine kinase signaling pathway, resulting in suppressed B cells and CD4 + OT-II responses.