Insulin B-chain reactive CD4+ regulatory T-cells induced by oral insulin treatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of diabetogenic effector T-cells.

Bergerot, Isabelle; Arreaza, Guillermo; Cameron, Mark J.; Burdick, Marie D.; Strieter, Robert M.; Chensue, Stephen W.; Chakrabarti, Subrata; Delovitch, Terry L.

doi:10.2337/diabetes.48.9.1720

Cited by 64 publications

(47 citation statements)

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“…Indeed, increased MIP-1␤ levels in the pancreas are associated with IL-4-mediated protection from diabetes only at 10 wk of age. The latter finding is consistent with our recent report that the transfer of regulatory T cells induced by oral insulin treatment of NOD mice elicits a nondestructive insulitis characterized by a MIP-1␤-enriched environment in the pancreas of NOD.Scid recipients (40). Inasmuch as an increased expression of MIP-1␤ occurs only in the pancreata of IL-4-treated NOD mice, MIP-1␤ may mediate the down-regulation of Th1 cell responses in the pancreas, but not secondary lymphoid organs (e.g., spleen).…”

Section: Discussionsupporting

confidence: 81%

Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes

Cameron

Arreaza

Grattan

et al. 2000

The Journal of Immunology

133

107

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We investigated the biological role of CC chemokines in the Th1-mediated pathogenesis of spontaneous type I diabetes in nonobese diabetic (NOD) mice. Whereas an elevated ratio of macrophage inflammatory protein-1α (MIP-1α):MIP-1β in the pancreas correlated with destructive insulitis and progression to diabetes in NOD mice, a decreased intrapancreatic MIP-1α:MIP-1β ratio was observed in nonobese diabetes-resistant (NOR) mice. IL-4 treatment, which prevents diabetes in NOD mice by polarizing intraislet Th2 responses, decreased CCR5 expression in islets and potentiated a high ratio of MIP-1β and monocyte chemotactic protein-1 (MCP-1): MIP-1α in the pancreas. Furthermore, NOD.MIP-1α−/− mice exhibited reduced destructive insulitis and were protected from diabetes. Neutralization of MIP-1α with specific Abs following transfer of diabetogenic T cells delayed the onset of diabetes in NOD.Scid recipients. These studies illustrate that the temporal expression of certain CC chemokines, particularly MIP-1α, and the CCR5 chemokine receptor in the pancreas is associated with the development of insulitis and spontaneous type I diabetes.

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Section: Discussionsupporting

confidence: 81%

Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes

Cameron

Arreaza

Grattan

et al. 2000

The Journal of Immunology

133

107

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“…Exogenous insulin treatment in animal models also results in both changes within the islet infiltrate with more IL-4-producing and less interferon--producing cells and a marked reduction in diabetes development (3). The diabetes protection after insulin treatment in mice can be transferred by CD4 spleen cells, and it is thought that the major protective effect by insulin therapy is through the induction of regulatory Th2 CD4 cells (22)(23)(24)(25). Supporting this view is the observation that the antibody response to insulin in these models is predominantly of the Th2-associated mouse IgG1 and IgG2b subclasses (6).…”

Section: A B C D Igg Subclass Responses To Exogenous Insulinmentioning

confidence: 99%

“…S a mples were analyzed from 29 patients with type 1 diabetes treated with either high-dose intravenous insulin infusion for 1-2 weeks followed by subcutaneous insulin therapy (n = 14) or subcutaneous insulin therapy alone (n = 15) (11). Those patients who were treated with intravenous plus subcutaneous insulin included 6 children (median age 7 years, range 2-12) and 8 adults (median age 29 years, range [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. Of the patients treated with subcutaneous insulin alone, 6 were children (median age 11 years, range 3-17) and 9 were adults (median age 31 years, range 24-37).…”

Section: S U B J E C T Smentioning

confidence: 99%

Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens.

et al. 2000

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Insulin immunization in animal models induces T-h e l p e r (Th) 2-like antibody subclass responses to insulin and other -cell antigens. The aim of this study was to d e t e rmine whether exposure to insulin in humans resulted in a similar subclass bias of the humoral immune response. Levels of IgG subclass antibodies to insulin (IAs), GAD, and IA-2 were measured before and after treatment w i t h insulin in the following groups of patients: 29 patients with newly diagnosed type 1 diabetes treated with intravenous and/or subcutaneous insulin; 10 newly diagnosed patients randomized to cyclosporin A (CsA) or placebo plus subcutaneous insulin for 12 months; and 14 islet cell antibody-positive relatives receiving either intravenous and subcutaneous insulin prophylaxis or no treatment. At the onset of diabetes, the major subclass distributions of insulin autoantibodies (IAAs) were IgG1 and, to a lesser extent, IgG4. After insulin treatment in the 29 new-onset patients, IAs were initially of the IgG1 subclass. IgG4-IAs appeared later, but at 12 months, they were at higher levels than IgG1-IAs in 11 patients. Responses were higher in children compared with adults and were higher in subjects with IAAs (P < 0.001). Insulin prophylaxis in relatives showed a similar profile, with a decline in levels of IgG1-IAs after cessation of daily subcutaneous insulin. Patients treated with CsA took longer to develop IAs and showed suppressed levels of IgG4-IAs; however, their levels of high-titer IgG1-IAs persistently rebounded after completion of CsA therapy. Despite the presence of IgG4-IAs in most insulin-treated patients and relatives, a shift to IgG4-anti-GAD or IgG4-IA-2 was not found for up to 3 years after the initiation of insulin t h e r a p y. While our findings need to be correlated with T-cell cytokine responses, we suggest that the strong IgG4-IA response in insulin-treated patients is consistent with an enhancement of Th2 immunity, but there is no evidence of subsequent spreading of potentially Th2-associated IgG4 responses to other autoantigens. D i a b e t e s 4 9 :9 1 8-925, 2000

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“…ϩ T-cells to the pancreas and prevention of destructive insulitis upon oral insulin administration (6), and protection from type 1 diabetes by a neutralizing anti-IL-16 monoclonal antibody depends on CCL4 activity. These results suggest that enhanced CCL4 expression in secondary lymphoid organs and the pancreas blocks the development of type 1 diabetes.…”

Section: Cd4mentioning

confidence: 99%

CCL4 Protects From Type 1 Diabetes by Altering Islet β-Cell–Targeted Inflammatory Responses

et al. 2007

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We previously reported that interleukin (IL)-4 treatment of nonobese diabetic (NOD) mice elevates intrapancreatic CCL4 expression and protects from type 1 diabetes. Here, we show that antibody neutralization of CCL4 abrogates the ability of T-cells from IL-4 -treated NOD mice to transfer protection against type 1 diabetes. Intradermal delivery of CCL4 via a plasmid vector stabilized by incorporation of the Epstein-Barr virus EBNA1/oriP episomal maintenance replicon (pHERO8100-CCL4) to NOD mice beginning at later stages of disease progression protects against type 1 diabetes. This protection was associated with a Th2-like response in the spleen and pancreas; decreased recruitment of activated CD8؉ T-cells to islets, accompanied by diminished CCR5 expression on CD8 ؉ T-cells; and regulatory T-cell activity in the draining pancreatic lymph nodes. Thus, inflammatory responses that target islet ␤-cells are suppressed by CCL4, which implicates the use of CCL4 therapeutically to prevent type 1 diabetes. Diabetes 56: 809 -817, 2007 D evelopment of type 1 diabetes depends upon the selective recruitment of pathogenic leukocytes to pancreatic islets by chemokines and their receptors (1-5). Previously, we demonstrated in nonobese diabetic (NOD) mice that treatment with interleukin (IL)-4 elevates intrapancreatic CCL4 levels that correlate with decreased intraislet CCR5 expression and protection from type 1 diabetes (4). Increased intrapancreatic CCL4 expression is associated with enhanced recruitment of insulin B-chain reactive regulatory CD4ϩ T-cells to the pancreas and prevention of destructive insulitis upon oral insulin administration (6), and protection from type 1 diabetes by a neutralizing anti-IL-16 monoclonal antibody depends on CCL4 activity. These results suggest that enhanced CCL4 expression in secondary lymphoid organs and the pancreas blocks the development of type 1 diabetes.In this study, we tested whether CCL4 protects against type 1 diabetes using a gene transfer approach. A plasmid vector stabilized by the Epstein-Barr virus EBNA1/oriP episomal maintenance replicon was utilized to sustain CCL4 expression in vivo. We demonstrate that intradermal gene transfer of CCL4 prevents type 1 diabetes and that antibody-mediated CCL4 blockade reverses the ability of T-cells from IL-4 -treated NOD mice to transfer protection against type 1 diabetes. This is the first demonstration that IL-4 -mediated protection against type 1 diabetes relies upon CCL4 activity in vivo and that CCL4 inhibits progression to type 1 diabetes. RESEARCH DESIGN AND METHODSNOD/Del, NOD.Scid (from Dr. Len Schultz; The Jackson Laboratories, Bar Harbor, ME) and NOD8.3 TCR transgenic mice were bred in a specific pathogen-free barrier facility at the Robarts Research Institute (7,8). Mice were maintained in a specific pathogen-free facility at the University of Western Ontario according to institutional guidelines. IL-4 treatment, cell transfer, and CCL4 neutralization. One hundred nanograms (1,000 units) of recombinant mIL-4 (Immunex, Seattle, WA...

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Insulin B-chain reactive CD4+ regulatory T-cells induced by oral insulin treatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of diabetogenic effector T-cells.

Cited by 64 publications

References 0 publications

Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes

Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes

Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens.

CCL4 Protects From Type 1 Diabetes by Altering Islet β-Cell–Targeted Inflammatory Responses

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