A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen-specific hyporesponsiveness.
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.
Zuo
Li
L
Division of Rheumatology, Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Cullen
Constance M
CM
DeLay
Monica L
ML
Thornton
Sherry
S
Myers
Linda K
LK
Rosloniec
Edward F
EF
Boivin
Gregory P
GP
Hirsch
Raphael
R
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D001483:Base Sequence; D019556:COS Cells; D002478:Cells, Cultured; D024043:Collagen Type II / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006825:Hybridomas; D007074:Immunoglobulin G / Q000235:genetics*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D017634:Self Tolerance; D018411:Spodoptera / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
D000941:Antigens; D024043:Collagen Type II; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins