title: Early treatment of NOD mice with B7-H4 reduces the incidence of autoimmune diabetes.
abstract: OBJECTIVE
  Autoimmune diabetes is a T cell-mediated disease in which insulin-producing β-cells are destroyed. Autoreactive T cells play a central role in mediating β-cell destruction. B7-H4 is a negative cosignaling molecule that downregulates T-cell responses. In this study, we aim to determine the role of B7-H4 on regulation of β-cell-specific autoimmune responses.
  
  
  METHODS
  Prediabetic (aged 3 weeks) female NOD mice (group 1, n = 21) were treated with intraperitoneal injections of B7-H4.Ig at 7.5 mg/kg, with the same amount of mouse IgG (group 2, n = 24), or with no protein injections (group 3, n = 24), every 3 days for 12 weeks.
  
  
  RESULTS
  B7-H4.Ig reduced the incidence of autoimmune diabetes, compared with the control groups (diabetic mice 28.6% of group 1, 66.7% of group 2 [P = 0.0081], and 70.8% of group 3 [group 1 vs. 3, P = 0.0035]). Histological analysis revealed that B7-H4 treatment did not block islet infiltration but rather suppressed further infiltrates after 9 weeks of treatment (group 1 vs. 2, P = 0.0003). B7-H4 treatment also reduced T-cell proliferation in response to GAD65 stimulation ex vivo. The reduction of diabetes is not due to inhibition of activated T cells in the periphery but rather to a transient increase of Foxp3(+) CD4(+) T-cell population at one week posttreatment (12.88 ± 1.29 vs. 11.58 ± 1.46%; n = 8; P = 0.03).
  
  
  CONCLUSIONS
  Our data demonstrate the protective role of B7-H4 in the development of autoimmune diabetes, suggesting a potential means of preventing type 1 diabetes by targeting the B7-H4 pathway.
authors: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Xiaojie
authors: X
authors: Wang
authors: Jianqiang
authors: J
authors: Hao
authors: Daniel L
authors: DL
authors: Metzger
authors: Alice
authors: A
authors: Mui
authors: Ziliang
authors: Z
authors: Ao
authors: Noushin
authors: N
authors: Akhoundsadegh
authors: Solomon
authors: S
authors: Langermann
authors: Linda
authors: L
authors: Liu
authors: Lieping
authors: L
authors: Chen
authors: Dawei
authors: D
authors: Ou
authors: C Bruce
authors: CB
authors: Verchere
authors: Garth L
authors: GL
authors: Warnock
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011236:Prediabetic State / Q000188:drug therapy; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000627:therapeutic use*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1