Asthma is a complex disease thought to derive largely from T cell- and eosinophil- mediated responses and
through participation of IgE as an important trigger for initiation of the allergic asthmatic response. The role of IgE
includes binding to its high affinity receptor (Fc-epsilon-RI) found on basophils and mast cells; subsequent Fc-
epsilon-RI-IgE cross-linking by multivalent antigen (allergen) leads to rapid release of various vasoactive and
bronchoconstrictive molecules. Targeted inhibition of this interaction is a viable strategy for prevention or
treatment of the atopic response.
Emerging evidence from our laboratory and the laboratory of Dr. M. Robertson (The Scripps Research Institute)
suggests that inhibition of Fc-epsilon-RI-IgE mediated cellular activation may be possible by targeting a novel Fc-
epsilon-RI sequence located on in the extracellular region of the Fc-epsilon-RI alpha-chain that is distinct from the
IgE-binding, site (1), and corresponding to the epitope of the mAb 5H5F8 (2) which has been mapped to the
membrane proximal Fc-epsilon-RI-alpha region (3).
The grant is intended to be used for studying the mechanistic features and other experimental details of this
intriguing biological activity (Specific Aims 1-6 below). In addition, the final aim of this proposal diverges
somewhat to explore the capacity of non-inhibitory anti-Fc-epsilon-RI-alpha mAb 5H5F8, to modulate IgE-
mediated Fc-epsilon-RI regulation in basophils and/or mast cells providing novel options for the rational
therapeutic intervention in IgE-mediated allergic responses that affect at least 20% of the people worldwide.
(1) Nechansky et al. (2000) J. Immunology, submitted
(2) Nechansky et al. (1997) Hybridoma 16:441-446
(3) Nechansky et al. (1998) FEBS Letters 441:225-230