Trypanosoma cruzi is a protozoan parasite which causes human Chagas' disease, a major health problem in Latin America. Infection with T. cruzi causes non-specific immune suppression which may provoke related pathologies associated with Chagas' disease. We are studying T. cruzi infections in mice as a model for infection-induced suppression of immune responsiveness. Mice with chronic infections, the form most commonly seen in humans, have suppressed T cell dependent immune responses, including antibody production and the generation of cytotoxic T lymphocytes (CTL). We and others have demonstrated that immune responsiveness can be restored with interleukin-2 (IL-2), both in vitro and in vivo.
The aims of this proposal are to define immune suppression in mice with T. cruzi infection at the molecular level. A primary emphasis will be on the involvement of cytokines in the immune response, both antibody and CTL production, with particular importance placed on therapeutic restoration of immune responsiveness in vitro and in vivo. Mechanisms by which cytokines function to restore immune responsiveness will be determined. For example, we have found that IL-1 is able to completely restore suppressed antibody production in infected mice. Using molecular probes, we will determine whether IL-2 is increased in these spleen cells following IL-1 treatment. We will examine spleen cells from infected mice for their ability to respond to antigenic and mitogenic stimuli with the production of cytokine and/or cytokine mRNA. We will determine whether suppressed IL-2 production is pre- or post-transcriptional or via post-translational regulation. A similar approach will be used to analyze production f other cytokines. The regulation of cytokine production by cells from infected mice will be analyzed. Immortalized macrophage hybridomas and T cell clones from infected mice will be generated to further these studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022726-07
Application #
3134249
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1985-09-01
Project End
1994-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Skeiky, Y A; Guderian, J A; Benson, D R et al. (1995) A recombinant Leishmania antigen that stimulates human peripheral blood mononuclear cells to express a Th1-type cytokine profile and to produce interleukin 12. J Exp Med 181:1527-37
Skeiky, Y A; Benson, D R; Guderian, J A et al. (1995) Immune responses of leishmaniasis patients to heat shock proteins of Leishmania species and humans. Infect Immun 63:4105-14
Skeiky, Y A; Benson, D R; Elwasila, M et al. (1994) Antigens shared by Leishmania species and Trypanosoma cruzi: immunological comparison of the acidic ribosomal P0 proteins. Infect Immun 62:1643-51
Reed, S G; Brownell, C E; Russo, D M et al. (1994) IL-10 mediates susceptibility to Trypanosoma cruzi infection. J Immunol 153:3135-40
Silva, J S; Barral-Netto, M; Reed, S G (1993) Aggravation of both Trypanosoma cruzi and murine leukemia virus by concomitant infections. Am J Trop Med Hyg 49:589-97
Skeiky, Y A; Benson, D R; Guderian, J A et al. (1993) Trypanosoma cruzi acidic ribosomal P protein gene family. Novel P proteins encoding unusual cross-reactive epitopes. J Immunol 151:5504-15
Arnholdt, A C; Piuvezam, M R; Russo, D M et al. (1993) Analysis and partial epitope mapping of human T cell responses to Trypanosoma cruzi cysteinyl proteinase. J Immunol 151:3171-9
Piuvezam, M R; Russo, D M; Burns Jr, J M et al. (1993) Characterization of responses of normal human T cells to Trypanosoma cruzi antigens. J Immunol 150:916-24
Skeiky, Y A; Benson, D R; Parsons, M et al. (1992) Cloning and expression of Trypanosoma cruzi ribosomal protein P0 and epitope analysis of anti-P0 autoantibodies in Chagas' disease patients. J Exp Med 176:201-11
Silva, J S; Morrissey, P J; Grabstein, K H et al. (1992) Interleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection. J Exp Med 175:169-74

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