• 1.

    Alvar J, Yactayo S, Bern C, 2006. Leishmaniasis and poverty. Trends Parasitol 22: 552557.

  • 2.

    Haldar JP, Ghose S, Saha KC, Ghose AC, 1983. Cell-mediated immune response in Indian kala-azar and post-kala-azar dermal leishmaniasis. Infect Immun 42: 702707.

    • Search Google Scholar
    • Export Citation
  • 3.

    Carvalho EM, Badaro R, Reed SG, Jones TC, Johnson WD Jr, 1985. Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis. J Clin Invest 76: 20662069.

    • Search Google Scholar
    • Export Citation
  • 4.

    Carvalho EM, Bacellar O, Brownell C, Regis T, Coffman RL, Reed SG, 1994. Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis. J Immunol 152: 59495956.

    • Search Google Scholar
    • Export Citation
  • 5.

    Holaday BJ, Pompeu MM, Jeronimo S, Texeira MJ, Sousa Ade A, Vasconcelos AW, Pearson RD, Abrams JS, Locksley RM, 1993. Potential role for interleukin-10 in the immunosuppression associated with kala azar. J Clin Invest 92: 26262632.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ghalib HW, Piuvezam MR, Skeiky YA, Siddig M, Hashim FA, el-Hassan AM, Russo DM, Reed SG, 1993. Interleukin 10 production correlates with pathology in human Leishmania donovani infections. J Clin Invest 92: 324329.

    • Search Google Scholar
    • Export Citation
  • 7.

    Basu R, Bhaumik S, Basu JM, Naskar K, De T, Roy S, 2005. Kinetoplastid membrane protein-11 DNA vaccination induces complete protection against both pentavalent antimonial-sensitive and -resistant strains of Leishmania donovani that correlates with inducible nitric oxide synthase activity and IL-4 generation: evidence for mixed Th1- and Th2-like responses in visceral leishmaniasis. J Immunol 174: 71607171.

    • Search Google Scholar
    • Export Citation
  • 8.

    Goto Y, Bogatzki LY, Bertholet S, Coler RN, Reed SG, 2007. Protective immunization against visceral leishmaniasis using Leishmania sterol 24-c-methyltransferase formulated in adjuvant. Vaccine 25: 74507458.

    • Search Google Scholar
    • Export Citation
  • 9.

    Ghosh A, Zhang WW, Matlashewski G, 2001. Immunization with A2 protein results in a mixed Th1/Th2 and a humoral response which protects mice against Leishmania donovani infections. Vaccine 20: 5966.

    • Search Google Scholar
    • Export Citation
  • 10.

    Rafati S, Zahedifard F, Nazgouee F, 2006. Prime-boost vaccination using cysteine proteinases type I and II of Leishmania infantum confers protective immunity in murine visceral leishmaniasis. Vaccine 24: 21692175.

    • Search Google Scholar
    • Export Citation
  • 11.

    Stager S, Smith DF, Kaye PM, 2000. Immunization with a recombinant stage-regulated surface protein from Leishmania donovani induces protection against visceral leishmaniasis. J Immunol 165: 70647071.

    • Search Google Scholar
    • Export Citation
  • 12.

    Aguilar-Be I, da Silva Zardo R, Paraguai de Souza E, Borja-Cabrera GP, Rosado-Vallado M, Mut-Martin M, Garcia-Miss Mdel R, Palatnik de Sousa CB, Dumonteil E, 2005. Cross-protective efficacy of a prophylactic Leishmania donovani DNA vaccine against visceral and cutaneous murine leishmaniasis. Infect Immun 73: 812819.

    • Search Google Scholar
    • Export Citation
  • 13.

    Goto Y, Howard RF, Bhatia A, Trigo J, Nakatani M, Netto EM, Reed SG, 2009. Distinct antigen recognition pattern during zoonotic visceral leishmaniasis in humans and dogs. Vet Parasitol 160: 215220.

    • Search Google Scholar
    • Export Citation
  • 14.

    Bhatia A, Daifalla NS, Jen S, Badaro R, Reed SG, Skeiky YA, 1999. Cloning, characterization and serological evaluation of K9 and K26: two related hydrophilic antigens of Leishmania chagasi. Mol Biochem Parasitol 102: 249261.

    • Search Google Scholar
    • Export Citation
  • 15.

    Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, Hoff ST, Andersen P, Reed SG, Morris SL, Roederer M, Seder RA, 2007. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13: 843850.

    • Search Google Scholar
    • Export Citation
  • 16.

    Cassatella MA, Hartman L, Perussia B, Trinchieri G, 1989. Tumor necrosis factor and immune interferon synergistically induce cytochrome b-245 heavy-chain gene expression and nicotinamide-adenine dinucleotide phosphate hydrogenase oxidase in human leukemic myeloid cells. J Clin Invest 83: 15701579.

    • Search Google Scholar
    • Export Citation
  • 17.

    Gantt KR, Goldman TL, McCormick ML, Miller MA, Jeronimo SM, Nascimento ET, Britigan BE, Wilson ME, 2001. Oxidative responses of human and murine macrophages during phagocytosis of Leishmania chagasi. J Immunol 167: 893901.

    • Search Google Scholar
    • Export Citation
  • 18.

    Kemp K, Kemp M, Kharazmi A, Ismail A, Kurtzhals JA, Hviid L, Theander TG, 1999. Leishmania-specific T cells expressing interferon-gamma (IFN-gamma) and IL-10 upon activation are expanded in individuals cured of visceral leishmaniasis. Clin Exp Immunol 116: 500504.

    • Search Google Scholar
    • Export Citation
  • 19.

    Stager S, Maroof A, Zubairi S, Sanos SL, Kopf M, Kaye PM, 2006. Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells. Eur J Immunol 36: 17641771.

    • Search Google Scholar
    • Export Citation
  • 20.

    Nylen S, Maurya R, Eidsmo L, Manandhar KD, Sundar S, Sacks D, 2007. Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis. J Exp Med 204: 805817.

    • Search Google Scholar
    • Export Citation
  • 21.

    Bhaumik S, Basu R, Sen S, Naskar K, Roy S, 2009. KMP-11 DNA immunization significantly protects against L. donovani infection but requires exogenous IL-12 as an adjuvant for comparable protection against L. major. Vaccine 27: 13061316.

    • Search Google Scholar
    • Export Citation
  • 22.

    Kovacsovics-Bankowski M, Clark K, Benacerraf B, Rock KL, 1993. Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages. Proc Natl Acad Sci USA 90: 49424946.

    • Search Google Scholar
    • Export Citation
  • 23.

    Mendonca SC, De-Luca PM, Olafson RW, Jardim A, Coutinho SG, 1994. Does lipophosphoglycan enhance the T cell-stimulatory activity of lipophosphoglycan-associated proteins? Braz J Med Biol Res 27: 553557.

    • Search Google Scholar
    • Export Citation
 
 
 
 

 

 

 

 

 

 

 

 

 

Evaluation of Ex Vivo Human Immune Response against Candidate Antigens for a Visceral Leishmaniasis Vaccine

View More View Less
  • Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India; Infectious Disease Research Institute, Seattle, Washington

People cured from visceral leishmaniasis (VL) develop protection mediated by Th1-type cellular responses against new infections. We evaluated cytokine responses against 6 defined candidate vaccine antigens in 15 cured VL subjects and 5 healthy endemic controls with no evidence of previous exposure to Leishmania parasites. Of the 6 cytokines examined, only interferon-gamma (IFN-γ) differentiated cured VL patients from non-exposed individuals, with cured patients mounting a significantly higher IFN-γ response to a crude parasite antigen preparation. Among candidate vaccine antigens tested, the largest number of cured subjects recognized cysteine proteinase B, leading to heightened IFN-γ responses, followed by sterol 24-c-methyltransferase. These two antigens were the most immunogenic and protective antigens in a murine VL model, indicating a relationship between T cell recall responses of humans cured from VL and protective efficacy in an experimental model. Further studies may help prioritize antigens for clinical development of a subunit vaccine against VL.

Author Notes

*Address correspondence to Yasuyuki Goto, Infectious Disease Research Institute, 1124 Columbia Street, Suite 400, Seattle, WA 98104. E-mail: ygoto@idri.org

Financial support: This work was supported by a grant from the Bill and Melinda Gates Foundation (no. 39129), the National Institutes of Health grant AI25038, and Sitaram Memorial Trust, KAMRC, Muzaffarpur.

Authors' addresses: Rajiv Kumar, Kamlesh Gidwani, and Shyam Sundar, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. Yasuyuki Goto, Karen D. Cowgill, and Steven G. Reed, Infectious Disease Research Institute, Seattle, WA, E-mail: ygoto@idri.org.

Save