The primary goal of this training program is to build a solid foundation in molecular biology and immunology that will allow the applicant to pursue a productive career in the study of the gastrointestinal (GI) immune system in health and disease. Phase I emphasizes a didactic program based on the Ph.D. requirements in the UCLA Molecular Biology Institute. A committee consisting of Dr. Mitchell Kronenberg, Dr. Stephan Targan and Dr. Leroy Hood will determine eligibility for progression to phase II. During phase I the candidate will work on a research project investigating the molecular genetics of T cell antigen receptors (TCR) of murine GI intraepithelial lymphocytes (IEL). The TCR of most IEL are encoded by gamma and delta genes whereas the TCR of most non-epithelial T-cells are encoded by alpha and beta to determine: 1. if gamma delta IEL can recognize specific antigens 2. if recognition is major histocompatibility complex (MHC) restricted and 3. how gamma delta TCR genes encode for antigen specificity and MHC restriction. Gamma delta IEL from mice with enteric lymphocytic choriotropic meningitis virus (LCMV) infections will be isolated and cloned. Gamma delta IEL antigen specificity will be assessed in functional assays using a panel of MHC syngeneic antigen presenting cells; either uninfected, infected with native LCMV virus, or infected with recombinant vaccinia viruses expressing a restricted portion of the LCMV genome. MHC restriction will be determined by response to a panel of LCMV infected L cells transfected with specific MHC Class I genes. TCR genes of cloned gamma delta IEL will be sequenced and correlated with the clone's antigen specificity and MHC restriction. During phase II, the expertise gained in Phase I will be applied to the study of the target specificity and TCR gene sequences of cloned human GI cytotoxic T-lymphocytes (CTL) from inflammatory bowel disease (IBD) patients. Phase II specific aims are to determine 1. if these CTL clones kill human colonic epithelial cell targets and 2. if the diversity of their TCR gene sequences is limited, consistent with response to a specific antigen. The ultimate goal of this research is to determine whether it is feasible to development specific T cell vaccines or monoclonal antibodies for the treatment of IBD.
| Sydora, B C; Mixter, P F; Houlden, B et al. (1993) T-cell receptor gamma delta diversity and specificity of intestinal intraepithelial lymphocytes: analysis of IEL-derived hybridomas. Cell Immunol 152:305-22 |
