The candidate is an assistant professor of dermatology at Johns Hopkins and has commenced the fourth year of this KO8 research program. This application constitutes a request for the fifth year of funding. Langerhans cells (LC) are the principal antigen presenting cells in the skin and part of the network of professional antigen presenting cells. They are responsible for primary and secondary immune T cell responses. Recently the high affinity receptor of IgE (FcERI) has been identified on LC. FcERI complex plays a central role in allergic inflammation. While the function of FcERI in the degranulation of mast cells and basophils is well documented, little is known about the function of this receptor on antigen presenting cells.
The aims of this proposal are: 1) To create a model system to study the role of FcERI on Langerhans cells and dendritic cells. 2) To determine the phenotype and changes induced in epidermal Langerhans cells following the ligation of FcERI, and 3) To determine in vivo and in vitro the functional changes induced in epidermal Langerhans cells following the ligation of FcERI. Related studies will determine if FcERI on LC plays a role in the polarization of T cells towards a Th2 phenotype. The studies proposed will be conducted in vitro, and in vivo using a unique transgenic murine model. Unlike human epidermal LC, FcERI is not expressed on murine epidermal LC. However, the mouse that is transgenic for human FcERI alpha (developed by the sponsor) expresses FcERI on epidermal LC. Thus, this mouse is uniquely suited for the study of FcERI on epidermal Langerhans cells in a murine system. Since LC occur in small numbers in human epidermis, a murine model may be the only meaningful way to study this receptor. This tansgenic mouse is exclusively available in the Laboratory of Jean-Pierre Kinet M.D., the candidate's sponsor. For this reason, the performance site of this grant is The Laboratory of Allergy and Immunology, Beth Israel Deaconess Medical Center, Boston MA. Preliminary studies of phenotype have determined that IgE regulates the expression of FcEl on Langerhans cells and that up-regulation is independent of transcriptional regulation or signaling. The studies proposed here will further explore the mechanisms of upregulation. Preliminary functional studies indicated a need to cross the human alpha transgenic mouse onto a murine alpha knock-out background. Mice are now backcrossed 9 generations, and studies of function may proceed. A fifth year is requested to complete the specific aims indicated above.
| Borkowski, T A; Jouvin, M H; Lin, S Y et al. (2001) Minimal requirements for IgE-mediated regulation of surface Fc epsilon RI. J Immunol 167:1290-6 |
