The immunology of cutaneous DNA immunization.

The expression of a foreign protein in the skin or muscle following direct in vivo gene transfer results in the induction of potent cellular and humoral immune responses and represents a novel approach for vaccine development. This strategy, now known as genetic or DNA immunization, can be performed either by the bombardment of skin with plasmid DNA coated onto microscopic gold particles using a gene gun, or by injection of muscle with plasmid DNA in saline solution. DNA immunization leads to protective immunity in a variety of rodent models of infectious disease and cancer. Here we will review recent advances in this rapidly expanding research area. Most importantly, the cellular and molecular events leading to the induction of immune responses following DNA inoculation into the skin are now understood in much greater detail. It has become clear that the dendritic cell (DC) system of bone marrow-derived antigen presenting cells (APC) is the initiator of cellular immune responses. Evidence has accumulated that cutaneous DCs are directly transfected leading to endogenous antigen synthesis and processing. The gene transfer procedure results in the activation of DCs and initiates migration to regional lymph nodes, where antigen-expressing DCs efficiently stimulate proliferation of antigen-specific CD8+ as well as CD4+ T-lymphocytes. The nature of the immune response following plasmid DNA immunization may be manipulated by co-delivery of plasmids encoding immunomodulatory cytokines like (interferon) IFNalpha, IL-2 or IL-12 and costimulatory molecules like B7-1. Molecular re-engineering of antigen-encoding plasmids allows for specific targeting of antigen expression into the antigen processing machinery of DC for optimal presentation to CD8+ and CD4+ T-lymphocytes. DNA immunization is currently being developed for the prevention and treatment of a number of infectious diseases and cancer.