The ability of interleukin 2 (IL2) to induce Lymphokine-Activated Killer (LAK) cell activity against Natural Killer (NK)-resistant and fresh autologous tumor cells have provided the impetus for IL2/LAK therapy in cancer patients. However, we have recently found that IL2 can also induce LAK cells against autologous normal monocytes/macrophages which could account for some of the side effects noted during IL2 therapy. The purpose of this study is to define the mechanism of LAK cell lysis of monocytes and to determine the biological consequences of the depletion of the particular monocyte subset(s). Monocytes will be separated into subsets by affinity chromatography, antibody plus complement depletion, and FACS cell sorting, based on surface antigens such as FcR, LeuM2, OKM5, CD11. These monocyte subsets, as well as dendritic cells and differentiated macrophages will then be assessed for susceptibility to LAK lysis. Biological assays to assess the effect of the elimination of the susceptible monocyte subset will include allogeneic and autologous mixed lymphocyte reactions, PHA and PWM induced lymphoproliferation, cytostatic activity against A375 melanoma cells, and phagocytosis. These assays will allow us to determine if a helper or suppressor function of the monocyte is preferentially lost after interaction with LAK cells. The phenotype of the LAK precursor and effector cell will be examined to determine if more than one cell type is involved. Analysis of the mechanism of LAK lysis of monocytes will involveidentification of monocyte target structures recognized by LAK cells. Two approaches will be used, 1) inhibition of LAK cell lysis of monocytes by antibodies to known monocyte surface antigens and 2) by preparation of monocyte membrane fragments capable of binding LAK cells to prevent lysis of monocytes. Isolation of these membrane fragments will be followed by monoclonal antibody development against them. The possible release of a monocyte-lytic factor from LAK cells will also be examined. If the putative cytolytic factor is found, and it shows no identity with known cytokines, biochemical purification of and monoclonal antibody development against the molecule will be attempted. In identifying and characterizing the nature of LAK activity against autologous monocytes, it may provide valuable information for circumvention of some of the harmful side effects of LAK/IL2 therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA046820-02
Application #
3190246
Study Section
Experimental Immunology Study Section (EI)
Project Start
1988-05-01
Project End
1991-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
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