The fundamental objective of this project is to determine the differentiation program of murine natural killer (NK) and killer (K) cells and to define the modulating effects of neoplasia on the production of NK and K cells. In vivo cytokinetic studies with ?3?H-TdR, repopulation assays, and in vitro colony-forming assays are being used to determine the proliferative status and renewal rate of NK and K cells in the bone marrow and their life span in the periphery. Since NK cells acquire binding ability prior to lytic ability, we determined the proliferative status of target binding cells (TBC) in marrow. Six-week-old C578L/6 female mice were injected intravenously with ?3?H-TdR (1 micro Curie/gm body weight). Femoral marrow was obtained after 2, 12, 24, or 48 hrs and treated with anti-Ig and C to eliminate B cells. The remaining """"""""lymphoid"""""""" population comprised 17% of the initial BMC. Cytospots were radioautographed and subsequently examined with phase contrast fluorescence microscopy to assess the percent TBC. Two size classes of TBC could be distinguished on the basis of cell diameter: large, greater than 9 micrometers, and small, less than 9 micrometers. The percent of H-TdR-labeled small TBC in the marrow was 8, 16, 27, and 16% at 2, 12, 24, and 48 hrs, respectively, whereas the percent labeled large TBC was 24, 18, 21, and 14% at the four time points. The increase in labeling index of small TBC during the first 24 hrs and subsequent decrease indicate that small TBC are newly produced cells with a rapid turnover. The large marrow TBC appear to be a self-maintaining precursor pool that gives rise to small TBC. We are continuing to test the effect of in vivo depletion of NK and K cells during the neonatal period using our model for specific depletion by in vivo treatment with NK 1.1 antiserum. In the future, we will test the effects of specific depletion-of NK cells on: (1) the production and maturation of NK and K cells, and (2) the induction and growth of 3-methylcholanthrene- and Moloney sarcoma virus-induced sarcomas. (SR)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032553-05
Application #
3170445
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-09-01
Project End
1987-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
5
Fiscal Year
1986
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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