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Disease relevance of Leishmaniasis


High impact information on Leishmaniasis

  • In leishmaniasis, protection requires leishmanial-specific CD4+ T helper (TH) cells [6].
  • IRF-1(-/-) mice showed dramatically exacerbated Leishmaniasis [7].
  • Critical contribution of OX40 ligand to T helper cell type 2 differentiation in experimental leishmaniasis [8].
  • Finally, combined CD4(+) depletion and IL-4 neutralization were curative, indicating that neither increased parasite burden nor altered accessory cell function independently biased towards Th2 reconstitution in advanced leishmaniasis [9].
  • Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-gamma and macrophages of producing nitric oxide [10].

Chemical compound and disease context of Leishmaniasis


Biological context of Leishmaniasis


Anatomical context of Leishmaniasis

  • Because interleukin 12 (IL-12) has potent T cell growth and interferon gamma (IFN-gamma) stimulatory effects, we studied its effect on CD4+ T cell differentiation during murine leishmaniasis [21].
  • We sought to restore protective immunity in advanced leishmaniasis by depletion of Th2-biased CD4(+) populations and by cytokine-directed reconstitution of Th1 cellular responses during lymphocyte recovery [9].
  • Together, these data indicate that the stimulation of NK cells, through the production of IFN-gamma, plays an important role in initiating Th1 cell differentiation in leishmaniasis and in controlling early resistance to L. major [22].
  • We used the model of murine leishmaniasis to evaluate the signals enabling Ag-pulsed dendritic cells (DC) to prime a protective Th1 response in vivo [23].
  • The interleukin (IL)-4 driven, polarized T-helper 2 cell (Th2) response that controls non-healing infection with Leishmania major in BALB/c mice has long been embraced as the underlying principle with which to consider the pathogenesis of non-healing and systemic forms of leishmaniasis in humans [24].

Gene context of Leishmaniasis

  • Recombinant LeIF (rLeIF) downregulated both IL-10 mRNA in the "resting" PBMC of leishmaniasis patients and LPS-induced IL-10 production by patient PBMC. rLeIF also stimulated the production of IL-12 in cultured PBMC from both patients and uninfected individuals [25].
  • In the chronic and destructive mucocutaneous form of leishmaniasis, there was a mixture of type 1 and type 2 cytokines, with a striking abundance of IL-4 mRNA in lesions [26].
  • TGF-beta has also been recognized as an important immunoregulator in murine leishmaniasis, for which it increases susceptibility to disease [27].
  • Differences between IL-4- and IL-4 receptor alpha-deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling [28].
  • CD4(+) Th1 cells were the main source of IFN-gamma and TNF-alpha production in mucosal leishmaniasis patients [29].

Analytical, diagnostic and therapeutic context of Leishmaniasis


  1. In vitro responses to Leishmania antigens by lymphocytes from patients with leishmaniasis or Chagas' disease. Reed, S.G., Carvalho, E.M., Sherbert, C.H., Sampaio, D.P., Russo, D.M., Bacelar, O., Pihl, D.L., Scott, J.M., Barral, A., Grabstein, K.H. J. Clin. Invest. (1990) [Pubmed]
  2. A single intramuscular injection with an adenovirus-expressing IL-12 protects BALB/c mice against Leishmania major infection, while treatment with an IL-4-expressing vector increases disease susceptibility in B10.D2 mice. Gabaglia, C.R., Pedersen, B., Hitt, M., Burdin, N., Sercarz, E.E., Graham, F.L., Gauldie, J., Braciak, T.A. J. Immunol. (1999) [Pubmed]
  3. IL-9 is a susceptibility factor in Leishmania major infection by promoting detrimental Th2/type 2 responses. Arendse, B., Van Snick, J., Brombacher, F. J. Immunol. (2005) [Pubmed]
  4. Structures of type 2 peroxisomal targeting signals in two trypanosomatid aldolases. Chudzik, D.M., Michels, P.A., de Walque, S., Hol, W.G. J. Mol. Biol. (2000) [Pubmed]
  5. Human and murine immune responses to a novel Leishmania major recombinant protein encoded by members of a multicopy gene family. Webb, J.R., Campos-Neto, A., Ovendale, P.J., Martin, T.I., Stromberg, E.J., Badaro, R., Reed, S.G. Infect. Immun. (1998) [Pubmed]
  6. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Afonso, L.C., Scharton, T.M., Vieira, L.Q., Wysocka, M., Trinchieri, G., Scott, P. Science (1994) [Pubmed]
  7. Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Lohoff, M., Ferrick, D., Mittrucker, H.W., Duncan, G.S., Bischof, S., Rollinghoff, M., Mak, T.W. Immunity (1997) [Pubmed]
  8. Critical contribution of OX40 ligand to T helper cell type 2 differentiation in experimental leishmaniasis. Akiba, H., Miyahira, Y., Atsuta, M., Takeda, K., Nohara, C., Futagawa, T., Matsuda, H., Aoki, T., Yagita, H., Okumura, K. J. Exp. Med. (2000) [Pubmed]
  9. Cure of progressive murine leishmaniasis: interleukin 4 dominance is abolished by transient CD4(+) T cell depletion and T helper cell type 1-selective cytokine therapy. Heinzel, F.P., Rerko, R.M. J. Exp. Med. (1999) [Pubmed]
  10. Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. Giese, N.A., Gabriele, L., Doherty, T.M., Klinman, D.M., Tadesse-Heath, L., Contursi, C., Epstein, S.L., Morse, H.C. J. Exp. Med. (1997) [Pubmed]
  11. Hepatotoxicity of sodium stibogluconate in leishmaniasis. Hepburn, N.C., Siddique, I., Howie, A.F., Beckett, G.J., Hayes, P.C. Lancet (1993) [Pubmed]
  12. Co-trimoxazole for systemic leishmaniasis. Murphy, K.J., Bong, A.C. Lancet (1981) [Pubmed]
  13. An ATP-dependent As(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. Dey, S., Ouellette, M., Lightbody, J., Papadopoulou, B., Rosen, B.P. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  14. Therapy of leishmaniasis: superior efficacies of liposome-encapsulated drugs. Alving, C.R., Steck, E.A., Chapman, W.L., Waits, V.B., Hendricks, L.D., Swartz, G.M., Hanson, W.L. Proc. Natl. Acad. Sci. U.S.A. (1978) [Pubmed]
  15. Lem3p is essential for the uptake and potency of alkylphosphocholine drugs, edelfosine and miltefosine. Hanson, P.K., Malone, L., Birchmore, J.L., Nichols, J.W. J. Biol. Chem. (2003) [Pubmed]
  16. Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12- and IFN-gamma-dependent mechanisms. Walker, P.S., Scharton-Kersten, T., Krieg, A.M., Love-Homan, L., Rowton, E.D., Udey, M.C., Vogel, J.C. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  17. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Lohoff, M., Mittrücker, H.W., Prechtl, S., Bischof, S., Sommer, F., Kock, S., Ferrick, D.A., Duncan, G.S., Gessner, A., Mak, T.W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  18. Modulation of interferon-gamma-induced macrophage activation by phosphotyrosine phosphatases inhibition. Effect on murine Leishmaniasis progression. Olivier, M., Romero-Gallo, B.J., Matte, C., Blanchette, J., Posner, B.I., Tremblay, M.J., Faure, R. J. Biol. Chem. (1998) [Pubmed]
  19. Parasite-accessory cell interactions in murine leishmaniasis. II. Leishmania donovani suppresses macrophage expression of class I and class II major histocompatibility complex gene products. Reiner, N.E., Ng, W., McMaster, W.R. J. Immunol. (1987) [Pubmed]
  20. Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice. Heinzel, F.P., Rerko, R.M., Ahmed, F., Pearlman, E. J. Immunol. (1995) [Pubmed]
  21. Recombinant interleukin 12 cures mice infected with Leishmania major. Heinzel, F.P., Schoenhaut, D.S., Rerko, R.M., Rosser, L.E., Gately, M.K. J. Exp. Med. (1993) [Pubmed]
  22. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. Scharton, T.M., Scott, P. J. Exp. Med. (1993) [Pubmed]
  23. Dendritic cells (DC) activated by CpG DNA ex vivo are potent inducers of host resistance to an intracellular pathogen that is independent of IL-12 derived from the immunizing DC. Ramírez-Pineda, J.R., Fröhlich, A., Berberich, C., Moll, H. J. Immunol. (2004) [Pubmed]
  24. Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice. Sacks, D., Anderson, C. Immunol. Rev. (2004) [Pubmed]
  25. A recombinant Leishmania antigen that stimulates human peripheral blood mononuclear cells to express a Th1-type cytokine profile and to produce interleukin 12. Skeiky, Y.A., Guderian, J.A., Benson, D.R., Bacelar, O., Carvalho, E.M., Kubin, M., Badaro, R., Trinchieri, G., Reed, S.G. J. Exp. Med. (1995) [Pubmed]
  26. Cytokine patterns in the pathogenesis of human leishmaniasis. Pirmez, C., Yamamura, M., Uyemura, K., Paes-Oliveira, M., Conceição-Silva, F., Modlin, R.L. J. Clin. Invest. (1993) [Pubmed]
  27. Transforming growth factor-beta in human cutaneous leishmaniasis. Barral, A., Teixeira, M., Reis, P., Vinhas, V., Costa, J., Lessa, H., Bittencourt, A.L., Reed, S., Carvalho, E.M., Barral-Netto, M. Am. J. Pathol. (1995) [Pubmed]
  28. Differences between IL-4- and IL-4 receptor alpha-deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. Mohrs, M., Ledermann, B., Köhler, G., Dorfmüller, A., Gessner, A., Brombacher, F. J. Immunol. (1999) [Pubmed]
  29. Up-regulation of Th1-type responses in mucosal leishmaniasis patients. Bacellar, O., Lessa, H., Schriefer, A., Machado, P., Ribeiro de Jesus, A., Dutra, W.O., Gollob, K.J., Carvalho, E.M. Infect. Immun. (2002) [Pubmed]
  30. Oral Salmonella typhimurium (AroA-) vaccine expressing a major leishmanial surface protein (gp63) preferentially induces T helper 1 cells and protective immunity against leishmaniasis. Yang, D.M., Fairweather, N., Button, L.L., McMaster, W.R., Kahl, L.P., Liew, F.Y. J. Immunol. (1990) [Pubmed]
  31. Antibody responses of visceral leishmaniasis patients to gp63, a major surface glycoprotein of Leishmania species. Shreffler, W.G., Burns, J.M., Badaró, R., Ghalib, H.W., Button, L.L., McMaster, W.R., Reed, S.G. J. Infect. Dis. (1993) [Pubmed]
  32. Antileishmanial activity of liposome-encapsulated amphotericin B in hamsters and monkeys. Berman, J.D., Hanson, W.L., Chapman, W.L., Alving, C.R., Lopez-Berestein, G. Antimicrob. Agents Chemother. (1986) [Pubmed]
  33. Synergistic effect of interferon-gamma and mannosylated liposome-incorporated doxorubicin in the therapy of experimental visceral leishmaniasis. Kole, L., Das, L., Das, P.K. J. Infect. Dis. (1999) [Pubmed]
  34. Protection against cutaneous leishmaniasis induced by recombinant antigens in murine and nonhuman primate models of the human disease. Campos-Neto, A., Porrozzi, R., Greeson, K., Coler, R.N., Webb, J.R., Seiky, Y.A., Reed, S.G., Grimaldi, G. Infect. Immun. (2001) [Pubmed]
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