title: Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival.
abstract: Costimulation blockade is an effective way to prevent allograft rejection. In this study, we tested the efficacy of two negative co-signaling molecules in protecting islet allograft function. We used local expression of B7-H4 by adenoviral transduction of islets (Ad-B7-H4) and systemic administration of CTLA-4.Ig to investigate the outcomes of allograft survival. Five groups of streptozotocin-induced diabetic C57BL/6 mice received 400 islets each from BALB/c donors. The groups consisted of control (G1); CTLA-4.Ig (G2); Ad-LacZ (G3); Ad-B7-H4 (G4); and Ad-B7-H4 and CTLA-4.Ig combined (G5). G1 and G3 developed graft failure on average of two weeks. G2, G4 and G5 survived for 43.8 ± 34.8, 54.7 ± 31.2 and 77.8 ± 21.5 d, respectively. Activated T and B cells in the lymph nodes were significantly controlled by CTLA-4.Ig treatment. Significantly reduced infiltrates were also detected in the allografts of G2 compared with G1. By contrast, B7-H4 significantly inhibited Th1-associated IFN-gamma secretion in the early stage and increased Foxp3 (+)  T cells in the long-term surviving allografts. Our study suggests that CTLA-4 and B7-H4 inhibit alloimmune responses through distinct mechanisms, and that combination therapy which activates two negative co-signaling pathways can further enhance islet allograft survival.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wang
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hao
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Metzger
authors.forename: Alice
authors.initials: A
authors.lastname: Mui
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Lee
authors.forename: Noushin
authors.initials: N
authors.lastname: Akhoundsadegh
authors.forename: C Lieping
authors.initials: CL
authors.lastname: Chen
authors.forename: Dawei
authors.initials: D
authors.lastname: Ou
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Ao
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007136:Immunoglobulins / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014184:Transplantation, Homologous; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007136:Immunoglobulins; D007328:Insulin; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; D007371:Interferon-gamma