Leishmanial infections are worldwide in distribution, occurring in Africa, North and South America, Southern Europe, and Asia. The clinical manifestations of leishmaniasis are extremely varied and include visceral, cutaneous, diffuse cutaneous, and mucosal disease. There are an estimated 15-20 million cases of leishmaniasis worldwide and there are neither leishmania vaccines nor standardized tests for diagnosis. The existing treatment is expensive and often requires hospitalization. Notwithstanding, the leishmaniases are excellent candidates for the development of vaccines, antigen-based therapeutics, cytokine therapy, and effective diagnostics. The goal of this project is to develop leishmania recombinant antigens for vaccine development which would have worldwide application and be affordable in the developing world. Over the past years we have cloned several leishmania antigens. Some of them have been more extensively studied because they primarily stimulate the T helper phenotype responsible for protection in leishmaniasis. Two such antigens deserve primary attention. One of them, a L. braziliensis protein (LeIF) which we recently described, stimulates peripheral blood mononuclear cells (PBMC) from leishmania infected patients to proliferate, to produce a Th1 type of cytokine profile and to down regulate the IL-10 mRNA from both resting and activated cells. LeIF also stimulates the production of both IL-12 p40 subunit and IL-12 p70 in cultured PBMC from patients and uninfected individuals. More recently we observed that LeIF has exceptional adjuvant properties with a variety of antigens. The second antigen was discovered by cloning a Leishmania donovani gene based on the sequence of a peptide isolated from MHC class II molecules of infected mouse macrophages. This antigen (Idp23) is a parasite cell surface-associated molecule and also stimulates Th1 type of response.
The specific aims are as follows: 1) To define both the adjuvant moiety and the antigenic epitope mapping of LeIF; 2) To characterize the biological mechanisms of the adjuvant property of LeIF; 3) To clone and characterize novel leishmania vaccine candidate antigens; and 4) To use selected recombinant leishmania antigens in experimental vaccination protocols in mice, hamsters and dogs. The results obtained from these experiments will have direct impact on the protocols of vaccine development for humans and potentially for the diagnosis of leishmaniasis.
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