title: Peptides targeting inflamed synovial vasculature attenuate autoimmune arthritis.
abstract: Autoimmune diseases, such as rheumatoid arthritis, frequently target one major tissue/organ despite the systemic nature of the immune response. This is particularly perplexing in the case of ubiquitously distributed antigens invoked in arthritis induction. We reasoned that selective targeting of the synovial joints in autoimmune arthritis might be due in part to the unique attributes of the joint vasculature. We examined this proposition using the adjuvant-induced arthritis model of human rheumatoid arthritis, and profiled the synovial vasculature using ex vivo and in vivo screening of a defined phage peptide-display library. We identified phage that preferentially homed to the inflamed joints. The corresponding synthetic peptides showed binding to the joint-derived endothelial cells, as well as specificity in inhibiting binding of the respective phage to the synovial vasculature. Intriguingly, the treatment of arthritic rats with one such peptide resulted in efficient inhibition of the progression of arthritis. The suppression of arthritis was attributable in part to the peptide-induced reduction of T-cell trafficking into the joints and the inhibition of angiogenesis. This peptide differed in sequence, in receptor binding specificity, and in angiogenesis/inflammation-related cell signaling from the previously characterized arginine-glycine-aspartic acid-containing peptide. Thus, our study reveals joint-homing peptides that can be further exploited for the selective delivery of antiarthritic agents into the inflamed joints to enhance their efficacy while reducing systemic toxicity, and also for examining intricacies of the pathogenesis of arthritis. This approach can be customized for application to other organ-specific autoimmune diseases as well.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Yang
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rajaiah
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Moudgil
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013583:Synovial Membrane / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D014657:Vasculitis / Q000276:immunology* / Q000517:prevention & control
chemical_list: D019151:Peptide Library; D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3