title: Blocking lymphotoxin signaling abrogates the development of ectopic lymphoid tissue within cardiac allografts and inhibits effector antibody responses.
abstract: Tertiary lymphoid organs (TLOs) may develop within allografts, but their contribution to graft rejection remains unclear. Here, we study a mouse model of autoantibody-mediated cardiac allograft vasculopathy to clarify the alloimmune responses mediated by intragraft TLOs and whether blocking lymphotoxin-β-receptor (LTβR) signaling, a pathway essential for lymphoid organogenesis, abrogates TLO development. TLOs (defined as discrete lymphoid aggregates associated with high endothelial venules) were detectable in 9 of 13 heart allografts studied and were predominantly B cell in composition, harboring germinal-center activity. These are most likely manifestations of the humoral autoimmunity triggered in this model after transplantation; TLOs did not develop if autoantibody production was prevented. Treatment with inhibitory LTβR-Ig fusion protein virtually abolished allograft TLO formation (mean TLOs/heart: 0.2 vs. 2.2 in control recipients; P=0.02), with marked attenuation of the autoantibody response. Recipients primed for autoantibody before transplantation rejected grafts rapidly, but this accelerated rejection was prevented by postoperative administration of LTβR-Ig (median survival time: 18 vs. >50 d, respectively, P=0.003). Our results provide the first demonstration that TLOs develop within chronically rejecting heart allografts, are predominantly B cell in origin, and can be targeted pharmacologically to inhibit effector humoral responses.
authors.affiliation: Department of Surgery, Cambridge University, Cambridge, UK.
authors.forename: Reza
authors.initials: R
authors.lastname: Motallebzadeh
authors.forename: Sylvia
authors.initials: S
authors.lastname: Rehakova
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Conlon
authors.forename: Thet Su
authors.initials: TS
authors.lastname: Win
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Callaghan
authors.forename: Martin
authors.initials: M
authors.lastname: Goddard
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Bolton
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Ruddle
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Pettigrew
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002828:Choristoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002908:Chronic Disease; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007518:Isoantibodies / Q000276:immunology; D008221:Lymphoid Tissue / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053308:Lymphotoxin-beta / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D007518:Isoantibodies; C505887:Ltb protein, mouse; D053259:Lymphotoxin beta Receptor; D053308:Lymphotoxin-beta; D011993:Recombinant Fusion Proteins