title: Inhibition of cell adhesion and immune responses in the mouse model of collagen-induced arthritis with a peptidomimetic that blocks CD2-CD58 interface interactions.
abstract: CD2 and CD58 are two important costimulatory molecules involved in generating the signal II required for normal immune signaling. However, this interaction can be targeted to be of benefit in cases of abnormal immune signaling seen in autoimmune diseases. Our objective in this study was to design a peptidomimetic (compound 7) based on a β-strand structure of the adhesion domain of CD2 protein to inhibit CD2-CD58 protein-protein interaction and its effect on immunomodulation in the collagen-induced arthritis (CIA) model. The ability of compound 7 to bind to CD58 protein was assessed using flow cytometry. The effect of compound 7 on modulating the immune response was evaluated in an autoimmune disease using CIA in mice. The stability of compound 7 was evaluated in mouse serum using mass spectrometry. Antibody (Ab) binding inhibition studies suggested that compound 7 binds to CD58 protein. Compound 7 was successful in modulating immune responses when administered in the CIA mouse model along with reducing anti-collagen Ab levels and decreasing the level of interferon gamma (IFN-γ) relative to control treatments. Compound 7 was found to be nonimmunogenic and stable in mouse serum up to 48 h. Results suggest that compound 7 can serve as a lead compound for immunomodulation, and could be a therapeutic agent for the autoimmune disease rheumatoid arthritis (RA).
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201.
authors.forename: Ameya S
authors.initials: AS
authors.lastname: Gokhale
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201.
authors.forename: Rushikesh
authors.initials: R
authors.lastname: Sable
authors.affiliation: Pathobiological Sciences, BioMMED, School of Veterinary Medicine, Louisiana State University Baton Rouge, 70803-8434.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Walker
authors.affiliation: Pathobiological Sciences, BioMMED, School of Veterinary Medicine, Louisiana State University Baton Rouge, 70803-8434.
authors.forename: Leslie
authors.initials: L
authors.lastname: McLaughlin
authors.affiliation: Pathobiological Sciences, BioMMED, School of Veterinary Medicine, Louisiana State University Baton Rouge, 70803-8434.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Kousoulas
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201.
authors.forename: Seetharama D
authors.initials: SD
authors.lastname: Jois
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001667:Binding, Competitive; D018801:CD2 Antigens / Q000276:immunology*; D018968:CD58 Antigens / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects*; D003094:Collagen / Q000187:drug effects* / Q000276:immunology; D005260:Female; D051379:Mice; D008811:Mice, Inbred DBA; D057786:Peptidomimetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018801:CD2 Antigens; D018968:CD58 Antigens; D057786:Peptidomimetics; D003094:Collagen
keywords: costimulatory molecules; immunomodulation; peptidomimetic; protein−protein interaction; rheumatoid arthritis