TRANSGENIC MICE EXPRESSING THE HUMAN HIGH-AFFINITY IMMUNOGLOBULIN (IG)E RECEPTOR ALPHA-CHAIN RESPOND TO HUMAN IGE IN MAST-CELL DEGRANULATION AND IN ALLERGIC REACTIONS

The high-affinity receptor for immunoglobulin (lg) E (Fc epsilon RI) o n mast cells and basophils plays a key role in IgE-mediated allergies. Fc epsilon RI is composed of one alpha, one beta, and two gamma chain s, which are all required for cell surface expression of Fc epsilon RI , but only the or chain is involved in the binding to IgE. Fc epsilon RI-IgE inter-action is highly species specific, and rodent Fc epsilon RI does not bind human IgE. To obtain a ''humanized'' animal model tha t responds to human IgE in allergic reactions, transgenic mice express ing the human Fc epsilon RI or chain were generated. The human Fc epsi lon RI alpha chain gene with a 1.3-kb promoter region as a transgene w as found to be sufficient for mast cell-specific transcription. Cell s urface expression of the human Fc epsilon RI cr chain was indicated by the specific binding of human IgE to mast cells from transgenic mice in now cytometric analyses. Expression of the transgenic Fc epsilon RI on bone marrow-derived mast cells was 4.7 X 10(4)/cell, and the human IgE-binding affinity was K-d = 6.4 nM in receptor-binding studies usi ng I-125-IgE. The transgenic human Fc epsilon RI alpha chain was compl exed with the mouse beta and gamma chains in immunoprecipitation studi es. Cross-linking of the transgenic Fc epsilon RI with human IgE and a ntigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the Fc epsilon RI beta and gamma chains and other c ellular proteins. Mast cell degranulation in transgenic mice could be triggered by human IgE and antigens, as demonstrated by P-hexosaminida se release in vitro and passive cutaneous anaphylaxis in vivo. The res ults demonstrate that the human Fc epsilon RI alpha chain alone not on ly confers the specificity in human IgE binding, but also can reconsti tute a functional receptor by coupling with the mouse beta and gamma c hains to trigger mast cell activation and degranulation in a whole ani mal system: These transgenic mice ''humanized'' in IgE-mediated allerg ies may be valuable for development of therapeutic agents that target the binding of IgE to its receptor.