Title

Studies on the mechanisms involved in the decreased natural killer cell activity of mice bearing a chemically-induced mammary adenocarcinoma

Date of Award

1989

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Diana M. Lopez, Committee Chair

Abstract

Natural Killer (NK) cells have been implicated as playing an important role in host defense against virally induced and malignant disease. This in part is due to their unique ability to lyse a wide variety of cells in a MHC nonrestricted manner and without prior sensitization. Paradoxically, we have observed a profound decrease in the splenic NK acitivy of mice bearing a serially transplanted, chemically induced mammary adenocarcinoma(D1-DMBA-3). This depressed activity was a direct consequence of tumor burden since long exposure to few numbers of tumor cells delayed the onset of the decrease. In addition, the downregulation of the NK activity in tumor bearers was not due to the presence of a regulatory cell population, although sera collected from tumors bearers did partially inhibit NK activity of spleen cells from normal mice. Determination of the numbers of NK cells, both morphologically and phenotypically, failed to demonstrate a decrease in the number of NK cells that could account for the depressed activity observed in tumor bearers. However, the cells did appear more immature and displayed forward and right angle scatter patterns consistent with that of a blast cell. Single cell assay demonstrated that the NK cells from the tumor bearing mice could bind their target efficiently but failed to complete the lytic process. These cells could, however, effect ADCC very efficiently and displayed enhanced expression of Fc receptors. Ca2+ influx and cytoskeletal studies suggested that the NK cells were triggered, as defined by calcium mobilization, but failed to cap surface proteins and reorient their Golgi apparatus and microtubules upon conjugation with a NK sensitive target. In addition, NK cells from mice bearing large tumors appeared to either contain diminished levels of NKCF or were unable to efficiently secrete this cytotoxic factor into the extracellular mileau. These studies indicate that the depressed NK activity observed in these tumor bearing mice is due to a defect in a postbinding event(s) leading to secretion of granule associated cytolytic factors and/or a decrease in the amount of functional cytolytic factors necessary for target cell lysis.

Keywords

Health Sciences, Immunology

Link to Full Text

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