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A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness¹

Li Zuo^*, Constance M. Cullen^*, Monica L. DeLay^*, Sherry Thornton^*, Linda K. Myers, Edward F. Rosloniec, Gregory P. Boivin and Raphael Hirsch^*,2

^* Division of Rheumatology, Children’s Hospital Medical Center, and Division of Comparative Pathology, University of Cincinnati, Cincinnati, OH 45229; and Department of Pediatrics, University of Tennessee, and Veterans Affairs Medical Center, Memphis, TN 38163

T cells play a central role in many autoimmune diseases. A method to specifically target the function of autoreactive T cell clones would avoid the global immunosuppression associated with current therapies. To develop a molecule capable of inhibiting autoreactive T cell responses in vivo, single-chain peptide-I-A-IgG3 fusion proteins were constructed and expressed in both mammalian and insect cells. The fusion proteins were designed with an IgG3 Fc moiety to make them divalent, allowing TCR cross-linking, while lacking FcR binding and costimulation. The fusion proteins stimulated T cell hybridomas in vitro in a peptide-specific, MHC-restricted manner but failed to do so in soluble form. In vivo administration of an I-A^q fusion protein, containing an immunodominant collagen II peptide, significantly delayed the onset and reduced the severity of collagen-induced arthritis in DBA/1 mice by induction of Ag-specific hyporesponsiveness. Such fusion proteins may be useful to study novel therapeutic approaches for T cell-mediated autoimmune diseases.

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