Gene transfer of virally encoded chemokine antagonists vMIP-II and MC148 prolongs cardiac allograft survival and inhibits donor-specific immunity

Introducing immunomodulatory molecules into allografts by gene transfer may avoid the side-effects of systemic immunosuppression. vMIP-II and MC148 are two recently identified chemokine homologues encoded by human herpes virus 8 and Molluscum contagiosum, respectively that have antagonistic activities against multiple different CC and CXC chemokine receptors. We hypothesized that introduction of these molecules into cardiac allografts may block leukocyte infiltration into the grafts and prolong survival. Vascularized and nonvascularized cardiac allografts in mice were performed and plasmid DNA encoding vMIP-II, MC148 and/or vIL-10 was transferred into the allograft at the time of transplantation. Gene transfer of either vMIP-II or MC148 into cardiac allografts markedly prolonged graft survival. Combining gene transfer of either one of these chemokine antagonists with vIL-10 gene transfer, which has a mechanistically different immunosuppressive action, further enhanced graft survival. vMIP-II and MC148 gene transfer both resulted in a marked decrease of donor-specific cytotoxic T lymphocytes (CTL) infiltrating the grafts and inhibited alloantibody production. These results demonstrate that plasmid-mediated gene transfer of virally encoded chemokine antagonists vMIP-II and MC148 can block donor-specific lymphocyte immunity within cardiac allografts and prolong graft survival. This is a new mechanistic approach to analyze, treat, and prevent graft rejection. Delivery of these or related molecules by gene transfer or conventional pharmacologic means may represent a novel therapeutic modality for alloactivation.