title: Regulation of allograft survival by inhibitory FcγRIIb signaling.
abstract: Fcγ 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 overexpressed FcγRIIb on B cells (B cell transgenic [BTG]). Acute heart allograft rejection occurred at the same tempo in FcγRIIb(-/-) C57BL/6 (B6) recipients as wild type 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 was delayed in BTG recipients. Similarly, whereas MHC class I-mismatched B6.K(d) 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.K(d) heart graft rejection was abrogated by increasing T cell help through transfer of additional H2.K(d)-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 transplant survival.
authors.affiliation: Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Callaghan
authors.forename: Thet Su
authors.initials: TS
authors.lastname: Win
authors.forename: Reza
authors.initials: R
authors.lastname: Motallebzadeh
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Conlon
authors.forename: Manu
authors.initials: M
authors.lastname: Chhabra
authors.forename: Inês
authors.initials: I
authors.lastname: Harper
authors.forename: Siva
authors.initials: S
authors.lastname: Sivaganesh
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Bolton
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brownlie
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Pettigrew
mesh_terms: D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D056945:Hep G2 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000502:physiology*; D007518:Isoantibodies / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C499172:Fcgr2b protein, mouse; D007074:Immunoglobulin G; D007518:Isoantibodies; D017452:Receptors, IgG