*Purpose: Recipients of a kidney transplant from a haplo-identical sibling had accelerated early acute rejection episodes, followed by improved long-term graft survival if the transplant donor was mismatched for Non-Inherited Maternal HLA Antigens (NIMA). NIMA was subsequently found to selectively induce a Treg response in the fetus (Mold et al., Science 2008). We recently showed in mice (Bracamonte-Baran et al, PNAS 2017) that membrane allo-antigen acquisition (mAAQ) from maternal exosomes, aka “cross-dressing”(XD) of offspring dendritic cells (DCs), is associated with a type of “split” tolerance– increased functionality of semi-direct pathway (recently shown to be the cause of acute allograft rejection) and a decreased functionality of the indirect pathway (critical for antibody formation and chronic rejection) due to PD-L1-based anergy. Here we explored the relevance of these findings to human neonates.We hypothesized that, in newborns, production of exosomes (EXO) by rare maternal cells/microchimerism, leads to both mAAQ and PD-L1 expression by baby’s DCs, thus changing their APC status, leading to lifelong “split” tolerance to NIMA

*Methods: We examined 5 cord blood (CB) samples for DC expression of “acquired” NIMA- class I (HLA-A2, -B57, or -B8; aka “NIMA XD”) and PD-L1 by conventional and imaging flow cytometry.

*Results: We found a very small % of both pDC ( 1.9 +2.2%) and mDC (1.4 + 0.3) with NIMA XD. However these few XD DCs strongly expressed PD-L1 (pDC 65.2+ 8.7%, MFI= 5483+2235; mDC 62.6 + 2.6%, MFI= 1886+1922), as compared with weak PD-L1 expression by non- XD cord blood DC (pDC 0.09 + 0.12%, MFI= 39.2+ 70; mDC 7.8+ 11.0% MFI= 121+ 91.) In preliminary analysis by Image Stream, the NIMA-HLA and PD-L1 appeared to be associated (Bright Detail Similarity Index [BDSI] value> 1.7) on the cell surface of fetal mDC, but were not associated on the surface of pDC (BDSI value < 1).

*Conclusions: Consistent with previous findings in mature (6 wk old) mice, there appeared to be a strong correlation between acquisition of maternal exosomes, indicated by XD of offspring DC, and expression of PD-L1. However, whereas in mature mice the position of the XD MHC on both pDC and mDC surface was separate and distinct from that of PD-L1, this only appeared to be true of pDC in human cord blood, not the mDC. This suggests a developmental pathway from “full” PD-L1-mediated tolerance of NIMA at birth, to a “split” tolerance as the offspring matures. Further investigation of maternal exosome-based alteration of CB and neonatal DC are in progress.

« Back to 2020 American Transplant Congress