SYSTEMIC IMMUNOLOGICAL EFFECTS OF CYTOKINE GENES INJECTED INTO SKELETAL-MUSCLE

Somatic gene therapy is an interesting approach for the delivery of cy tokines for prolonged periods. The present experiments show that direc t injections into mouse skeletal muscle of cDNA expression vectors enc oding interleukin 2 (IL-2), IL-4, or type beta1 transforming growth fa ctor (TGF-beta1) induce biological effects characteristic of these cyt okines in vivo. Mice injected intramuscularly with a vector encoding I L-2 had enhanced humoral and cellular immune responses to an exogenous antigen, transferrin, that was delivered at a separate site. These IL -2 effects were abolished by coadministration of a vector directing sy nthesis of TGF-beta1. The TGF-beta1 vector by itself depressed the ant i-transferrin antibody response and caused an 8-fold increase in plasm a TGF-beta1 activity. The TGF-beta1 plasmid injection did not cause mu scle infiltration with monocytes or neutrophils and there was no evide nce for fibrotic changes. Muscle injection with a cDNA encoding IL-4 s electively increased IgG1 levels but did not alter the cellular immune response to transferrin. In lupus-prone mice (MRL/lpr/lpr), injection with IL-2 expression vectors increased and TGF-beta1 vectors decrease d autoantibodies to chromatin. These results demonstrate that intramus cular injection of cytokine genes, in the absence of infectious viral vectors, can regulate humoral and cellular immune responses in vivo.