Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major

Abstract

To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-γ (IFN-γ) production. Moreover, both the enhancement of IFN-γ production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8+ T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8+ T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

Dendritic Cell (DC)-Based Protection Against an Intracellular Pathogen Is Dependent Upon DC-Derived IL-12 and Can Be Induced by Molecularly Defined Antigens

“…Upon adoptive transfer into naive recipients, LC loaded with a mixture of the recombinant Leishmania Ag LACK, KMP-11, gp63, and PSA were shown to mediate significant protection against a challenge with L. major parasites. The significance of LC as the vaccine carrier is emphasized by the previous observation that gp63, LACK, and KMP-11 are unable to induce protective responses when administered as proteins without adjuvant (23,28,31). Most importantly, we identified LeIF as a single leishmanial Ag that, upon loading into LC, protected mice from uncontrolled parasite infection.…”

“…For this purpose, several prominent Leishmania Ag were chosen that have already been shown to be strongly immunogenic. The Leishmania homolog of receptor for activated C kinase (LACK) is a highly conserved intracellular protein that has been shown to play an important role in the immunopathogenesis of experimental L. major infections (21,22), and vaccination with DNA encoding LACK induces protection against a challenge with parasites (23). Leishmania homolog of eukaryotic ribosomal elongation and initiation factor 4a (LeIF) is a Leishmania protein that elicits IL-12 production and a Th1 response of human PBMCs (24).…”

Induction of Protective Immunity againstSchistosoma mansonivia DNA Priming and Boosting with the Large Subunit of Calpain (Sm-p80): Adjuvant Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-4

“…APCs can directly uptake the DNA vaccine and present the expressed antigen, or the DNA vaccine can also be expressed by somatic cells, and the released antigen is then picked up by APCs (53). Major APCs involved in DNA vaccines appear to be the dendritic cells (20), and several studies have demonstrated that introduction of plasmid encoding GM-CSF results in the accumulation of dendritic cells in vivo (21,31). Dendritic cells stimulated with GM-CSF are also known to differentiate and mature into increasingly effective APCs (42).…”

Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines

“…The protective immunity detected was mostly mediated by specific CD4 Th1 cells, although protective immunity was also partly dependent on CD8 T lymphocytes (Gurunathan et al 1997). A further evaluation of the role of CD8 T cells found that they may function as helpers for the development of effector CD4 T cells.…”