The goal of this research is to understand and control the activation of pathogenic T cells. The interaction between the MHC/peptide-antigen complex and the T cell receptor (TCR) is essential for antigen-specific T cell activation. Antigen analogs can act as powerful and specific inhibitors of T cell activation and provide a rational approach to antigen-specific immuno-intervention in allergies and autoimmune diseases. Recent studies have lead to the development of a platform molecular RecombinantTCR Ligand (RTL) technology derived from domains of MHC Class II molecules. These protein therapeutics have demonstrated direct antigen-specific binding and inhibition of pathogenic T cells. Furthermore, these molecules could be used to prevent and treat experimental autoimmune encephalomyelitis (EAE), a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CMS) that is used as a model for the human disease multiple sclerosis (MS). During the tenure of this proposal RTLs will be characterized using relapsing- remitting and chronic models of EAE, allowing us to explore the molecular and systemic mechanism(s) by which RTLs control pathogenic T cells in vivo. We propose the following specific aims:
SPECIFIC AIM 1. Biochemical and biophysical characterization of l-As- and l-AB-derived Recombinant TCR Ligands (RTLs).
SPECIFIC AIM 2. Characterization of the molecular mechanism(s) by which RTLs effect T cell activation in vitro.
SPECIFIC AIM 3. Evaluation of the in vivo effects RTLs have on relapsing-remitting and chronic models of EAE. The work proposed will provide a solid base for pharmacological intervention in CD4+ T cell mediated autoimmune diseases. ? ? ?
|Vandenbark, Arthur A; Meza-Romero, Roberto; Benedek, Gil et al. (2013) A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance. J Autoimmun 40:96-110|
|Yadav, Vijayshree; Bourdette, Dennis N; Bowen, James D et al. (2012) Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study. Autoimmune Dis 2012:954739|
|Burrows, Gregory G; Meza-Romero, Roberto; Huan, Jianya et al. (2012) Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis. Metab Brain Dis 27:143-9|
|Dahan, Rony; Tabul, Moran; Chou, Yuan K et al. (2011) TCR-like antibodies distinguish conformational and functional differences in two- versus four-domain auto reactive MHC class II-peptide complexes. Eur J Immunol 41:1465-79|
|Huan, J; Meza-Romero, R; Mooney, J L et al. (2011) Single-chain recombinant HLA-DQ2.5/peptide molecules block ?2-gliadin-specific pathogenic CD4+ T-cell proliferation and attenuate production of inflammatory cytokines: a potential therapy for celiac disease. Mucosal Immunol 4:112-20|
|Offner, Halina; Sinha, Sushmita; Burrows, Gregory G et al. (2011) RTL therapy for multiple sclerosis: a Phase I clinical study. J Neuroimmunol 231:7-14|
|Itakura, Asako; Aslan, Joseph E; Sinha, Sushmita et al. (2010) Characterization of human platelet binding of recombinant T cell receptor ligand. J Neuroinflammation 7:75|
|Adamus, Grazyna; Karren, Landon J; Mooney, Jeff et al. (2010) A promising therapeutic approach for treatment of posterior uveitis: recombinant T cell receptor ligand protects Lewis rats from acute and recurrent experimental autoimmune uveitis. Ophthalmic Res 44:24-33|
|Sinha, Sushmita; Miller, Lisa; Subramanian, Sandhya et al. (2010) Binding of recombinant T cell receptor ligands (RTL) to antigen presenting cells prevents upregulation of CD11b and inhibits T cell activation and transfer of experimental autoimmune encephalomyelitis. J Neuroimmunol 225:52-61|
|Sinha, Sushmita; Subramanian, Sandhya; Emerson-Webber, Ashley et al. (2010) Recombinant TCR ligand reverses clinical signs and CNS damage of EAE induced by recombinant human MOG. J Neuroimmune Pharmacol 5:231-9|
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