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J Autoimmun. 2013 Feb;40:96-110. doi: 10.1016/j.jaut.2012.08.004. Epub 2012 Sep 29.

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.

Author information

1
Research Service, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.
2
Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.
3
Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.
4
Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
5
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
6
Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
7
Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
8
Department of Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.
9
Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
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Contributed equally

Abstract

Treatment with partial (p)MHC class II-β1α1 constructs (also referred to as recombinant T-cell receptor ligands - RTL) linked to antigenic peptides can induce T-cell tolerance, inhibit recruitment of inflammatory cells and reverse autoimmune diseases. Here we demonstrate a novel regulatory pathway that involves RTL binding to CD11b(+) mononuclear cells through a receptor comprised of MHC class II invariant chain (CD74), cell-surface histones and MHC class II itself for treatment of experimental autoimmune encephalomyelitis (EAE). Binding of RTL constructs with CD74 involved a previously unrecognized MHC class II-α1/CD74 interaction that inhibited CD74 expression, blocked activity of its ligand, macrophage migration inhibitory factor, and reduced EAE severity. These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases.

PMID:
23026773
PMCID:
PMC3789252
DOI:
10.1016/j.jaut.2012.08.004
[Indexed for MEDLINE]
Free PMC Article

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