Abstract
The emergence of an increasing number of Leishmania donovani strains resistant to pentavalent antimonials (SbV), the first line of treatment for visceral leishmaniasis worldwide, accounts for decreasing efficacy of chemotherapeutic interventions. A kinetoplastid membrane protein-11 (KMP-11)-encoding construct protected extremely susceptible golden hamsters from both pentavalent antimony responsive (AG83) and antimony resistant (GE1F8R) virulent L. donovani challenge. All the KMP-11 DNA vaccinated hamsters continued to survive beyond 8 mo postinfection, with the majority showing sterile protection. Vaccinated hamsters showed reversal of T cell anergy with functional IL-2 generation along with vigorous specific anti-KMP-11 CTL-like response. Cytokines known to influence Th1- and Th2-like immune responses hinted toward a complex immune modulation in the presence of a mixed Th1/Th2 response in conferring protection against visceral leishmaniasis. KMP-11 DNA vaccinated hamsters were protected by a surge in IFN-gamma, TNF-alpha, and IL-12 levels along with extreme down-regulation of IL-10. Surprisingly the prototype candidature of IL-4, known as a disease exacerbating cytokine, was found to have a positive correlation to protection. Contrary to some previous reports, inducible NO synthase was actively synthesized by macrophages of the protected hamsters with concomitant high levels of NO production. This is the first report of a vaccine conferring protection to both antimony responsive and resistant Leishmania strains reflecting several aspects of clinical visceral leishmaniasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Protozoan / biosynthesis
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Antigens, Protozoan / immunology
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Antimony / pharmacology*
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Cell Line
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Cricetinae
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Cytotoxicity, Immunologic / immunology
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Drug Resistance / genetics
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Humans
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Immunoglobulin G / biosynthesis
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Interleukin-2 / biosynthesis
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Interleukin-4 / biosynthesis*
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Leishmania donovani / genetics
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Leishmania donovani / immunology*
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Leishmania donovani / pathogenicity
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Leishmaniasis, Visceral / immunology
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Leishmaniasis, Visceral / parasitology
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Leishmaniasis, Visceral / pathology
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Leishmaniasis, Visceral / prevention & control*
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Liver Diseases, Parasitic / immunology
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Liver Diseases, Parasitic / parasitology
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Liver Diseases, Parasitic / pathology
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Liver Diseases, Parasitic / prevention & control
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism*
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Protozoan Proteins / administration & dosage
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Protozoan Proteins / genetics
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Protozoan Proteins / immunology*
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Reactive Nitrogen Species / biosynthesis
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Reactive Oxygen Species / metabolism
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Spleen / parasitology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / parasitology
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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Th1 Cells / parasitology
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Th2 Cells / parasitology
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Vaccines, DNA / administration & dosage
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Vaccines, DNA / immunology*
Substances
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Antibodies, Protozoan
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Antigens, Protozoan
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Immunoglobulin G
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Interleukin-2
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Membrane Glycoproteins
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Protozoan Proteins
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Reactive Nitrogen Species
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Reactive Oxygen Species
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Vaccines, DNA
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kinetoplastid membrane protein 11, Leishmania donovani
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Interleukin-4
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Antimony
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Nitric Oxide Synthase