Lymphocytes can be induced to mediate cytotoxic reactions against a variety of target cells by in vitro manipulations. These reactions can be against either NK-sensitive target cells (""""""""NK-like"""""""" or """"""""anomalous"""""""" killing) or against NK-resistant targets (""""""""lymphokine activated killing""""""""). Cytotoxic reactivity can be induced with various stimuli including mixed lymphocyte culture or interleukin-2 (IL-2). These types of cytotoxicity bear a number of similarities with natural killer (NK) cell mediated cytotoxicity, although some features such as the spectrum of target cells killed are quite different. We propose to investigate the similarities between these types of cellular cytotoxicity basing our studies on the hypothesis that LAK and NK are of the same lineage, are regulated similarly, and recognize the same target structures. The ideal means to study the development of these effector cells would allow for the induction of cytotoxicity from non-cytotoxic precursors. We have developed two such precursor systems; the induction of cytotoxicity with IL-2 from naturally NK-inactive human thymocytes and IL-2 stimulation of peripheral blood lymphocytes depleted of NK cells with the toxic lysosomotropic drug L-leucine methyl ester. The phenotype of cells capable of developing cytotoxic reactivity, the sequence of signals that must be delivered to these cells to develop cytotoxic function, and the specificity of the induced cytotoxicity will be studied. The effects of adherent cells and adherent cell products on the in vitro development of cytotoxicity will be studied. We have demonstrated the existance of suppressor cells for NK effector function and for the acquisition of the IL-2 and transferrin receptors. These cells will be characterized and their mode of action determined. The specificity of LAK and NK cells will be compared by immunoselection of target cells with LAK or NK effector cells and comparing the sensitivity of the selected targets to these effector systems. By examining the similarities and differences between LAK and NK at the precursor, regulatory, and effector levels we expect to be able to determine the functional relationship between these cell types.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034442-06
Application #
3172120
Study Section
Experimental Immunology Study Section (EI)
Project Start
1987-02-12
Project End
1992-01-31
Budget Start
1989-02-01
Budget End
1990-01-31
Support Year
6
Fiscal Year
1989
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
Dadmarz, R; Bockstoce, D C; Golub, S H (1994) Interleukin-7 selectively enhances natural kill cytotoxicity mediated by the CD56bright natural killer subpopulation. Lymphokine Cytokine Res 13:349-57
Shau, H; Gupta, R K; Golub, S H (1993) Identification of a natural killer enhancing factor (NKEF) from human erythroid cells. Cell Immunol 147:1-11
Iho, S; Shau, H; Golub, S H (1992) IL-6 enhances the cytotoxic activity of thymocyte-derived CD56+ cells. Cell Immunol 144:1-10
Shau, H; Kim, A; Golub, S H (1992) Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin. J Leukoc Biol 51:343-9
Iho, S; Shau, H Y; Golub, S H (1991) Characteristics of interleukin-6-enhanced lymphokine-activated killer cell function. Cell Immunol 135:66-77
Ebina, N; Gallardo, D; Shau, H et al. (1990) IL-1 and IL-4 as reciprocal regulators of IL-2 induced lymphocyte cytotoxicity. Br J Cancer 62:619-23
Ibayashi, Y; Gray, J D; Golub, S H et al. (1990) The heterogeneity of target recognition by lymphokine-activated killer precursor cells. Jpn J Cancer Res 81:927-35
Shau, H Y; Golub, S H (1989) Inhibition of lymphokine-activated killer- and natural killer-mediated cytotoxicities by neutrophils. J Immunol 143:1066-72
Tokuda, Y; Ebina, N; Golub, S H (1989) The inhibitory effect of human interferon alpha on the generation of lymphokine-activated killer activity. Cancer Immunol Immunother 30:205-12
Shau, H; Gray, J D; Golub, S H (1988) Studies on cytotoxicity generated in human mixed lymphocyte culture. IV. Interleukin 2 alone or from mixed lymphocyte culture yields natural killer-like cytotoxic cells distinct from allospecific cytotoxic T lymphocytes. Cancer Immunol Immunother 27:255-60

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