The regulation of natural killer (NK) cells has been widely studied because of the numerous important protective and regulatory functions NK cells are thought to fulfill in vivo. The long range goal of this project is the thorough understanding of how NK activity is regulate at the cellular and molecular levels. Specifically, the present proposal seeks to test three hypotheses which are derived from previous data. (1) The first hypothesis suggests that monocytes augment NK activity of enriched null cell populations through an ILI-IL2 pathway. It proposes that monocytes augment the NK activity by supplying either membrane-associated ILI or another surface component pius soluble ILI to the enriched null cells. This results in (a) increased IL2 receptor (IL2R) affinity and/or increased numbers of IL2R/ cell and/or increased numbers of cells with IL2R; and (b) increased IL2 production by NK cells. The final proposed step is the IL2-induced activation of a population of non LGL target-binding cells in the enriched null cell population (2) The second hypothesis is that IL2R participate in the IL2 radiated augmentation of human NK activity. (3) The third hypothesis is that the monocyte mediated augmentation of NK activity enables NK cells to lyse fresh tumor target cells, which are normally insensitive to NK cells. A corollary is that the monocyte mediated modulation of NK is altered in cancer patients.
The specific aims and methods to test these hypotheses are: (i) To demonstrate the presence of membrane IL1 on human monocytes and correlate it with the monocyte mediated augmentation. (ii) To assess changes in IL2R numbers and affinity in enriched null cells and NK cell lines following exposure to monocytes. (iii) To test at the molecular level for changes in IL2 production by the cell types in the enriched null cell population following exposure to monocytes. (iv) To characterize the cell which is susceptible to the monocyte effect. (v) To assess IL2R changes and IL2-mRNA production in resting and IL2-stimulated null cells and LGL. (vi) To assess the vulnerability of normally insensitive fresh tumor cells to monocyte-augmented NK activity. And (vii) to determine the correlation between the augmentative capacity of monocytes and the sensitivity to augmentation of null cells in cancer patients with different stages of diseases. Methodologies involving cell isolation and mixture techniques, use of monoclonal and polyclonal reagents, receptor-ligand binding studies, and analyses of protein and mRNA synthesis are proposed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030187-09
Application #
3169118
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-02-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1992-06-30
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Fong, T C; Babbitt, J T; Bloom, E T (1989) Increase in Tac mRNA expression in natural killer-like cell line in response to interleukin-1 and interleukin-2 shown at the population and cellular level by in situ hybridization. Nat Immun Cell Growth Regul 8:165-72
Fiatarone, M A; Morley, J E; Bloom, E T et al. (1989) The effect of exercise on natural killer cell activity in young and old subjects. J Gerontol 44:M37-45
Bloom, E T; Kubota, L F (1989) Effect of IL-2 in vitro on CTL generation in spleen cells of young and old mice: asialo GM1+ cells are required for the apparent restoration of the CTL response. Cell Immunol 119:73-84
Bloom, E T; Kubota, L F; Kawakami, K (1988) Age-related decline in the lethal hit but not the binding stage of cytotoxic T-cell activity in mice. Cell Immunol 114:440-6

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