Progression to islet destruction in a cyclophosphamide-induced transgenic model: a microarray overview.
Type 1 diabetes appears to progress not as an uncontrolled autoimmune attack on the pancreatic islet beta-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 beta-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-gamma dominated the changes in gene expression to a striking degree, because close to one-half of the induced transcripts issued from interferon-gamma-regulated genes.
Section on Immunology and Immunogenetics, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA.
Michael
M
Matos
Richard
R
Park
Diane
D
Mathis
Christophe
C
Benoist
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D023281:Genomics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis / Q000592:standards; D015203:Reproducibility of Results
D016207:Cytokines; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D003520:Cyclophosphamide