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MHC Class II Derived Recombinant T Cell Receptor Ligands Protect DBA/1LacJ Mice from Collagen-Induced Arthritis¹

Jianya Huan^*,, Laurie J. Kaler^*, Jeffery L. Mooney, Sandhya Subramanian^*, Corwyn Hopke^*, Arthur A. Vandenbark^*,,, Edward F. Rosloniec^¶, Gregory G. Burrows and Halina Offner^2,*,,

^* Neuroimmunology Research, Veterans Affairs Medical Center, Department of Neurology, Deptartment of Molecular Microbiology and Immunology, and Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97201; and ^¶ Veterans Affairs Medical Center, Memphis, TN 38104

We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the 1 and β1 domains of MHC class II molecules genetically linked with an immunodominant peptide, in experimental autoimmune encephalomyelitis. In the current study, we produced a monomeric murine I-A^q-derived RTL construct covalently linked with bovine collagen type II peptide (bCII257–270) suitable for use in DBA/1LacJ mice that develop collagen-induced arthritis (CIA), an animal model of human rheumatoid arthritis, after immunization with bCII protein in CFA. In this study, we demonstrate that the I-A^q-derived RTLs reduced the incidence of the disease, suppressed the clinical and histological signs of CIA and induced long-term modulation of T cells specific for arthritogenic Ags. Our results showed that the I-A^q/bCII257–270 molecule could systemically reduce proinflammatory IL-17 and IFN- production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-A^q/bCII257–270 molecule could also selectively inhibit IL-1β, IL-6, and IL-23 expression in local joint tissue. This is the first report demonstrating effective prevention of joint inflammation and clinical signs of CIA with an I-A^q-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants MD001833, AI43960, NS41965, and DK068881, Grant 10255 from the Northwest Health Foundation, and Biomedical Laboratory Research and Development Service, Department of Veterans Affairs.

² Address correspondence and reprint requests to Dr. Halina Offner, Neuroimmunology Research, Research and Development-31, Portland Veterans Affairs Medical Center, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239. E-mail address: offnerva{at}ohsu.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; RTL, recombinant T cell receptor ligands; CIA, collagen-induced arthritis; CII, type II collagen; Th17, Th type 17; Tg, transgenic; Treg, T regulatory cell.

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