The overall goal of this proposal is to test the hypothesis that induction of immunity against synthetic peptides that resemble natural human TCR V-beta-5.2 idiotopes can regulate potentially pathogenic T cells that preferentially express V-beta-5.2. Our prior studies in rats and mice demonstrated that TCR V-beta-8.2 CDR2 peptides can prevent and treat clinical signs of experimental encephalomyelitis by inducing T cells and antibodies that can inhibit the mono-V-beta-8.2 T cell response to myelin basic protein (BP). Recently, we found biased use of V-beta-5.2 and V-beta-6.1 by BP-specific T cells from multiple sclerosis (MS) patients, a result corroborated by others who found V-beta-5.2+ T cells with a BP-specific CDR3 motif in MS plaques. We have now shown that anti-TCR specific T cells and antibodies can be induced by injecting TCR V-beta-5.2 or V-beta-6.1 peptides into MS patients. Thus the stage is set to test whether these T cells and antibodies can regulate V-beta-5.2 + T cells, including those specific for BP. Successful regulation of BP reactivity would allow a critical evaluation of the role of BP in the MS disease process, and would establish a prototypic approach for the treatment of other autoimmune diseases characterized by limited V gene expression.
AIM 1. To assess the frequency, specificity, TCR repertoire, and encephalitogenicity of human BP-specific T cells. In this aim, we will develop the ability to rapidly and repeatedly evaluate MS disease- associated changes in BP-specific T cell responses in blood and CSF. Moreover, we will assess the encephalitogenic activity of these T cells by passive transfer into MHC compatible, bone marrow reconstituted SCID-Hu mice.
AIM 2. To establish the effects of TCR peptide injection on TCR and BP responses. With a focus on V-beta-5.2, we will inject overlapping peptides into MS patients with V-beta-5.2-biased responses to BP to determine which regions are immunodominant T and B cell idiotopes. In responders, we will monitor functional changes in V-beta-5.2+ T cells and in responses to BP.
AIM 3. To evaluate potential regulatory mechanisms induced by TCR peptides. In this aim, we will isolate and characterize distinct anti-TCR peptide-specific T cell clonotypes and antibodies induced after TCR peptide boosting. We will evaluate each T cell clonotype and affinity purified antibodies for their ability to regulate autologous V-beta-5.2+ BP-reactive T cells in vitro and in the SCID-Hu mouse.
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