GENETIC IMMUNIZATION WITH GLYCOPROTEIN-63 CDNA RESULTS IN A HELPER T-CELL TYPE-1 IMMUNE-RESPONSE AND PROTECTION IN A MURINE MODEL OF LEISHMANIASIS

Genetic immunization is a promising gene therapy approach for the prev ention and treatment of infectious disease, Plasmid DNA expressing gen es of pathogens is directly introduced into host cells and specific ce ll-mediated and/or humoral immune responses are elicited against the e ncoded protein. Leishmaniasis is a significant world-wide health probl em for which no vaccine exists, In susceptible animals, such as BALB/c mice, protection from leishmaniasis requires induction of a Th1 immun e response, In this study, cell-mediated immunity to Leishmania major (L, major) was induced by injecting BALB/c mice intradermally with pla smid DNA expressing the conserved L, major cell surface glycoprotein g p63 (gp63-pcDNA-3), CD4 T lymphocytes from gp63-pcDNA-3-immunized mice proliferated and produced IFN-gamma (but not IL-4) when stimulated in vitro with freeze-thawed parasites, consistent with a Th1 immune resp onse. In contrast, lymphocyte proliferation in animals immunized with freeze-thawed parasites was associated with IL-4 (but not IFN-gamma) p roduction, suggesting a nonprotective Th2 response. Challenge studies revealed that gp63-pcDNA-3 vaccination protected 30% of susceptible mi ce (21 of 70) from Leishmania infection while neither gp63 protein (0 of 20) nor freeze-thawed parasite vaccines (0 of 50) were efficacious, Dendritic cells derived from skin of gp63-pcDNA-3-injected mice also immunized naive recipients and protected them from leishmaniasis, We c onclude that gp63-pcDNA-3 genetic vaccination results in a CD4-depende nt Th1 immune response that correlates with protection from disease, a nd suggest that skin-derived dendritic cells are involved in priming t his response.