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. Lewis rats immunized with myelin basic protein (MBP) or MBP peptides develop experimental autoimmune encephalomyelitis (EAE), a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CNS) that is used as a model for the human disease multiple sclerosis (MS). In the Lewis rat model of EAE, T cells specific for MBP-72-89 dominate the autoimmune response and TCR expression on the pathogenic T cells is well characterized. This model provides an excellent opportunity to test the hypothesis that regulating the context in which MHC/peptide interacts with TCR can be used to control antigen-directed T cell activation. We have recently developed a family of novel molecules derived from the rat MHC class II alpha-1 and beta-1 domains, with and without a genetically linked polypeptide epitope. Both the non-covalent and covalent beta1alpha1/MBP-72-89 constructs inhibited activation of pathogenic MBP-72-89 reactive T cells and could be used to prevent and treat EAE. The potential of these molecules in the treatment of human autoimmune disease provides a strong rationale to further characterize the mechanism by which these molecules regulate CD4+ pathogenic T cells. We propose to 1) Characterize the beta1alpha1 molecules biochemically; 2) Determine the specificity of the beta1alpha1/peptide molecules by direct binding studies to define the interaction surface between the TCR and beta1alpha1/peptide molecules; 3) To characterize the in vitro effects of the beta1alpha1/peptide molecules and define the time-frame and context within which beta1alpha1/peptide treatment can alter the activation of effector cells in response to antigen stimulation; and 4) To characterize the in vivo effects of the beta1alpha1/peptide molecules, with the goal of defining the mechanism by which the beta1alpha1/peptide molecules block the induction of EAE in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043960-05
Application #
6643539
Study Section
Special Emphasis Panel (ZRG1-SSS-4 (01))
Program Officer
Esch, Thomas R
Project Start
1999-08-15
Project End
2004-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$291,767
Indirect Cost
Name
Oregon Health and Science University
Department
Neurology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
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
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

Showing the most recent 10 out of 26 publications