title: Endogenous expression of B7-H4 improves long-term murine islet allograft survival.
abstract: BACKGROUND
  Allograft rejection is one of the main obstacles for islet transplantation. B7-H4 plays a key role in maintaining T-cell homeostasis by reducing T-cell proliferation and cytokine production. In this study, we investigated whether the endogenous expression of B7-H4 in β cells from B7-H4 transgenic mice enhances islet allograft survival.
  
  
  METHODS
  B7-H4 transgenic C57BL/6 (B6) mice (RIP.B7-H4) were developed by inserting the entire B7-H4 open reading frame under the rat insulin promoter (RIP). B7-H4 protein expression was examined by flow cytometric analysis and immunohistochemical staining. Islet allograft survival was investigated in streptozotocin-induced diabetic recipient BALB/c (H-2d) mice transplanted with 400 islets from RIP.B7-H4 (H-2b) mice under the kidney capsule. The recipient control group received islets from wild-type B6 donors.
  
  
  RESULTS
  B7-H4 protein was significantly up-regulated in isolated islets from RIP.B7-H4 compared with wild-type B6 mice (56%±23% vs. 3%±1.2%). B7-H4 was coexpressed with insulin, but not glucagon, suggesting that B7-H4 is expressed in a β-cell-specific manner. Recipient BALB/c mice transplanted with RIP.B7-H4 islets established euglycemia for 42.3±18.4 days (mean±SD; n=9) compared with controls at 23.1±7.8 days (mean±SD; n=12; P<0.004, log-rank test).
  
  
  CONCLUSIONS
  The endogenous expression of B7-H4 in donor β cells from transgenic mice prolongs islet allograft survival, confirming the negative role of B7-H4 in regulating alloreactive T-cell responses.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, 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: Ziliang
authors.initials: Z
authors.lastname: Ao
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Dawei
authors.initials: D
authors.lastname: Ou
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen / Q000502:physiology; D006085:Graft Survival; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse