Progression to Islet Destruction in a Cyclophosphamide-Induced Transgenic Model

A Microarray Overview

  1. Michael Matos12,
  2. Richard Park1,
  3. Diane Mathis1 and
  4. Christophe Benoist1
  1. 1Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  2. 2Division of Pediatric Endocrinology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  1. 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
  2. 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

Abstract

Type 1 diabetes appears to progress not as an uncontrolled autoimmune attack on the pancreatic islet β-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 β-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-γ dominated the changes in gene expression to a striking degree, because close to one-half of the induced transcripts issued from interferon-γ–regulated genes.

Footnotes

| Table of Contents