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Department of Pathology and Center for Clinical Immunobiology and Transplantation, McGill University, Montreal, Quebec, Canada
Nonobese diabetic (NOD) mice develop insulitis and diabetes through
an autoimmune process. Since TGF-ß1 down-regulates many immune
responses, we hypothesized that TGF-ß1 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-ß1 (pCMV-TGF-ß1).
Treatment with pCMV-TGF-ß1 resulted in the retention and expression
of the vector in muscle cells, associated with a considerable elevation
in the plasma levels of TGF-ß1, that was not observed in control
vector-treated mice. The levels of TGF-ß1 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-ß1-treated mice, pancreatic IL-12 and IFN-
mRNA
expression was depressed, and the ratio of IFN- 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- 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.
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