TGF-BETA-1 SOMATIC GENE-THERAPY PREVENTS AUTOIMMUNE-DISEASE IN NONOBESE DIABETIC MICE

Nonobese diabetic (NOD) mice develop insulitis and diabetes through an autoimmune process. Since TGF-beta 1 down-regulates many immune respo nses, we hypothesized that TGF-beta 1 could prevent disease in NOD mic e 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-beta 1 (pCMV-TGF-be ta 1), Treatment with pCMV-TGF-beta 1 resulted in the retention and ex pression of the vector in muscle cells, associated with a considerable elevation in the plasma levels of TGP-beta 1, that was not observed i n control vector-treated mice. The levels of TGF-beta 1 produced were sufficient to exert immunosuppressive effects, Delayed-type hypersensi tivity responses were suppressed, and autoimmunity-prone NOD mice were protected from insulitis and diabetes in models of cyclophosphamide-a ccelerated and natural course disease. In pCMV-TGF-beta 1-treated mice , pancreatic IL-12 and IFN-gamma mRNA expression was depressed, and th e ratio of IFN-gamma to IL-4 mRNA was decreased, as determined by semi quantitative reverse-transcription PCR. In contrast, NOD mice injected with a vector encoding the proinflammatory cytokine IFN-gamma develop ed 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.