title: B7-H4.Ig inhibits the development of type 1 diabetes by regulating Th17 cells in NOD mice.
abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by immunological destruction of insulin-producing pancreatic β-cells and subsequent hyperglycemia. The non-obese diabetic (NOD) mouse strain spontaneously develops a disease similar to human T1D and is commonly used as an animal model for studying this disease. We have previously shown that the administration of B7-H4-immunoglobulin fusion protein (B7-H4.Ig), a newly identified T-cell co-inhibitory signaling molecule, blocks the onset of diabetes in NOD mice. However, the mechanism(s) by which B7-H4 protects NOD mice from T1D is not fully understood. IL-17 is a pro-inflammatory cytokine, produced by Th17 cells, that activates T cells and other immune cells to produce a variety of cytokines and chemokines. Increasing evidence has shown that therapeutic agents targeting the IL-17 molecule or directly inhibiting IL-17-producing cells regulate autoimmune diabetes in NOD mice, suggesting that IL-17 is involved in the pathogenesis of this disease. In this study, we investigate whether B7-H4.Ig treatment inhibits the generation of Th17 cells which subsequently decreases IL-17 production and prevents the onset of T1D in NOD mice. Pre-diabetic female NOD mice were injected intraperitoneally with control mouse IgG or B7-H4.Ig starting at 4 weeks of age for 12 weeks. Our data showed that the frequency of Th17 cells in B7-H4.Ig-treated mice was significantly decreased. In addition, our data showed that B7-H4.Ig-treated mice had decreased levels of pro-inflammatory cytokines and Th17-associated cytokines, and an increased level of the potent Th17 inhibitor IFN-γ. To further investigate the effect of B7-H4.Ig on differentiation of Th17 cells, we co-cultured splenocytes with Th17-polarizing cytokines in the absence or presence of B7-H4.Ig. Our results indicated that splenocytes, under the Th17 driving conditions in the presence of B7-H4.Ig, had significantly decreased the numbers of Th17 cells compared to cells co-cultured in the absence of B7-H4.Ig. Together, this study suggests that blocking the generation of Th17 cells with the administration of B7-H4.Ig effectively inhibits the development of T1D in NOD mice.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Lee
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wang
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hao
authors.forename: Noushin
authors.initials: N
authors.lastname: Akhoundsadegh
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Linda
authors.initials: L
authors.lastname: Liu
authors.forename: Sol
authors.initials: S
authors.lastname: Langermann
authors.forename: Dawei
authors.initials: D
authors.lastname: Ou
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007136:Immunoglobulins; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; D007371:Interferon-gamma