The long-term objective is to analyze the potential role of a recently-identified novel mechanism of T cell-mediated activation of macrophage antileishmanial effects in host defense in vivo. This mechanism of activation involves antigen-specific interactions between effector T cells and infected macrophages, interactions that are neither lymphokine-mediated nor involve cytotoxicity to host cells. Different well-studied murine models of leishmaniasis will be investigated in an effort to establish whether a correlation exists between the in vitro expression of the lymphokine-independent activation mechanism (referred to as """"""""contact-mediated"""""""") and resolution of infection in mice. As a corollary, the possibility that suppressor cells (or their soluble products) from BALB/c mice with disseminated L. major infections can down-regulate expression of the effector T cells in vitro will be explored. In related studies, lymphokine-mediated and cell contact-mediated mechanisms of macrophage activation will be compared for their dependence on an oxidative burst to impart an antileishmanial effect in vitro, and for their influence on phagolysosomal pH. Finally, the murine macrophage activation assay will be adapted to human cell cultures to permit subsequent clinical studies. These studies of a novel T cell-mediated mechanism activation of macrophage antimicrobial defense can be expected to have direct relevance to leishmaniasis as well as have potentially important implications for understanding host defense to certain other intracellular pathogens. Since this novel defenes mechanism involves a subclass of murine lymphocytes analogous to those infected by HIV in humans, results of this line of investigation could bear on infectious complications in patients with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017151-09
Application #
3127004
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1980-07-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1991-11-30
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Sypek, J P; Jacobson, S; Vorys, A et al. (1993) Comparison of gamma interferon, tumor necrosis factor, and direct cell contact in activation of antimycobacterial defense in murine macrophages. Infect Immun 61:3901-6
Birkland, T P; Sypek, J P; Wyler, D J (1992) Soluble TNF and membrane TNF expressed on CD4+ T lymphocytes differ in their ability to activate macrophage antileishmanial defense. J Leukoc Biol 51:296-9
Sypek, J P; Matzilevich, M M; Wyler, D J (1991) Th2 lymphocyte clone can activate macrophage antileishmanial defense by a lymphokine-independent mechanism in vitro and can augment parasite attrition in vivo. Cell Immunol 133:178-86
Sypek, J P; Wyler, D J (1991) Antileishmanial defense in macrophages triggered by tumor necrosis factor expressed on CD4+ T lymphocyte plasma membrane. J Exp Med 174:755-9
Sypek, J P; Wyler, D J (1990) T-cell hybridomas reveal two distinct mechanisms of antileishmanial defense. Infect Immun 58:1146-52
Sypek, J P; Wyler, D J (1988) Susceptibility of lymphokine-resistant Leishmania to cell contact-mediated macrophage activation. J Infect Dis 158:392-7
Wyler, D J (1987) Fibronectin in parasitic diseases. Rev Infect Dis 9 Suppl 4:S391-9
North, T W; Wyler, D J (1987) DNA synthesis in promastigotes of Leishmania major and L. donovani. Mol Biochem Parasitol 22:215-21
Wyler, D J; Beller, D I; Sypek, J P (1987) Macrophage activation for antileishmanial defense by an apparently novel mechanism. J Immunol 138:1246-9
Crawford, G D; Wyler, D J; Dinarello, C A (1985) Parasite-monocyte interactions in human leishmaniasis: production of interleukin-1 in vitro. J Infect Dis 152:315-22

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