Mice devoid of T, B, NK, and innate lymphoid cells distinguish between self and allogeneic non-self despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce IL-12 and activate the T cells that mediate graft rejection. The molecular mechanisms, however, by which the innate immune system senses allogeneic non-self to generate these mature DCs are not known. Using positional cloning, we identified donor polymorphism in the gene encoding signal regulatory protein alpha (SIRPa as a key modulator of the recipient's innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. Donors carrying SIRPa variants from the NOD and CAST strains, which display enhanced binding to the cognate ligand CD47, produced the strongest response. The allorecognition response was disrupted by treatment of the recipient with a recombinant CD47-Fc decoy protein and was absent in CD47-deficient mice. Our findings delineate a mechanism of allorecognition by monocytes based on sensing of donor SIRPa polymorphism by recipient CD47 that is relevant to the rejection of cell and organ transplants.

CITATION INFORMATION: Dai H, Friday A, Abou-Daya K, Williams A, Oberbarnscheidt M, Danska J, Lakkis F. Donor SIRPa Polymorphism Modulates the Innate Immune Response to Allogeneic Grafts. Am J Transplant. 2017;17 (suppl 3).

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