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}
  • C.M. is currently affiliated with Dendreon Corporation, Seattle, Washington.


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.


  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.

| Table of Contents