Five years after specializing in pediatric emergency medicine, Dr. Richard Strait took an academic position in this specialty at Cincinnati Children's Hospital Medical Center and initiated research in anaphylaxis, an area pertinent to emergency medicine, with Dr. Fred Finkelman as mentor. Although this research has been productive, Dr. Strait, Dr. Finkelman, and Dr. Strait's supervisors at CHMC realize that additional training in Immunology and Molecular Biology will be required for Dr. Strait to develop into an independent investigator. Consequently, a four year training program has been designed that will allow Dr. Strait to attend journal clubs, research conferences, and formal classes in Immunology and Molecular Biology and to continue his training in laboratory research under Dr. Finkelman, using studies of anaphylaxis as a vehicle for this training. Anaphylaxis is important both as a disease and as a physiological mechanism: the cellular processes that cause anaphylactic shock are systemic exaggerations of processes central to both allergic pathophysiology and host defense against gastrointestinal nematode parasites. The cytokine IL-4 contributes to anaphylaxis by promoting IgE and IgG1 responses and mast cell proliferation. Recently, Dr. Strait discovered that IL-4 has an additional important effect: it sensitizes animals to stimuli that cause anaphylaxis, so that a stimulus that causes a mild anaphylactic reaction in the absence of IL- 4 will cause lethal anaphylaxis in the presence of IL- 4. This proposal will characterize this novel effect of IL-4. Experiments will determine: 1) the dose-response and kinetics of the IL-4 effect; 2) the ability of endogenously produced IL-4 to enhance anaphylaxis, 3) the signaling pathway involved in IL- 4 enhancement of anaphylaxis and 4) whether IL-4 enhances anaphylaxis by increasing mediator release and/or by increasing responsiveness to released mediators. In addition to providing basic information about the pathogenesis of anaphylaxis and the mechanisms by which IL-4 contributes to both allergy and protective immunity, results of these experiments should suggest how IL-4 antagonists could best be used to treat allergic disorders

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AI050006-01
Application #
6364142
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2001-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$119,610
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Strait, Richard T; Morris, Suzanne C; Finkelman, Fred D (2006) IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking. J Clin Invest 116:833-41
Brandt, Eric B; Strait, Richard T; Hershko, Dan et al. (2003) Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest 112:1666-77
Strait, Richard T; Morris, Suzanne C; Smiley, Kristi et al. (2003) IL-4 exacerbates anaphylaxis. J Immunol 170:3835-42
Strait, Richard T; Morris, Suzanne C; Yang, Mingyan et al. (2002) Pathways of anaphylaxis in the mouse. J Allergy Clin Immunol 109:658-68