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

Abstract

We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the α1 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-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-γ 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-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-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.

The genetics of celiac disease: A comprehensive review of clinical implications

“…This approach has shown promising results for multiple sclerosis treatment, showing solid results in phase I clinical study [136] and also has demonstrated a potential use for other autoimmune diseases [137,138]. Briefly, the goal of this strategy is the same than the one targeted for the above mentioned HLA-blocker peptides: to modulate the immune response; although for each one the target would be different.…”

Partial MHC class II constructs as novel immunomodulatory therapy for stroke

“…Partial MHC class II constructs were shown previously to prevent and/or reverse clinical signs of EAE, collagen-induced arthritis and experimental autoimmune uveitis, through reducing the number and frequency of activated cells in the affected tissues, downregulation of endothelial cell adhesion molecules and reduction of CNS chemokines/receptors (Adamus et al, 2012; Adamus et al, 2006; Huan et al, 2008; Sinha et al, 2010; Sinha et al, 2007). Based on these findings, a pMHC construct (RTL551, mouse I-A b α1β1 domains linked to mouse MOG-35-55 peptide) was used to treat experimental stroke in C57BL/6 mice.…”

Recombinant T Cell Receptor Ligand Treats Experimental Stroke

“…Unlike four-domain MHC II molecules that can induce T cell activation and apoptosis (12), RTL are partial agonists that deviate autoreactive T cells to become non-pathogenic (13,14). We previously demonstrated that RTL could prevent and/or reverse clinical signs of experimental autoimmune encephalomyelitis (EAE) (15-17), collagen-induced arthritis (18) and experimental autoimmune uveitis (19). Recent studies with RTL551 (I-A b molecule covalently tethered to mouse myelin oligodendrocyte glycoprotein - mMOG-35−55 peptide), showed dramatic reversal of MOG-35−55-induced EAE, reduction of pathogenic CNS cells, down-regulation of endothelial cell adhesion molecules (ICAM and VCAM) and broad reduction of CNS chemokines/receptors (20).…”