Regulation of Allograft Survival by Inhibitory FcγRIIb Signaling

Abstract

Fc gamma receptors (FcγR) provide important immunoregulation. Targeting inhibitory FcγRIIb may therefore prolong allograft survival, but its role in transplantation has not been addressed. FcγRIIb signaling was examined in murine models of acute or chronic cardiac allograft rejection by transplanting recipients that either lacked FcγRIIb expression (FcγRIIb−/− ) or over-expressed FcγRIIb on B cells (BTG). Acute heart allograft rejection occurred at the same tempo in FcγRIIb−/− C57Bl/6 (B6) recipients as WT recipients, with similar IgG alloantibody responses. In contrast, chronic rejection of MHC class II-mismatched bm12 cardiac allografts was accelerated in FcγRIIb−/− mice, with development of more severe transplant arteriopathy and markedly augmented effector autoantibody production. Autoantibody production was inhibited, and rejection delayed, in BTG recipients. Similarly, whereas MHC class I-mismatched B6.Kd hearts survived indefinitely and remained disease-free in B6 mice, much stronger alloantibody responses and progressive graft arteriopathy developed in FcγRIIb−/− recipients. Notably, FcγRIIb-mediated inhibition of B6.Kd heart graft rejection was abrogated by increasing T cell help through transfer of additional H2.Kd-specific CD4 T cells. Thus, inhibitory FcγRIIb signaling regulates chronic but not acute rejection, most likely because the supra-optimal helper CD4 T cell response in acute rejection overcomes FcγRIIb-mediated inhibition of the effector B cell population. Immunomodulation of FcγRIIb in clinical transplantation may hold potential for inhibiting progression of transplant arteriopathy and prolonging heart transplant survival.

Fcγ Receptors in Solid Organ Transplantation

“…In this model, a chronic vasculopathy is observed, analogous to that in human hearts with chronic rejection, which is driven by autoantibody production. FcγRIIB-deficient mice demonstrated elevated autoantibody production and more severe arteriopathy [66•]. These data are consistent with the known role for FcγRIIB in regulating B cells, but this study did not dissect the relative effect of FcγRIIB on B cells versus myeloid cells.…”

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

“…19 However, several studies also implicate a pathogenic role for IgG in atherosclerosis, albeit indirectly, [20][21][22] and vascular pathologies, such as chronic cardiac rejection and large vessel vasculitis, are thought to be driven by pathogenic autoantibodies. 23,24 Emerging paradigms reveal many non-antibody-dependent functions of B cells that could play important roles in atherosclerosis. [25][26][27] We and others have shown follicular B2 cell interactions with CD4 + T cells, antagonized by marginal zone B2 cells, promote pathogenic T cell responses in the atherosclerotic setting.…”

Rational clinical trial design for antibody mediated renal allograft injury

“…The inhibitory FcRIIB is the most broadly expressed FcR, and is present on virtually all leukocytes with the exception of NK cells and T cells and are involved in endocytosis or phagocytosis of immune complexes (33). A recent study on FcRIIb signaling in cardiac allografts in mice showed that it regulates chronic but not acute rejection (34). Authors postulated that helper CD4 T cell response in acute rejection overcomes FcRIIb-mediated inhibition of the effector B cell population.…”

“…Authors postulated that helper CD4 T cell response in acute rejection overcomes FcRIIb-mediated inhibition of the effector B cell population. Similar studies in renal allografts are lacking (34). In another study in cardiac allografts in mice, monoclonal alloantibodies to immunoglobulin to MHC I antigens can augment graft injury by stimulating EC to produce MCP-1 and by activating mononuclear cells through their Fc receptors.…”