Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts

Abstract

Mice devoid of T, B, and NK 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 initiate graft rejection. The molecular mechanisms, however, by which the innate immune system detects allogeneic non-self to generate these DCs are not known. To address this question, we studied the innate response of Rag2−/−γc−/− mice, which lack T, B, NK cells, to grafts from allogeneic donors. We identified by positional cloning that donor polymorphism in the gene encoding signal regulatory protein alpha (SIRPα) is 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. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic non-self independently of T, B, and NK cells.

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

“…Although we are greatly simplifying a complex topic (eg, because SIRP‐α is polymorphic whereas CD47 is monomorphic), pig CD47 is not recognized by primate SIRP‐α as self, and therefore, macrophages are activated against the graft (Figure A). Transfection of cells with the gene for CD47 from the same species as the recipient macrophages prevents phagocytosis by activation of SIRP‐α in both mouse and human models.…”

Innate allorecognition by monocytic cells and its role in graft rejection

“…A recently completed genetic mapping study in the mouse demonstrated that recipient monocytes detect polymorphism in donor signal regulatory protein alpha (SIRPα) that influences the binding of SIRPα to its receptor CD47 on host monocytes (17). SIRPα is highly expressed on myeloid cells and delivers inhibitory signals that suppress such cells.…”

“…The ligand for SIRPα is the ubiquitously expressed molecule CD47 (18), and dual signaling that is either inhibitory (via SIRPα) or stimulatory (via CD47) regulates monocyte, DC and macrophage functions, guaranteeing tolerance to self in the innate immune system when the two signaling pathways are in balance. However, the introduction of an allograft with a SIRPα molecule that is mismatched with that of the recipient creates an imbalance that in some cases - if donor SIRPα has higher affinity to CD47 than self SIRPα - causes monocytic cell activation (17). In other situations, such as in certain tumor models, SIRPα signaling promotes the generation of myeloid derived suppressor cells which inhibit anti-tumor immunity (19).…”

What’s hot, what’s new: Report from the American Transplant Congress 2017

“…61 Evidence is accumulating that monocytes and macrophages can directly respond to allogeneic nonself. 62 As mature dendritic cells stimulate robust activation of alloreactive T cells, such innate allorecognition can contribute to allograft rejection. Lakkis and colleagues presented data that blood monocytes used the CD47/Sirpα pathway to distinguish self from allogeneic nonself.…”