title: The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis.
abstract: OBJECTIVE
  The histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models.
  
  
  METHODS
  H4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood.
  
  
  RESULTS
  Both H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro.
  
  
  CONCLUSIONS
  These results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.
authors.affiliation: Department of Immunology, Janssen Research & Development, , San Diego, California, USA.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Cowden
authors.forename: Fuqu
authors.initials: F
authors.lastname: Yu
authors.forename: Homayon
authors.initials: H
authors.lastname: Banie
authors.forename: Mandana
authors.initials: M
authors.lastname: Farahani
authors.forename: Ping
authors.initials: P
authors.lastname: Ling
authors.forename: Steven
authors.initials: S
authors.lastname: Nguyen
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Mai
authors.initials: M
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dunford
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020381:Interleukin-17 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology*; D011968:Receptors, Histamine / Q000172:deficiency / Q000276:immunology*; D000074040:Receptors, Histamine H4; D012720:Severity of Illness Index; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C498829:Hrh4 protein, mouse; D020381:Interleukin-17; D008070:Lipopolysaccharides; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
keywords: Cytokines; Inflammation; Rheumatoid Arthritis; T Cells