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.
Piccirillo
C A
CA
Department of Pathology and Center for Clinical Immunobiology and Transplantation, McGill University, Montreal, Quebec, Canada.
Chang
Y
Y
Prud'homme
G J
GJ
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