title: Inducible costimulator (ICOS) blockade inhibits accumulation of polyfunctional T helper 1/T helper 17 cells and mitigates autoimmune arthritis.
abstract: OBJECTIVE
  Inducible costimulator (ICOS) and its ligand (ICOSL) regulate T and B cell responses. Glucose-6-phosphate isomerase (G6PI)-induced arthritis requires T and B lymphocytes. It was hypothesised that blocking ICOS/ICOSL interactions ameliorates G6PI-induced arthritis and reduces G6PI-specific B and T lymphocyte responses.
  
  
  METHODS
  DBA/1 mice were injected with a blocking, non-depleting anti-ICOSL monoclonal antibodies (mAbs) during the induction or effector phase of G6PI-induced arthritis. G6PI-specific antibody responses were measured by ELISA. G6PI-specific T helper (Th) cell responses were assayed by polychromatic flow cytometry.
  
  
  RESULTS
  Transient blockade of ICOS/ICOSL interactions profoundly reduced the severity of G6PI-induced arthritis. ELISA and proliferation assays showed no clear ex vivo correlates of protection. Polychromatic flow cytometry revealed two major findings: the absolute number of G6PI-specific Th cells was markedly diminished in secondary lymphatic organs from mice with blocked ICOS/ICOSL interactions. Within the pool of G6PI-specific Th cells the frequency of interleukin 17 (IL17), interferon gamma or tumour necrosis factor alpha producers or polyfunctional Th cells (expressing two or more of these cytokines) was higher in treated than in control mice.
  
  
  CONCLUSIONS
  ICOS costimulation is not mandatory for the differentiation of Th1 or Th17 cells. Instead, the lack of ICOS costimulation results in reduced survival of G6PI-specific Th cells irrespective of their functional differentiation. This study demonstrates that a thorough examination of the quantity and the quality of antigen-specific immune responses is useful to determine ex vivo correlates of efficacy for immunomodulating treatments.
authors.affiliation: Institut für Immunologie, Universitätsklinikum Jena, Jena 07743, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Frey
authors.forename: Juliane
authors.initials: J
authors.lastname: Meisel
authors.forename: Andreas
authors.initials: A
authors.lastname: Hutloff
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bonhagen
authors.forename: Lisa
authors.initials: L
authors.lastname: Bruns
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kroczek
authors.forename: Lars
authors.initials: L
authors.lastname: Morawietz
authors.forename: Thomas
authors.initials: T
authors.lastname: Kamradt
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D019298:Glucose-6-Phosphate / Q000276:immunology; D007136:Immunoglobulins / Q000096:biosynthesis; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17 / Q000032:analysis; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008811:Mice, Inbred DBA; D011506:Proteins / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D007136:Immunoglobulins; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D008024:Ligands; D011506:Proteins; D019298:Glucose-6-Phosphate