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 ar e two recently identified chemokine homologues encoded by human herpes viru s 8 and Molluscum contagiosum, respectively that have antagonistic activiti es against multiple different CC and CXC chemokine receptors. We hypothesiz ed that introduction of these molecules into cardiac allografts may block l eukocyte infiltration into the grafts and prolong survival. Vascularized an d nonvascularized cardiac allografts in mice were performed and plasmid DNA encoding vMIP-II, MC148 and/or vIL-10 was transferred into the allograft a t the time of transplantation. Gene transfer of either vMIP-II or MC148 int o cardiac allografts markedly prolonged graft survival. Combining gene tran sfer of either one of these chemokine antagonists with vIL-10 gene transfer , which has a mechanistically different immunosuppressive action, further e nhanced graft survival. vMIP-II and MC148 gene transfer both resulted in a marked decrease of donor-specific cytotoxic T lymphocytes (CTL) infiltratin g the grafts and inhibited alloantibody production. These results demonstra te that plasmid-mediated gene transfer of virally encoded chemokine antagon ists vMIP-II and MC148 can block donor-specific lymphocyte immunity within cardiac allografts and prolong graft survival. This is a new mechanistic ap proach 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.