Neutralization of Interleukin-16 Protects Nonobese Diabetic Mice From Autoimmune Type 1 Diabetes by a CCL4-Dependent Mechanism

  1. Terry L. Delovitch1,2
  1. 1Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada;
  2. 2Laboratory of Autoimmune Diabetes, Robarts Research Institute, London, Ontario, Canada;
  3. 3Department of Immunology, University of California, San Francisco, California;
  4. 4The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
  1. Corresponding author: Terry L. Delovitch, del{at}robarts.ca.
  • C.M. is currently affiliated with Dendreon Corporation, Seattle, Washington.

Abstract

OBJECTIVE The progressive infiltration of pancreatic islets by lymphocytes is mandatory for development of autoimmune type 1 diabetes. This inflammatory process is mediated by several mediators that are potential therapeutic targets to arrest development of type 1 diabetes. In this study, we investigate the role of one of these mediators, interleukin-16 (IL-16), in the pathogenesis of type 1 diabetes in NOD mice.

RESEARCH DESIGN AND METHODS At different stages of progression of type 1 diabetes, we characterized IL-16 in islets using GEArray technology and immunoblot analysis and also quantitated IL-16 activity in cell migration assays. IL-16 expression was localized in islets by immunofluorescence and confocal imaging. In vivo neutralization studies were performed to assess the role of IL-16 in the pathogenesis of type 1 diabetes.

RESULTS The increased expression of IL-16 in islets correlated with the development of invasive insulitis. IL-16 immunoreactivity was found in islet infiltrating T-cells, B-cells, NK-cells, and dendritic cells, and within an insulitic lesion, IL-16 was derived from infiltrating cells. CD4+ and CD8+ T-cells as well as B220+ B-cells were identified as sources of secreted IL-16. Blockade of IL-16 in vivo protected against type 1 diabetes by interfering with recruitment of CD4+ T-cells to the pancreas, and this protection required the activity of the chemokine CCL4.

CONCLUSIONS IL-16 production by leukocytes in islets augments the severity of insulitis during the onset of type 1 diabetes. IL-16 and CCL4 appear to function as counterregulatory proteins during disease development. Neutralization of IL-16 may represent a novel therapy for the prevention of type 1 diabetes.

Footnotes

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  • Received January 28, 2009.
  • Accepted July 27, 2010.

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  1. Diabetes vol. 59 no. 11 2862-2871
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