In patients with asthma the mucosal mast cell is strategically positioned at the host environmental interface to initiate airway inflammation by release of preformed and newly generated spasmogenic mediators in response to inhaled allergen cross linking high affinity mast cell surface IgE receptors. The regulation of mucosal mast cell number provides an alternate therapeutic strategy to inhibition of mucosal mast cell mediator release in limiting mast cell mediated inflammation. Rodent mast cells are the best characterized model of mast cell heterogeneity and provide suitable purified populations of mast cells to study growth factor regulation of mast cells in vitro and in vivo. In rodents, the mucosal mast cell has been shown to proliferate in response to the T cell derived lymphokine interleukin-3. The chemically transformed RBL-1 cell line is considered homologous with the mucosal mast cell but has abrogated the mucosal mast cell requirement for exogenous IL-3 for continued proliferation and survival. The concept of autocrine stimulation of cellular proliferation requires that a cell can both produce and respond to a particular growth factor. The hypothesis that the RBL-1 cell line is an autocrine mucosal mast cell tumor producing and responding to its own growth factor interleukin-3 will be tested in vitro and in vivo. The RBL-1 cell line supernatant IL-3 activity will be purified by ammonium sulphate precipitation and sequential column fractionation using DEAE cellulose, hydroxylapatite, G-75 sephadex, and RP-HPLC. IL-3 activity will be assessed in a 3H-thymidine incorporation assay using the IL-3 dependent cell lines FDC-P1 and DA-1. Monoclonal antibodies to IL-3 and the IL-3 receptor will be produced in an attempt to inhibit cellular proliferation in vitro and in vivo. The ability to regulate mucosal mast cell proliferation in vitro and in vivo could suggest possible therapeutic strategies to control mucosal mast cell proliferation in allergic diseases such as asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI000845-02
Application #
3078805
Study Section
Allergy, Immunology, and Transplantation Research Committee (AITC)
Project Start
1987-09-30
Project End
1990-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093