The goal of this research is to understand and control the activation of pathogenic T cells. Activation of T cells is a multi-step process initiated by co-ligation of antigen-specific T cell receptor (TCR) and co-receptor CD4 with the MHC class II/peptide complex present on antigen presenting cells (APC) (signal I), and includes co-stimulation through T cell surface molecules such as CD28 (signal 2). Our working hypothesis is that T cells can be controlled by regulating the context in which MHC/peptide interacts with the TCR. In order to test this hypothesis we have recently developed a family of novel Recombinant TCR ligands (RTLs) derived from HLADR2 alpha-1 and beta-l domains, with and without a covalently linked peptide antigen. The RTL technology was first described in the context of the animal model of multiple sclerosis, EAE (experimental autoimmune encephalomyelitis). RTLs inhibited activation of pathogenic MBP72-89 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 strong rationale to develop human RTLs and further characterize the mechanism by which the molecules regulate CD4+ pathogenic T cells. We propose to 1) Characterize human RTLs biochemically to enhance the pharmacological utility of the molecules; 2) Study the effect RTLs have on immune synapse formation and quantitate the binding interactions between RTL and TCR using surface plasmon resonance (Biacore); and 3) Characterize the molecular mechanism(s) by which RTLs effect signal transduction and T cell activation, to define the time-frame and context within which RTL treatment can alter effector cells in an antigen-specific manner. Completion of this proposal will identify unique points of intervention for controlling T cells and in turn the T cell immune response and repertoire. Understanding how these unique, rationally engineered drugs work will provide a solid foundation for pharmacological intervention in CD4+ T cell mediated autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041965-03
Application #
6614448
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Utz, Ursula
Project Start
2001-08-01
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$352,500
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
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; Subramanian, Sandhya; Miller, Lisa et al. (2009) Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand. J Neurosci 29:3816-23
Offner, Halina; Sinha, Sushmita; Wang, Chunhe et al. (2008) Recombinant T cell receptor ligands: immunomodulatory, neuroprotective and neuroregenerative effects suggest application as therapy for multiple sclerosis. Rev Neurosci 19:327-39
Huan, Jianya; Kaler, Laurie J; Mooney, Jeffery L et al. (2008) MHC class II derived recombinant T cell receptor ligands protect DBA/1LacJ mice from collagen-induced arthritis. J Immunol 180:1249-57
Sinha, Sushmita; Subramanian, Sandhya; Proctor, Thomas M et al. (2007) A promising therapeutic approach for multiple sclerosis: recombinant T-cell receptor ligands modulate experimental autoimmune encephalomyelitis by reducing interleukin-17 production and inhibiting migration of encephalitogenic cells into the CNS. J Neurosci 27:12531-9
Link, Jason M; Rich, Cathleen M; Korat, Maya et al. (2007) Monomeric DR2/MOG-35-55 recombinant TCR ligand treats relapses of experimental encephalomyelitis in DR2 transgenic mice. Clin Immunol 123:95-104
Wang, Chunhe; Chou, Yuan K; Rich, Cathleen M et al. (2006) AlphaB-crystallin-reactive T cells from knockout mice are not encephalitogenic. J Neuroimmunol 176:51-62
Wang, Chunhe; Gold, Bruce G; Kaler, Laurie J et al. (2006) Antigen-specific therapy promotes repair of myelin and axonal damage in established EAE. J Neurochem 98:1817-27

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