Mast cells are the major effector cells in diseases of immediate hypersensitivity. Understanding how mast cells develop from primitive blood cells may have implication for treatment of certain allergic diseases. Because mast cells may be uniquely related to hematopoietic stem cells, studies of early events in mast cell differentiation may have broader implications for hematopoiesis in general. The research proposed in this grant application extends the mast cell model system developed in the previous grant period. This system takes advantage of the fact that committed progenitors, but not uncommitted ones, can respond to stem cell factor alone by production of mast cell colonies in methylcellulose. There is continuing attention to the different roles that the c-kit/stem cell factor receptor-ligand complex may play in different stages of differentiation may have broader implications for hematopoiesis in general. The research proposed in this grant application extends the mast cell model system developed in the previous grant period. This system takes advantage of the fact that committed progenitors, but not uncommitted ones, can respond to stem cell factor alone by production of mast cell colonies in methylcellulose. There is continuing attention to the different roles that the c-kit/stem cell factor receptor-ligand complex may play in different stages of differentiation; however, the major focus in this grant application addresses Fc receptors on mast cells and their progenitors, because of recent provocative findings that in mast cells, both FcRI and FcRIII associated gamma chain dimers to transduce signals for activation and cytokine biosynthesis. We are particularly interested in the possibility that an induced autocrine IL-3 loop may be critical element in the committed state of these progenitors. The first specific aim is to determine whether bone marrow progenitors, particularly those which may be part of the early mast cell lineage, bear FcRI and FcRIII and if these receptors transduce a signal to induce an autocrine IL-3 loop which is necessary for commitment. In the second specific aim, mast cell-committed progenitors or granulated mast cells from MLN or peritoneal washouts will be tested to determine if FcRI/FcRIII-mediated signalling affects expression of autocrine cytokines, GATA transcription factors, or proteases. We will also determine if the continued occupancy of FcRI on mast cells in necessary for continued division of successive generations of daughter cells. The third specific aims takes advantage of an exciting new models system for the study of hematopoiesis; embryonic stem (ES) cell cultures. Once these very primitive cells are allowed to differentiate in culture, the expression of message and protein for FcRI/FcRIII will be monitored to correlate with the appearance of mast cells and autocrine IL-3 inducibility. These experiments may reveal similarities or differences between proposed in this grant application should contribute not only to our understanding of mast cell differentiation but also to Fc receptor ontogeny and stem cell development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025537-10
Application #
2607767
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-02-01
Project End
2000-11-30
Budget Start
1997-12-01
Budget End
2000-11-30
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Shelburne, C P; Huff, T F (1999) Inhibition of kit expression in P815 mouse mastocytoma cells by a hammerhead ribozyme. Clin Immunol 93:46-58
Kauma, S W; Huff, T F; Hayes, N et al. (1999) Placental Fas ligand expression is a mechanism for maternal immune tolerance to the fetus. J Clin Endocrinol Metab 84:2188-94
Ryan, J J; DeSimone, S; Klisch, G et al. (1998) IL-4 inhibits mouse mast cell Fc epsilonRI expression through a STAT6-dependent mechanism. J Immunol 161:6915-23
Ryan, J J; Huang, H; McReynolds, L J et al. (1997) Stem cell factor activates STAT-5 DNA binding in IL-3-derived bone marrow mast cells. Exp Hematol 25:357-62
Kauma, S; Huff, T; Krystal, G et al. (1996) The expression of stem cell factor and its receptor, c-kit in human endometrium and placental tissues during pregnancy. J Clin Endocrinol Metab 81:1261-6
Lantz, C S; Huff, T F (1995) Murine KIT+ lineage- bone marrow progenitors express Fc gamma-RII but do not express Fc epsilon-RI until mast cell granule formation. J Immunol 154:355-62
Lantz, C S; Huff, T F (1995) Differential responsiveness of purified mouse c-kit+ mast cells and their progenitors to IL-3 and stem cell factor. J Immunol 155:4024-9
Ryan, J J; Klein, K A; Neuberger, T J et al. (1994) Role for the stem cell factor/KIT complex in Schwann cell neoplasia and mast cell proliferation associated with neurofibromatosis. J Neurosci Res 37:415-32
Plummer 3rd, H; Catlett, J; Leftwich, J et al. (1993) c-myc expression correlates with suppression of c-kit protooncogene expression in small cell lung cancer cell lines. Cancer Res 53:4337-42
Leftwich, J A; Westin, E H; Huff, T F (1992) Expression of c-kit by mesenteric lymph node cells from Nippostrongylus brasiliensis-infected mice and by mast cell colonies developing from these cells in response to 3T3 fibroblast-conditioned medium. J Immunol 148:2894-8

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