Early treatment of NOD mice with B7-H4 reduces the incidence of autoimmune diabetes

Xiaojie Wang, Jianqiang Hao, Daniel L. Metzger, Alice Mui, Ziliang Ao, Noushin Akhoundsadegh, Solomon Langermann, Linda Liu, Lieping Chen, Dawei Ou, C. Bruce Verchere, Garth L. Warnock

Research output: Contribution to journalArticlepeer-review

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. RESEARCH DESIGN AND 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.

Original languageEnglish (US)
Pages (from-to)3246-3255
Number of pages10
JournalDiabetes
Volume60
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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