Immune-mediated destruction of transfected myocytes following DNA vaccination occurs via multiple mechanisms

The delivery of antigenic proteins in the context of a DNA vaccine leads to the intracellular synthesis of antigen and the induction of both humoral a nd cellular immune responses. Subsequent to immune activation, any transfec ted cell expressing the immunogenic protein should, by the rules of immunol ogy, become a legitimate target for removal by immune-mediated mechanisms. Herein, we have used an indirect assay of myocyte integrity following intra muscular (i.m.) delivery of a DNA vaccine, in mice with various immune defi ciencies, to determine which immunological mechanisms may be involved in de struction of antigen-expressing cells. We demonstrate that destruction of a ntigen-expressing myocytes following i.m. injection of a DNA vaccine is dep endent on major histocompatability complex (MHC) class II restricted CD4(+) T cell activation, but is not mediated solely by MHC I-restricted or perfo rin-mediated lysis and appears to have a component that is antibody-mediate d. Although we studied myocytes, the results likely represent what happens to any transfected cell expressing a foreign antigen. This study underscore s the ability of DNA vaccines at inducing antigen-specific immune responses that include a number of effector mechanisms. From the perspective of gene therapy, this study highlights the significance of immune activation when considering strategies where maintenance of therapeutic gene expression is desired.