CCL4 Protects From Type 1 Diabetes by Altering Islet β-Cell–Targeted Inflammatory Responses
- Craig Meagher12,
- Guillermo Arreaza2,
- Andrew Peters3,
- Craig A. Strathdee4,
- Philippe A. Gilbert3,
- Qing-Sheng Mi3,
- Pere Santamaria5,
- Gregory A. Dekaban13 and
- Terry L. Delovitch12
- 1Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
- 2Laboratory of Autoimmune Diabetes, Robarts Research Institute, London, Ontario, Canada
- 3BioTherapeutics Research Group, Robarts Research Institute, London, Ontario, Canada
- 4Amgen, Seattle, Washington
- 5Julia McFarlane Diabetes Research Centre, University of Calgary, Calgary, Alberta, Canada
- Address correspondence and reprint requests to Dr. Terry L. Delovitch, Laboratory of Autoimmune Diabetes, Robarts Research Institute, 100 Perth Dr., London, Ontario, N6A 5K8, Canada. E-mail: del{at}robarts.ca
Abstract
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 β-cells are suppressed by CCL4, which implicates the use of CCL4 therapeutically to prevent type 1 diabetes.
- ELISA, enzyme-linked immunosorbent assay
- FITC, fluorescein isothiocyanate
- IGLN, inguinal lymph node
- IL, interleukin
- IFN, interferon
- PLN, pancreatic draining lymph node
- Treg, regulatory T
Footnotes
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C.M. is currently affiliated with the Diabetes Research Center, University of California San Francisco, San Francisco, California.. Q.-S.M. is currently affiliated with the Center for Biotechnology and Genomic Medicine, Departments of Pathology and Medicine, Medical College of Georgia, Augusta, Georgia.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0619.
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.
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- Accepted December 4, 2006.
- Received May 4, 2006.
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