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 prevention and treatment of infectious disease. Plasmid DNA expressing genes of pathogens is directly introduced into host cells and specific cell-mediated and/or humoral immune responses are elicited against the encoded protein. Leishmaniasis is a significant world-wide health problem for which no vaccine exists. In susceptible animals, such as BALB/c mice, protection from leishmaniasis requires induction of a Thl immune response. In this study, cell-mediated immunity to Leishmania major (L. major) was induced by injecting BALB/c mice intradermally with plasmid DNA expressing the conserved L. major cell surface glycoprotein gp63 (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 response. In contrast, lymphocyte proliferation in animals immunized with freeze-thawed parasites was associated with IL-4 (but not IFN-gamma) production, suggesting a nonprotective Th2 response. Challenge studies revealed that gp63-pcDNA-3 vaccination protected 30% of susceptible mice (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 conclude that gp63-pcDNA-3 genetic vaccination results in a CD4-dependent Th1 immune response that correlates with protection from disease, and suggest that skin-derived dendritic cells are involved in priming this response.
Walker
P S
PS
Dermatology Branch, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
Scharton-Kersten
T
T
Rowton
E D
ED
Hengge
U
U
Bouloc
A
A
Udey
M C
MC
Vogel
J C
JC
D019264:Adoptive Transfer; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics; D018076:DNA, Complementary / Q000008:administration & dosage; D003713:Dendritic Cells; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control*; D008213:Lymphocyte Activation; D008666:Metalloendopeptidases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D012867:Skin / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
D000953:Antigens, Protozoan; D018076:DNA, Complementary; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; D015847:Interleukin-4; D007371:Interferon-gamma; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania