Maternal microchimerism (MMc) has been associated with allo-specific graft tolerance in mice and humans. This tolerance is associated with membrane allo-antigen acquisition (mAAQ), which is mediated through exosomes released by rare maternal resident cells within the offspring. In murine models, those allogeneic exosomes induce functional changes in host dendritic cells (DCs), leading to MHC II-restricted allo-peptide presentation in co-localization with mAAQ-induced PD-L1 as inhibitory signal. This phenomenon induces anergy in indirect antigen-specific effector T cell clones. In humans, we found a similar pattern of acquired allo-antigen expression in circulating myeloid DCs (from fresh PBMCs) in a kidney transplant patient (A2,24 B35,57 DR4,11) with excellent renal function 11 years after a 1-HLA haplotype-mismatched sibling transplant (A2,24 B44,57 DR4,11), indicating in vivo mAAQ from graft. PBMCs from an HLA-identical (non-transplanted) sibling were cultured with exosomes isolated from plasma of the transplanted patient and from proper syngeneic healthy control. We observed that patient-derived, but not control-derived, exosomes replicated HLA-B44 mAAQ in vitro in both myeloid (m)DCs and plasmacytoid (p)DCs. Interestingly, the patterns of surface expression of acquired MHC mimicked those seen in mice DCs. We propose that exosomes can induce PD-L1 and CD80/86 expression on human mDCs and pDCs, as addressed with in vitro culture experiments. Furthermore, the co-localization pattern of PD-L1 or CD80/86 with mAAQ patches in mDCs and pDCs (as determined by microscopy flow cytometry, Image Stream) might modulate the anergy/activation balance of allo-specific T cell clones. Taken together, these data suggest a potential mechanism similar to that of MMc-induced tolerance in mice. In that phenomenon, graft cells are able to induce allo-tolerance via exosomes by generating clustering of indirectly presented allo-peptides/MHC complexes with co-inhibitory signals (PD-L1) in specific microdomains on recipient mAAQ+ DCs. These findings could explain important mechanisms of chimerism-related tolerance, translate into better transplant outcomes and lead to potential therapeutic targets.

CITATION INFORMATION: Lema D, Bracamonte-Baran W, Jankowska-Gan E, Claas F, van Rood J, Mulder A, Burlingham W. Chimerism-Related Allotolerance Is Induced by Exosome Acquisition and Reprogramming of Host Dendritic Cells. Am J Transplant. 2017;17 (suppl 3).

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