title: A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis.
abstract: BACKGROUND
  The Rho family GTPase Rac1 regulates cytoskeletal rearrangements crucial for the recruitment, extravasation and activation of leukocytes at sites of inflammation. Rac1 signaling also promotes the activation and survival of lymphocytes and osteoclasts. Therefore, we assessed the ability of a cell-permeable Rac1 carboxy-terminal inhibitory peptide to modulate disease in mice with collagen-induced arthritis (CIA).
  
  
  METHODS
  CIA was induced in DBA/1 mice, and in either early or chronic disease, mice were treated three times per week by intraperitoneal injection with control peptide or Rac1 inhibitory peptide. Effects on disease progression were assessed by measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Serum levels of anti-collagen type II antibodies were measured by enzyme-linked immunosorbent assay. T-cell phenotypes and activation were assessed by fluorescence-activated cell sorting analysis. Results were analyzed using Mann-Whitney U and unpaired Student t tests.
  
  
  RESULTS
  Treatment of mice with Rac1 inhibitory peptide resulted in a decrease in paw swelling in early disease and to a lesser extent in more chronic arthritis. Of interest, while joint destruction was unaffected by Rac1 inhibitory peptide, anti-collagen type II antibody production was significantly diminished in treated mice, in both early and chronic arthritis. Ex vivo, Rac1 inhibitory peptide suppressed T-cell receptor/CD28-dependent production of tumor necrosis factor alpha, interferon gamma and interleukin-17 by T cells from collagen-primed mice, and reduced induction of ICOS and CD154, T-cell costimulatory proteins important for B-cell help.
  
  
  CONCLUSIONS
  The data suggest that targeting of Rac1 with the Rac1 carboxy-terminal inhibitory peptide may suppress T-cell activation and autoantibody production in autoimmune disease. Whether this could translate into clinically meaningful improvement remains to be shown.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands. j.r.abreu@amc.uva.nl
authors.forename: Joana Rf
authors.initials: JR
authors.lastname: Abreu
authors.forename: Wendy
authors.initials: W
authors.lastname: Dontje
authors.forename: Sarah
authors.initials: S
authors.lastname: Krausz
authors.forename: Daphne
authors.initials: D
authors.lastname: de Launay
authors.forename: Paula B
authors.initials: PB
authors.lastname: van Hennik
authors.forename: Anne-Marieke
authors.initials: AM
authors.lastname: van Stalborch
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Ten Klooster
authors.forename: Marjolein E
authors.initials: ME
authors.lastname: Sanders
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
authors.forename: Margriet J
authors.initials: MJ
authors.lastname: Vervoordeldonk
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis / Q000187:drug effects* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004487:Edema / Q000188:drug therapy; D004797:Enzyme-Linked Immunosorbent Assay; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009479:Neuropeptides / Q000037:antagonists & inhibitors*; D010455:Peptides; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D020830:rac1 GTP-Binding Protein
chemical_list: D018501:Antirheumatic Agents; D001323:Autoantibodies; D024043:Collagen Type II; D016207:Cytokines; D009479:Neuropeptides; D010455:Peptides; C484602:Rac1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein