One of the major experimental approaches that has been widely employed for preventing abnormal responses to self antigens is based on deliberate induction of T cell tolerance to a potentially pathogenic self determinant in the neonatal and/or adult period of life of the animal. The rationale for this approach was to inactivate (either physically or functionally) the T cell subset potentially directed against the pathogenic self determinant of a given autoantigen. In this proposal, we describe a novel approach for immunological control of autoimmunity: it involves deliberate induction of determinant-specific T cell response for regulation of autoimmunity by altering antigen processing and presentation. This can be achieved by modulating the function of the antigen presenting cells (APC) as well as by changing the physical form of the immunogen. Our recent studies in adjuvant arthritis (AA) have shown that during the course of AA (in the late phase) in the Lewis rat, there was diversification of the T cell response to the C-terminal determinants of the 65-kD mycobacterial heat shock protein (Bhsp65), and that Bhsp65 C-terminal determinants (BCTD) are involved in natural remission from acute inflammatory arthritis. However, under normal circumstances (in the absence of inflammation or disease) these BCTD are poorly, if at all processed and presented (cryptic determinants) from Bhsp65. Therefore, the beneficial effect of BCTD in the case of AA-susceptible Lewis rats could only be harnessed if the antigen processing of Bhsp65 were altered in such a way that following challenge with this antigen, Lewis rats raised an early and vigorous response to BCTD. We will explore three different approaches to enhance the display of BCTD within Bhsp65-- a) treatment of APC by interferon-g/interleukin-12 (IL-12)/IL-4/IL-6 etc.; b) altering the physical form of Bhsp65 by mild digestion with different cathepsins or cleavage by cyanogen bromide, and c) introduction at defined positions within Bhsp65 of 'dibasic' sites, which are targets of a subset of proteolytic enzymes. Finally, one or more of these approaches will be tested for their ability to prevent and/or treat AA in the Lewis rat. We believe that such a predetermined, experimentally programmed display hierarchy of regulatory determinants would pave the way for novel immunotherapeutic strategies for prevention and treatment of arthritis and other autoimmune diseases.
| Stevens, David B; Gold, Daniel P; Sercarz, Eli E et al. (2002) The Wistar Kyoto (RT1(l)) rat is resistant to myelin basic protein-induced experimental autoimmune encephalomyelitis: comparison with the susceptible Lewis (RT1(l)) strain with regard to the MBP-directed CD4+ T cell repertoire and its regulation. J Neuroimmunol 126:25-36 |
| Moudgil, K D; Kim, E; Yun, O J et al. (2001) Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65. J Immunol 166:4237-43 |
