title: Preventing and curing citrulline-induced autoimmune arthritis in a humanized mouse model using a Th2-polarizing iNKT cell agonist.
abstract: Invariant natural killer T (iNKT) cells are innate lymphocytes with unique reactivity to glycolipid antigens bound to non-polymorphic CD1d molecules. They are capable of rapidly releasing pro- and/or anti-inflammatory cytokines and constitute attractive targets for immunotherapy of a wide range of diseases including autoimmune disorders. In this study, we have explored the beneficial effects of OCH, a Th2-polarizing glycolipid agonist of iNKT cells, in a humanized mouse model of rheumatoid arthritis (RA) in which citrullinated human proteins are targeted by autoaggressive immune responses in mice expressing an RA susceptibility human leukocyte antigen (HLA) DR4 molecule. We found for the first time that treatment with OCH both prevents and cures citrulline-induced autoimmune arthritis as evidenced by resolved ankle swelling and reversed histopathological changes associated with arthritis. Also importantly, OCH treatment blocked the arthritogenic capacity of citrullinated antigen-experienced splenocytes without compromising their global responsiveness or altering the proportion of splenic naturally occurring CD4(+)CD25(+)FoxP3(+) regulatory T cells. Interestingly, administering the Th1-promoting iNKT cell glycolipid ligand α-C-galactosylceramide into HLA-DR4 transgenic mice increased the incidence of arthritis in these animals and exacerbated their clinical symptoms, strongly suggesting a role for Th1 responses in the pathogenesis of citrulline-induced arthritis. Therefore, our findings indicate a role for Th1-mediated immunopathology in citrulline-induced arthritis and provide the first evidence that iNKT cell manipulation by Th2-skewing glycolipids may be of therapeutic value in this clinically relevant model, a finding that is potentially translatable to human RA.
authors.affiliation: Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walker
authors.forename: Mateusz
authors.initials: M
authors.lastname: Rytelewski
authors.forename: Delfina M
authors.initials: DM
authors.lastname: Mazzuca
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Meilleur
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mannik
authors.forename: David
authors.initials: D
authors.lastname: Yue
authors.forename: William C
authors.initials: WC
authors.lastname: Brintnell
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.forename: Ewa
authors.initials: E
authors.lastname: Cairns
authors.forename: S M Mansour
authors.initials: SM
authors.lastname: Haeryfar
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D002956:Citrulline; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000494:pharmacology*; D006017:Glycolipids / Q000494:pharmacology / Q000627:therapeutic use*; D015804:HLA-DR4 Antigen / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: C550181:C-galactosylceramide; D005699:Galactosylceramides; D006017:Glycolipids; D015804:HLA-DR4 Antigen; C501055:tetracosanoic acid 1-galactopyranosyloxy-3,4-dihydroxydec-2-yl amide; D002956:Citrulline