MECHANISMS OF HUMAN NATURAL KILLER CELL ACTIVATION

Project: Research project

Project Details

Description

Human natural killer (NK) cells participate in a broad range of immunologic
functions, including resistance to infection and anti-tumor immunity. NK
cells are also the participants in the recently developed anti-cancer
therapy that uses "lymphokine-activated killer" (LAK) cells (now in clinical
trials). However, attempts to define the mechanisms by which NK cells are
activated have been hampered by the difficulties in obtaining homogeneous,
well-characterized populations of these cells. This proposal describes an
in-depth evaluation of NK cells using cloned and characterized human NK cell
lines. These stable NK cell lines exhibit defined, measurable phenotypic
responses to cytokines, mediate normal cytotoxic functions, and grow in
numbers sufficient for biochemical analysis. This NK cell model will
therefore be used to determine how multiple ligand-receptor interactions can
mediate or modify distinct intracellular events during NK cell activation.
The principal focus will be on evaluating: 1) the interacting second
messenger pathways that operate during NK cell-mediated cytotoxic reactions;
2) the ways in which selected extracellular cytokines and adhesion molecules
modify the signalling system and subsequent functioning of NK cells. A
major emphasis will be placed on identifying and characterizing the signals
that mediate activation after an NK cell binds to a) NK-sensitive tumor
targets or virally-infected cells (direct, non-MHC restricted, cell-mediated
cytotoxicity); or b) Fc receptor-specific ligands (antibody-dependent cell-
mediated cytotoxicity). Preliminary data has identified roles for five
interrelated signal transduction pathways: 1) phosphoinositide turnover; 2)
protein kinase C activation; 3) calcium signalling; 4)cAMP-dependent second
messengers; and 5) eicosanoid metabolism. Recent experiments also suggest
that IL-2, IL-4, TGF-beta, and cell adhesion molecules all have the capacity
to modulate this NK cell activation. Further studies will be conducted to
link signal transduction changes induced by these cytokines with their
subsequent alterations in NK cell growth, differentiation, and function.
Experiments designed to define the roles of these interacting factors will
significantly enhance our understanding of both NK cell activation and its
potential for therapeutic manipulation.
StatusFinished
Effective start/end date3/12/901/31/14

Funding

  • National Cancer Institute: $302,744.00
  • National Cancer Institute: $302,744.00
  • National Cancer Institute: $312,108.00
  • National Cancer Institute: $312,108.00
  • National Cancer Institute: $312,108.00
  • National Cancer Institute: $289,782.00

ASJC

  • Medicine(all)

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