Human mast cells, effectors of immediate hypersensitivity and potentially of innate immunity, have been classified into two phenotypes based on the protease composition of their secretory granules. MCTc cells contain tryptase, chymase, cathepsin G and mast cell carboxypeptidase; MCT cells contain only tryptase. Stem cell factor is the major differentiation factor for human mast cells. The involvement of mast cells in human disease depends on the numbers and types of mast cells recruited, and their activation status and survival. The current proposal addresses fundamental aspects of mast cell biology that relate to these factors.
Aim I examines the development and survival of human mast cells. Chymase mRNA expression and potential induction will be examined in MCT cells. The newly-appreciated ability of IL-4 to induce apoptosis in mast cells, and of IL-6 to modulate this process will be explored. New technology allowing mast cells to develop from single cells will be exploited to examine the precursor frequency and proliferative potential of mast cell progenitors. The role of ganglioside GD3 in mast cell development will be examined.
Aim 2 explores three potential pathways to modulate activation of human mast cells. GD3 involvement in FcepsilonR1- mediated activation will be determined. Adenosine, known to augment FcepsilonR1-mediated degranulation of human mast cells, is hypothesized to act through an adenosine 2b receptor. FimH, a mannoside-binding component on enterobacterial fimbria, will be examined for its ability to activate human mast cells.
Aim 3 will attempt to immortalize human mast cells by forcing mast cell progenitors to express telomerase. This reverse transcriptase maintains telomeres, preserves cell proliferative activity and prevents cell senescence. Phenotypic and functional features of immortalized mast cell lines will be characterized. A better understanding of mast cell development and activation in humans will provide a more precise understanding of their involvement in human disease, and better strategies for therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI027517-13
Application #
6373151
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Plaut, Marshall
Project Start
1988-12-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
13
Fiscal Year
2001
Total Cost
$232,421
Indirect Cost
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Le, Quang Trong; Lotfi-Emran, Sahar; Min, Hae-Ki et al. (2014) A simple, sensitive and safe method to determine the human ?/?-tryptase genotype. PLoS One 9:e114944
Ward, Brant R; Arslanian, Silva A; Andreatta, Elisa et al. (2012) Obesity is not linked to increased whole-body mast cell burden in children. J Allergy Clin Immunol 129:1164-6
Alvarez-Twose, I; Vano-Galvan, S; Sanchez-Munoz, L et al. (2012) Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis. Allergy 67:813-21
Le, Quang T; Gomez, Gregorio; Zhao, Wei et al. (2011) Processing of human protryptase in mast cells involves cathepsins L, B, and C. J Immunol 187:1912-8
Le, Quang T; Min, Hae-Ki; Xia, Han-Zhang et al. (2011) Promiscuous processing of human alphabeta-protryptases by cathepsins L, B, and C. J Immunol 186:7136-43
Teodosio, Cristina; García-Montero, Andrés C; Jara-Acevedo, María et al. (2010) Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes. J Allergy Clin Immunol 125:719-26, 726.e1-726.e4
Sabato, M Fernanda; Irani, Anne-Marie; Bukaveckas, Bonny L et al. (2008) A simple and rapid genotyping assay for simultaneous detection of two ADRB2 allelic variants using fluorescence resonance energy transfer probes and melting curve analysis. J Mol Diagn 10:258-64
Zhao, Wei; Gomez, Gregorio; Yu, Shao-Hua et al. (2008) TGF-beta1 attenuates mediator release and de novo Kit expression by human skin mast cells through a Smad-dependent pathway. J Immunol 181:7263-72
Fukuoka, Yoshihiro; Xia, Han-Zhang; Sanchez-Munoz, Laura B et al. (2008) Generation of anaphylatoxins by human beta-tryptase from C3, C4, and C5. J Immunol 180:6307-16
Gomez, Gregorio; Jogie-Brahim, Sherryline; Shima, Mika et al. (2007) Omalizumab reverses the phenotypic and functional effects of IgE-enhanced Fc epsilonRI on human skin mast cells. J Immunol 179:1353-61

Showing the most recent 10 out of 56 publications