MHC class II derived recombinant T cell receptor ligands protect DBA/1LacJ mice from collagen-induced arthritis.
We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the alpha1 and beta1 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-Aq-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-Aq-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-Aq/bCII257-270 molecule could systemically reduce proinflammatory IL-17 and IFN-gamma production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-Aq/bCII257-270 molecule could also selectively inhibit IL-1beta, 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-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.
Huan
Jianya
J
Neuroimmunology Research, Veterans Affairs Medical Center, Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland 97201, USA.
Kaler
Laurie J
LJ
Mooney
Jeffery L
JL
Subramanian
Sandhya
S
Hopke
Corwyn
C
Vandenbark
Arthur A
AA
Rosloniec
Edward F
EF
Burrows
Gregory G
GG
Offner
Halina
H
D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002417:Cattle; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D007596:Joints / Q000473:pathology; D008024:Ligands; D051379:Mice; D008811:Mice, Inbred DBA; D011948:Receptors, Antigen, T-Cell / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D013154:Spleen / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
D000941:Antigens; D016207:Cytokines; C496506:Foxa3 protein, mouse; D000949:Histocompatibility Antigens Class II; C527100:I-A(q)-bCII257-270 protein; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D051543:Hepatocyte Nuclear Factor 3-gamma