Host defences to Listeria monocytogenes in mice are mediated by specifically sensitized T lymphocytes (T cells) that enhance the activity of non-specific effector mechanisms, primarily macrophages. Listerial infection in mice is the prototype for cell-mediated immunity to infection, yet the mechanism of this immunity is incompletely understood. We hypothesize that T lymphocytes mediate immune host defenses by increasing the capacity to form granulomas at sites of infection and by stimulating resident and inflammatory macrophage killing function. The capacity to form granulomas requires both the production of monocytes in bone marrow and the movement of monocytes into infected tissues. To test this hypothesis, we plan to generate antigen specific T cell clones and investigate their function. T cell clones will be recovered from mice immune to Listeria, expanded with listerial antigen and phenotyped by surface antigens and histocompatibility restriction. Clones will be selected for their capacity to transfer immunity to Listeria to non-immune mice. The specific function of individual clones that can transfer immunity will then be determined by investigating macrophage function in Listeria- infected mice receiving cloned T cells or supernatants from clones. Specifically, in vivo phagocytic function, number of macrophage progenitor cells, macrophage-colony stimulating factor concentration, monocyte numbers, and granuloma formation will be determined. In addition, the effect of clone supernatants will also be measured in vitro on Kupffer cell and peritoneal macrophage surface membrane markers, metabolism, directed chemotaxis and antimicrobial activity. The results of these studies should indicate how specific T cell clones enhance innate host defense mechanisms to increase resistance. Potential findings will have wide implication for our understanding of how immune host defenses function and suggest ways of manipulating host defenses during infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024141-03
Application #
3136852
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1987-09-01
Project End
1990-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jiang, X; Gregory, S H; Wing, E J (1995) Hepatocytes can serve as accessory cells in the response of immune T lymphocytes to heat-killed Listeria monocytogenes. Infect Immun 63:926-33
Cooper, M H; Gregory, S H; Starzl, T E et al. (1994) Rapamycin but not FK506 inhibits the proliferation of mononuclear phagocytes induced by colony-stimulating factors. Transplantation 57:433-9
Gregory, S H; Sagnimeni, A J; Wing, E J (1994) Arginine analogues suppress antigen-specific and -nonspecific T lymphocyte proliferation. Cell Immunol 153:527-32
Gregory, S H; Wing, E J (1993) IFN-gamma inhibits the replication of Listeria monocytogenes in hepatocytes. J Immunol 151:1401-9
Gregory, S H; Wing, E J (1993) Macrophage colony-stimulating factor and the enhanced migration of monocytes are essential in primary but not secondary host defenses to Listeria organisms. J Infect Dis 168:934-42
Gregory, S H; Wing, E J; Hoffman, R A et al. (1993) Reactive nitrogen intermediates suppress the primary immunologic response to Listeria. J Immunol 150:2901-9
Gregory, S H; Barczynski, L K; Wing, E J (1992) Effector function of hepatocytes and Kupffer cells in the resolution of systemic bacterial infections. J Leukoc Biol 51:421-4
Gregory, S H; Wing, E J; Tweardy, D J et al. (1992) Primary listerial infections are exacerbated in mice administered neutralizing antibody to macrophage colony-stimulating factor. J Immunol 149:188-93
Cooper, M H; Gregory, S H; Thomson, A W et al. (1991) Evaluation of the influence of FK 506, rapamycin, and cyclosporine on processing and presentation of particulate antigen by macrophages: assessment of a drug ""carry-over"" effect. Transplant Proc 23:2957-8
Magee, D M; Williams, D M; Wing, E J et al. (1991) Production of colony-stimulating factors during pneumonia caused by Chlamydia trachomatis. Infect Immun 59:2370-5

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