Natural killer (NK) cells, cytotoxic T-lymphocytes (CTL's), and mononuclear phagocytes (MP) represent three major systems of host defense against tumors. Our laboratory is actively involved in the molecular dissection of cell-surface events important in the cytotoxic response mediated by these cells, through the use of monoclonal antibodies as probes of structure and function. In this project, we propose to continue our studies examining the role of the Lymphocyte Function-Associated Antigen-One (LFA-1) heterodimeric family of surface glycoproteins on cytotoxic cells, with special emphasis on the NK system and a closely-related effector cell, Lymphokine (IL-2)-Activated Killer Cells. Our laboratory is currently exploring the following hypotheses in cytotoxic systems: (1) that cell surface density of LFA-1 family members is important in expression of cell-mediated cytotoxicity in these systems; (2) that LFA-1 subserves non-adherence related function(s) in the NK system, possibly playing a role in a late step in the cytolytic mechanism or in more global regulation of cellular processes (e.g., transmembrane signalling events); and (3) that one important effect of IL-2 in modulating cytolytic activity is in enhancing expression of LFA-1, through as yet unknown mechanisms. In this Competing Continuation Application, we propose a series of experiments designed to further test these hypotheses through detailed study of the structure, function, expression, and biosynthesis of this important family of surface molecules, as well as proposals to attempt to isolate and identify the putative target cell ligand for LFA-1 in the NK system. In so doing, we will continue to pursue our long-term goal of better understanding, at the molecular level, cell-mediated host defense against tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA037026-05
Application #
3174699
Study Section
Experimental Immunology Study Section (EI)
Project Start
1987-08-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Guthrie Foundation for Education and Research
Department
Type
DUNS #
City
Sayre
State
PA
Country
United States
Zip Code
18840
Akella, R; Hall, R E (1992) Expression of the adhesion molecules ICAM-1 and ICAM-2 on tumor cell lines does not correlate with their susceptibility to natural killer cell-mediated cytolysis: evidence for additional ligands for effector cell beta integrins. Eur J Immunol 22:1069-74
Noti, J D; Gordon, M; Hall, R E (1992) Human p150,95 alpha-subunit: genomic organization and analysis of the 5'-flanking region. DNA Cell Biol 11:123-38
Kostyal, D A; Beezhold, D H; Hall, R E (1991) Differentiation-inducing cytokine P48 exists in a membrane-associated form. J Immunol 147:893-8
Leftwich, J A; Hall, R E (1990) Initial characterization of a cytokine which induces differentiation and cytolytic activity in HL-60 promyelocytic leukemia cells: evidence that the cytokine is distinct from other known differentiation-active cytokines. J Leukoc Biol 47:87-96
Grant, A J; Merchant, R E; Hall, R E (1989) Interleukin-2 modulates the expression of lymphocyte function-associated antigen-one (LFA-1) and p150,95 during the generation of lymphokine-activated killer (LAK) cells. Immunology 66:117-24
Beezhold, D H; Leftwich, J A; Hall, R E (1989) P48 induces tumor necrosis factor and IL-1 secretion by human monocytes. J Immunol 143:3217-21
Leftwich, J A; Hall, R E (1989) Purification and further characterization of a non-tumor necrosis factor alpha or beta differentiation-inducing cytokine, P48. Cancer Res 49:4459-65
Schuetz, J D; Gorse, K M; Goldman, I D et al. (1988) Transient inhibition of DNA synthesis by 5-fluorodeoxyuridine leads to overexpression of dihydrofolate reductase with increased frequency of methotrexate resistance. J Biol Chem 263:7708-12
Leftwich, J A; Carlson, P; Adelman, B et al. (1987) HL-60-1E3, a novel phorbol diester-resistant HL-60 cell line. Cancer Res 47:1319-24
Ely, C M; Leftwich, J A; Chenevix-Trench, G et al. (1987) Altered regulation of c-myc in an HL-60 differentiation resistant subclone, HL-60-1E3. Cancer Res 47:4595-600

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