TGF-beta1 somatic gene therapy prevents autoimmune disease in nonobese diabetic mice.
Nonobese diabetic (NOD) mice develop insulitis and diabetes through an autoimmune process. Since TGF-beta1 down-regulates many immune responses, we hypothesized that TGF-beta1 could prevent disease in NOD mice and that there would be several advantages to cytokine delivery by a somatic gene therapy approach. We opted for i.m. injection of a naked plasmid DNA expression vector encoding murine TGF-beta1 (pCMV-TGF-beta1). Treatment with pCMV-TGF-beta1 resulted in the retention and expression of the vector in muscle cells, associated with a considerable elevation in the plasma levels of TGF-beta1, that was not observed in control vector-treated mice. The levels of TGF-beta1 produced were sufficient to exert immunosuppressive effects. Delayed-type hypersensitivity responses were suppressed, and autoimmunity-prone NOD mice were protected from insulitis and diabetes in models of cyclophosphamide-accelerated and natural course disease. In pCMV-TGF-beta1-treated mice, pancreatic IL-12 and IFN-gamma mRNA expression was depressed, and the ratio of IFN-gamma to IL-4 mRNA was decreased, as determined by semiquantitative reverse-transcription PCR. In contrast, NOD mice injected with a vector encoding the proinflammatory cytokine IFN-gamma developed diabetes earlier. Intramuscular administration of cytokine-encoding plasmid vectors proved to be an effective method of cytokine delivery in these mice, and altered autoimmune disease expression.
Department of Pathology and Center for Clinical Immunobiology and Transplantation, McGill University, Montreal, Quebec, Canada.
C A
CA
Piccirillo
Y
Y
Chang
G J
GJ
Prud'homme
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016212:Transforming Growth Factor beta / Q000235:genetics*
D016212:Transforming Growth Factor beta