Proteolipid protein (PLP) is the major protein component of central nervous system (CNS) myelin and is now recognized as a major autoantigen involved in the development of experimental autoimmune encephalomyelitis (EAE), an experimental model for human multiple sclerosis (MS). Just as MS is known to occur in certain human populations at a higher frequency, it is also known that some strains of mice are highly susceptible to PLP induced EAE (e.g., SJL) while others are highly resistant (e.g., B10.S). This is so even though the mice are H-2 compatible, suggesting that the susceptibility to EAE is an inherited trait. However, the cellular or genetic elements responsible for the differences in disease susceptibility are not known. Dr. Kuchroo has developed T cell receptor (TcR) transgenic mice specific for one of the major encephalitogenic determinants of PLP, peptide 139-151. He has also generated a series of altered peptides by selectively changing the major TcR contact residues in the encephalitogenic PLP peptide. Some of these altered peptides inhibit and reverse EAE. However, the mechanism by which the altered peptides suppress EAE is not clear. With the PLP 139-151-specific TcR transgenic mice and altered peptides, he proposes to: 1) Study the cellular basis for the difference in the susceptibility by breeding the TcR transgenic mice onto susceptible SJL and resistant B10.S backgrounds. The transgenic mice on these two backgrounds will be tested for the development of EAE and whether resistance in the B10.S mice correlates with the production of anti-inflammatory cytokines, changes in the frequency of the PLP 139-151 specific T precursor cells (Thp) or in the numbers of TcR., CD4 and CD28 molecules expressed on PLP 139-151 specific transgenic T cells; 2) Understand the mechanism by which the TcR antagonist peptide inhibits EAE by studying whether protective effects of the altered peptides are due to changing cytokine balance of PLP 139-151 reactive T cells from pro-inflammatory to anti-inflammatory cytokines, and determining what effects antagonist peptides have on naive PLP 139-151 specific Thp cells; and 3) Test the effect of PLP deficiency on the selection of PLP T cell repertoire by intercrossing PLP TcR transgenic mice with PLP knockout mice on both the susceptible (SJL) and resistant (B10.S) backgrounds. The results should provide information on the mechanism by which PLP specific T cells induce autoimmunity of the CNS, and how the disease inducing T cells are regulated in the resistant background or by the altered peptides.
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