The hypothesis to be tested is that the production of natural killer (NK) cells is a dynamic developmental process analogous to the production of other myeloid and lymphoid lineages and is dependent upon the interactions of three components: NK lineage progenitor cells, stromal cells, and growth factors.
The aims of this proposal are to develop the methods and cell lines necessary to analyze NK cell production and maturation in vitro and to use those methods to answer fundamental questions about the control of production of NK cells from their progenitors. Long and short term bone marrow cultures will be used to analyze the requirements for progenitor cells (obtained either from bone marrow by Percoll gradient centrifugation, positive and negative selection with antibodies or from established lines of progenitor cells), stromal cells (cultured whole bone marrow stroma or selected lines) and growth factors (IL-2, IL-3, IL-1, IL-4 and other factors (NK-CSF?) found in Con A supernatant. Limiting dilution assays will be used to assess the effects on NK lineage cells of the neutrophilia-inducing tumor CE1460 and the biological response modifiers AIPP (2-amino-5-iodo-6-phenyl-4-pyrimidinone) and OK-432 (a pharmaceutical preparation of Streptococcus pyogenes). Transforming oncogenes (ab1, myc, and myc/raf) will be used to infect selected populations of NK lineage cells to obtain immortalized lines of NK cells and their progenitors. The long range goal of these studies is to understand the roles of NK cells both as products and as regulators of hemopoiesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032553-09
Application #
3170448
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-09-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tsuji, J M; Pollack, S B (1995) Maturation of murine natural killer precursor cells in the absence of exogenous cytokines requires contact with bone marrow stroma. Nat Immun 14:44-56
Linnemeyer, P A; Tsuji, J M; Gill, S et al. (1994) Hamster monoclonal antibodies to murine natural killer cells. Nat Immun 13:49-60
Linnemeyer, P A; Pollack, S B (1994) Stage-specific expression of activation antigens on NK cells at uterine implantation sites in mice. J Immunol 153:1478-86
Pollack, S B (1993) Production and differentiation of NK linkage cells in bone marrow. Nat Immun 12:177-93
Linnemeyer, P A; Pollack, S B (1993) Prostaglandin E2-induced changes in the phenotype, morphology, and lytic activity of IL-2-activated natural killer cells. J Immunol 150:3747-54
Pollack, S B; Tsuji, J (1993) Effects of rIL-7 on murine bone marrow NK precursor cells. Cell Immunol 151:1-11
Winter, B K; Wu, S; Nelson, A C et al. (1992) Renal cell carcinoma and natural killer cells: studies in a novel rat model in vitro and in vivo. Cancer Res 52:6279-86
Pollack, S B; Tsuji, J; Rosse, C (1992) Production and differentiation of NK lineage cells in long-term bone marrow cultures in the absence of exogenous growth factors. Cell Immunol 139:352-62
Bilge, A; Pollack, S B (1992) Regulation of natural killer cell production in bone marrow of mice: no evidence for negative feedback control. Nat Immun 11:156-66
Linnemeyer, P A; Pollack, S B (1991) Monoclonal antibody 4H12 recognizes subsets of adherent-lymphokine activated killer cells and splenic natural killer cells from pregnant and neonatal mice. J Immunol 146:3729-35

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