THE V3 MASTOCYTOSIS MOUSE--MAST CELL DIFFERENTIATION, MATURATION, AND FUNCTION

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It has been known for sometime that mast cells residing in different tissue locations store their granules varied types and amounts of proteoglycans and neutral proteases. Although in vitro studies have given in sight as to which cytokines probably regulate mast cell granule heterogeneity in the BALB/c mouse, it has not been possible to address tissue-directed mast cell differentiation and maturation in this mouse strain. It also has not been possible to experimentally address the functional significance of granule heterogeneity in vivo. We have recently discovered that when an immature v-abl-transformed mouse mast cell line (V3-MC) is adoptively transferred into a BALB/c mouse, systemic mastocytosis develops rapidly in the liver, spleen, lung, and intestine. The long term objective of project 2 is to use the V3 mastocytosis mouse to study mast cell differentiation, maturation, and function; three specific aims are proposed. Preliminary data indicate that the V3-MC that develop in the liver and intestine of this diseased mouse exhibit different granule phenotypes. Thus, protease specific antibodies and gene-specific probes will be used in specific aim 1 to investigate tissue-directed regulation of the differentiation and maturation processes of mast cells in V3 mastocytosis mice. Because fibrosis is usually associated with increased number of cells that morphologically resemble fibroblasts, the adoptive transfer system will be used in specific aim 2 to study mast-cell mediated fibrosis. V3-MC associated fibrosis in the liver and spleen of the mastocytosis mouse will be compared with non-fibrotic tissue in the animals to determine if a specific mast cell phenotype regulate host tissue responses. Mast cells contain substantially more neutral protease than any other cell in the body. However, it is not known what happens to these proteases when they are exocytosed from the mast cell in vivo. As assessed by SDS- PAGE/immunoblot analysis, high levels of mouse mast cell protease 7 are present in the blood 30 minutes after V3 mastocytosis mice are systemically activated with IgE and antigen. Thus in specific aim 3, the fate of the different granular constituents exocytosed from cultured V3- MC and from V3 mastocytosis mice with or without Fc-epsilon-RI perturbation will be investigated.