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Diabetes 53:2310-2321, 2004
© 2004 by the American Diabetes Association, Inc.
Progression to Islet Destruction in a Cyclophosphamide-Induced Transgenic Model
A Microarray Overview
1 Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
2 Division of Pediatric Endocrinology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts
Type 1 diabetes appears to progress not as an uncontrolled autoimmune attack on the pancreatic islet ß-cells, but rather in a highly regulated manner. Leukocytic infiltration of the pancreatic islets by autoimmune cells, or insulitis, can persist for long periods of time before the terminal destruction of ß-cells. To gain insight on the final stage of diabetogenesis, we have studied progression to diabetes in a CD4+ T-cell receptor transgenic variant of the NOD mouse model, in which diabetes can be synchronously induced within days by a single injection of cyclophosphamide. A time-course analysis of the gene expression profiles of purified islets was performed using microarrays. Contrary to expectations, changes in transcripts subsequent to drug treatment did not reflect a perturbation of gene expression in CD4+ T-cells or a reduction in the expression of genes characteristic of regulatory T-cell populations. Instead, there was a marked decrease in transcripts of genes specific to B-cells, followed by an increase in transcripts of chemokine genes (cxcl1, cxcl5, and ccl7) and of other genes typical of the myelo-monocytic lineages. Interferon-
dominated the changes in gene expression to a striking degree, because close to one-half of the induced transcripts issued from interferon-–regulated genes.
Address correspondence and reprint requests to Diane Mathis and Christophe Benoist, Section on Immunology and Immunogenetics, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215. E-mail: cbdm{at}joslin.harvard.edu
Address correspondence and reprint requests to Diane Mathis and Christophe Benoist, Section on Immunology and Immunogenetics, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215. E-mail: cbdm{at}joslin.harvard.edu
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