In this study, the PI plans to test the hypothesis that therapies directed at either blocking autoreactive T cell recognition or inducing immune deviation (Th1 to Th2) switching) of CII reactive T cells might be effective in blocking the onset of CIA and ameliorating ongoing disease. This hypothesis will be tested using several different strategies: i) the X-ray structure of a Va domain derived from a representative, autoreactive TCR (designated 85.33) will be solved and used in combination with available X-ray data of Vb8.2 containing TCRs to build a model of the 85.33 TCR; ii) the regions that are responsible for autoantigen recognition will be identified by grafting CDRs from the 85.33 TCR to a TCR that only recognizes heterologous CII 260-270. These regions will be used as templates to generate random peptide libraries and peptides that bind with high affinity to autoantigen will be tested as blocking agents in the therapy of CIA. and iii) the PI will extend protein vaccination studies using soluble TCR V regions to the use of plasmids expressing TCR V regions in genetic vaccinations. Thus, the overall goal is to better understand autoreactive T cell recognition in murine CIA and to develop novel therapies that should, in the longer term have applications in the treatment of RA.
| Machius, M; Cianga, P; Deisenhofer, J et al. (2001) Crystal structure of a T cell receptor Valpha11 (AV11S5) domain: new canonical forms for the first and second complementarity determining regions. J Mol Biol 310:689-98 |
