This research program will explore the following hypotheses: (1) natural cell-mediated cytotoxicity (NCMC) is a complex phenomenon that is mediated by more than one mononuclear cell subset and is modulated by cellular interaction, and (2) NCMC is regulated by interferon and other soluble factors through differential effects on the various effector cell types to produce the resultant natural cytotoxic effects. In order to test these hypotheses, we intend: (1) to identify and isolate the cell types involved in NCMC using physical and biological criteria; (2) to define the roles and interactions of these lymphocyte subpopulations in the regulation of NCMC; and (3) to elucidate the roles of soluble mediators including interferon in the regulation and modulation of NCMC. Two cytotoxicity tests, chromium release and single cell assays, are used to study NCMC. Lymphocytes are separated by density and size as well as by methods using cell surface markers. Subpopulations thus obtained are mixed in different combinations to define interactions in cytotoxic reactions. Lymphocyte subsets are treated with interferon and other factors, and mixture experiments will be performed on treated and untreated combinations to understand the control mechanisms such factors exert on NCMC. Two populatlons of NCMC effectors that can be isolated by density have been identified. The LGL population sediments toward the top of the Percoll density gradient. A heavier population is identified by a smaller increase in activity at the bottom of the gradient. These populations may differ in their recycling abilities. NCMC effector cells self-regulate by producing interferon. Accessory and helper cells are being investigated. Monocytes can augment as well as depress NCMC. The augmentation is demonstrable following direct mixture of monocytes with null cells in the NK assay, and following preincubation of the cells prior to testing of the re-isolated null cells for NCMC. The augmentation is dependent upon monocyte concentration and length of the pre-incubation period, and is associated with an increased number of target binding cells with lytic activity. Purified LGL appear less susceptible to the effect of monocytes than the less pure null cell population. (IS)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030187-05
Application #
3169115
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-02-01
Project End
1987-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
5
Fiscal Year
1986
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
Umehara, H; Takashima, A; Minami, Y et al. (1993) Signal transduction via phosphorylated adhesion molecule, LFA-1 beta (CD18), is increased by culture of natural killer cells with IL-2 in the generation of lymphokine-activated killer cells. Int Immunol 5:19-27
Naliboff, B D; Benton, D; Solomon, G F et al. (1991) Immunological changes in young and old adults during brief laboratory stress. Psychosom Med 53:121-32
Makinodan, T; Hahn, T J; McDougall, S et al. (1991) Cellular immunosenescence: an overview. Exp Gerontol 26:281-8
Bloom, E T; Umehara, H; Bleackley, R C et al. (1990) Age-related decrement in cytotoxic T lymphocyte (CTL) activity is associated with decreased levels of mRNA encoded by two CTL-associated serine esterase genes and the perforin gene in mice. Eur J Immunol 20:2309-16
Bloom, E T; Babbitt, J T (1990) Prostaglandin E2, monocyte adherence and interleukin-1 in the regulation of human natural killer cell activity by monocytes. Nat Immun Cell Growth Regul 9:36-48
Umehara, H; Bloom, E T (1990) The IL-2 receptor beta subunit is absolutely required for mediating the IL-2-induced activation of NK activity and proliferative activity of human large granular lymphocytes. Immunology 70:111-5
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

Showing the most recent 10 out of 25 publications