EXCEED THE SPACE PROVIDED. The goal of this proposal is to develop innovative strategies based on novel chimeric Ig based proteins so as to prevent basophil and mast cell responses to FcaRI crosslinking, understand the mechanisms involved and ultimately treat and interrupt the cycle of immunological events responsible for disease progression in atopy and asthma. Allergen specific and allergen non-specific chimeric proteins will be produced and evaluated. When IgE bound to the high affmity IgE receptor, FcaRI, on tissue mast cells and peripheral blood basophils are crosslinked with specific antigen. degranulation causes the immediate phase of the allergic response. In addition, cytokines generated by activated mast cells and basophils help to maintain the Th2 environment that favors the late phase of this chronic disease. Activation signals mediated by ITAMs (immunoreceptor tyrosine-based activation motifs) in the FceRI are subject to negative regulation by the ITIM (immunoreceptor tyrosine-based inhibitory motifs)-containing receptor, including Fc`/RII. We have designed and tested one novel human gamma-epsilon Ig fusion protein which inhibits in vivo allergic responses and in vitro human mast cell and basophil functional and biochemical responses by FcyRII/FceRI co-aggregation.
Our specific aims will test the hypothesis that molecules which co-aggregate ITIM receptors with FceRI will alter FeeRI- signaling pathways and attenuate FcERI-mediated activation in vitro and in vivo.
Aim 1 is to design and produce novel chimeric proteins that function as negative regulators of basophils and mast cells. This will include antigen non-specific molecules where direct binding to FceRI is provided by the epsilon heavy chain and ITIM binding employs a single or multiple y1 or '(3 motifs. Antigen specific chimeric molecules comprised of allergen (e.g. Fel dl) plus an ITIM binding motif(s) will also be developed as a unique form of enhanced and safer immunotherapy.
Aim 2 will test the ability of novel antigen nonspeeifie and specific molecules for their ability to inhibit human mast cells and basophils functional responses in vitro and to inhibit in vivo IgE mediated reactivity in transgenic mice and non-human primates.
Aim 3 will dissect the biochemical mechanism by which such novel chimeric proteins negatively regulate FeeRI- mediated functional responses using human mast cells and basophils. The results of these experiments will reveal whether ITIM-receptors and their downstream effectors are potential targets for innovative therapeutic interventions to manage allergic inflammation. Further, understanding of the mechanisms underlying the control of activating receptors by inhibitory receptors will have broad reaching implications for the manipulation the immune response. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI015251-26
Application #
6827409
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Plaut, Marshall
Project Start
1978-08-01
Project End
2007-10-31
Budget Start
2004-11-01
Budget End
2005-10-31
Support Year
26
Fiscal Year
2005
Total Cost
$383,259
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Zhang, Ke; Behnecke, Anne; Li, Wei et al. (2009) A novel multi-potential dendritic cell targeted gene vaccination platform; application to food allergy and beyond. Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M 96:338-47; discussion 348
Zhang, Ke; Zhu, Daocheng; Kepley, Christopher et al. (2007) Chimeric human fcgamma-allergen fusion proteins in the prevention of allergy. Immunol Allergy Clin North Am 27:93-103
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Zhu, Daocheng; Kepley, Christopher L; Zhang, Ke et al. (2005) A chimeric human-cat fusion protein blocks cat-induced allergy. Nat Med 11:446-9
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