title: B7-H4 induces donor-specific tolerance in mouse islet allografts.
abstract: Negative cosignaling molecules play an important role in regulating T-cell responses to alloantigen stimulation. We recently reported that adenoviral-mediated transduction of islet allografts with B7-H4 inhibits allograft rejection. In this study, we investigate the mechanism for B7-H4-induced  prolongation of mouse islet allograft survival. Streptozotocin-induced diabetic C57BL/6 mice were rendered normoglycemic by renal subcapsular implants of B7-H4-transduced BALB/c islets. Grafts and spleens were removed after days 2, 10, and 60 (n = 8 each) for characterization of kinetics  of Foxp3 and interleukin 10 (IL-10) expression. Mixed lymphocyte reaction (MLR) was done at day 60. Ten mice were subjected to nephrectomy at 60 days and then five were implanted with secondary BALB/c islets and five were given third-party CBA/J islets. An increase in Foxp3 and IL-10 mRNA  expression was detected in recipients' spleens at day 60 and this was associated with increased quantities of Foxp3(+) cells. Splenocytes at day 60 showed hyporesponsiveness during MLR to alloantigen stimulation. Proliferation was partially restored after CD25(+) T-cell depletion.  Secondary BALB/c islets survived for 79 ± 29 days compared with 21 ± 3.6 days for CBA/J islets (p < 0.001). Local expression of B7-H4 induces long-term unresponsiveness to donor-specific alloantigens, and is associated with T regulatory cells, suggesting the development  of tolerance.
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: Ziliang
authors.initials: Z
authors.lastname: Ao
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Dawei
authors.initials: D
authors.lastname: Ou
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006085:Graft Survival; D016753:Interleukin-10 / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009392:Nephrectomy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014161:Transduction, Genetic; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics* / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; D016753:Interleukin-10