Early Treatment of NOD Mice With B7-H4 Reduces the Incidence of Autoimmune Diabetes

Author:

Wang Xiaojie1,Hao Jianqiang1,Metzger Daniel L.2,Mui Alice1,Ao Ziliang1,Akhoundsadegh Noushin1,Langermann Solomon3,Liu Linda3,Chen Lieping4,Ou Dawei1,Verchere C. Bruce5,Warnock Garth L.1

Affiliation:

1. Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada

2. Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada

3. Amplimmune, Inc., Rockville, Maryland

4. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut

5. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference50 articles.

1. Insulin-dependent diabetes mellitus;Tisch;Cell,1996

2. The pathogenesis of diabetes in the NOD mouse;Solomon;Adv Immunol,2004

3. Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic non-obese diabetic (NOD) mice: a longitudinal study;Miyazaki;Clin Exp Immunol,1985

4. Evidence for a long prediabetic period in type I (insulin-dependent) diabetes mellitus;Gorsuch;Lancet,1981

5. The NOD mouse: a model of immune dysregulation;Anderson;Annu Rev Immunol,2005

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