Innate recognition of allogeneic non-self by monocytes initiates the rejection of transplanted organs (P2128)

Abstract

Abstract It is generally assumed that inflammation or ‘danger’ at the time of transplantation triggers rejection. Here we tested the alternate hypothesis that the innate immune system distinguishes between self and allogeneic non-self, causing DC maturation and initiation of adaptive immunity. B6 Rag-/-γc-/- CX3CR1-GFP+/- reporter mice, which lack T, B, and NK cells, received syngeneic (B6) or allogeneic (Balb/c) vascularized heart grafts. >90% of DCs present in the grafts by d.1 after Tx were derived from host monocytes. Mono-DC (GFP+lineage-Ly-6G-CD45+CD11b+CD11c+F4/80lo) were observed in greater numbers in allo than syn grafts at early time points and persisted at later time points (>21d) only in allografts. Mono-DC in allografts were mature (MHCII+CD80+), expressed IL-12p40, and presented endotoxin-free OVA to CD4+ (OT-II) and CD8+ (OT-I) cells, causing proliferation and IFNγ production. Mono-DC from syn grafts were less mature, did not express IL-12p40, and failed to induce IFNγ production. In vivo exposure of monocytes to allogeneic non-self precipitated T cell-mediated rejection of single minor Ag-mismatched grafts that are otherwise accepted by the host. Transient depletion of host CD11b+ cells in WT mice abrogated T cell accumulation and IFNγ production in heart allografts and prevented acute rejection. Therefore, sensing allogeneic non-self by monocytes is a key, and previously unrecognized, innate pathway by which alloimmune responses are initiated.