The natural killer (NK) cell system in man is an important component of th immune surveillance network in which a specific subpopulation of lymphocytes can destroy virus-infected cells, tumor cells, and heterologous tissues. Additionally, data have now accrued which indicate that NK cells may also display non-lytic immunoregulatory functions. Recent studies in murine and human systems have shown that populations of lymphocytes containing NK cells can suppress B lymphocyte proliferation and immunoglobulin (lg) production in T cell-dependent systems. However, these studies have not utilized purified populations of NK cells nor have they examined the activity of NK cell subsets. Additionally, there has been no investigation of B cell function in non-T cell-dependent systems. Given the role of NK cells in immunity against tumors and the therapeutic modulation of NK activity with biologic response modifiers such as interferon, it will be extremely important to determine: 1) the interrelationship between NK cell cytotoxic and immunoregulatory function; 2) the modulation of these activities; 3) the regulatory activities of NK cell subsets; 4) the mechanism(s) of regulation; and 5) the NK regulatory function in patients with abnormalities of NK cytotoxic function. To determine these, three specific areas will be investigated. We will ascertain if NK cells can alter B cell function indirectly in T cell-dependent systems. For this, highly purified populations of NK cells will be utilized in pokeweed mitogen-dependent systems of B cell proliferation and lg production. Since all stages in the T cell-independent B cell differentiation sequence can be assessed, we will investigate the ability of NK cells to modulate the early and late steps in this sequence. Given our preliminary data that NK cells can affect B cell function, we will determine the mechanism of this activity (direct vs. indirect; cytoxic vs. non-cytotoxic). These studies will also assess the ability of NK cell subsets to act as modulators of B cell function through the isolation of specific subpopulations of NK cells. Additionally, subsets of NK cells will be isolated by cloning techniques and their ability to affect these responses determined. Lastly, patients with known NK cytotoxic defects (e.f., SLE, AIDS) will be assessed for NK immunoregulatory abnormalities. These studies should increase our knowledge of the roles, significance, and functional capabilities of normal NK cells and the potential importance of these lymphocytes in diseases of immunoregulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI024636-01
Application #
3137752
Study Section
Immunobiology Study Section (IMB)
Project Start
1987-03-01
Project End
1990-02-28
Budget Start
1987-03-01
Budget End
1988-02-28
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Katz, P; Yeager Jr, H; Whalen, G et al. (1990) Natural killer cell-mediated lysis of Mycobacterium-avium complex-infected monocytes. J Clin Immunol 10:71-7
Katz, P; Whalen, G; Mitchell, S R et al. (1990) Modulation of suppression of mitogen-induced T cell-dependent B cell responses by natural killer cells. Clin Immunol Immunopathol 55:148-55
Katz, P; Whalen, G; Cupps, T R et al. (1989) Natural killer cells can enhance the proliferative responses of B lymphocytes. Cell Immunol 120:270-6
Katz, P; Mitchell, S R; Cupps, T R et al. (1989) Suppression of B cell responses by natural killer cells is mediated through direct effects on T cells. Cell Immunol 119:130-42
Kehri, J H; Dukovich, M; Whalen, G et al. (1988) Novel interleukin 2 (IL-2) receptor appears to mediate IL-2-induced activation of natural killer cells. J Clin Invest 81:200-5