title: Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis.
abstract: OBJECTIVE
  The rationale for blocking interleukin-6 (IL-6) in rheumatoid arthritis (RA) lies chiefly in the proinflammatory effect of this cytokine. Few studies have evaluated the consequences of anti-IL-6 receptor (IL-6R) antibody treatment on Treg cells. This study was undertaken to elucidate the mechanism of action of anti-IL-6R antibody treatment by studying the effects on Treg cells in an experimental arthritis model and in patients with RA.
  
  
  METHODS
  Mice with collagen-induced arthritis (CIA) were treated with a mouse anti-IL-6R antibody (MR16-1), and changes in Treg, Th1, and Th17 cells were assessed at key time points during the course of the disease. Peripheral blood from 15 RA patients was collected on day 0 and after 3 months of tocilizumab treatment for flow cytometry analysis of Th17 and Treg cells.
  
  
  RESULTS
  In MR16-1-treated mice, Th17 cell frequencies were unchanged, whereas Treg cell frequencies were increased. The Treg cell phenotype showed marked changes, with an increase in the frequency of CD39+ Treg cells in the lymph nodes and spleen. Interestingly, similar CD39+ Treg cell expansion was observed in RA patients who were tocilizumab responders at 3 months, with no change in Th17 cell frequency. Moreover, fluorescence-activated cell-sorted CD39+ Treg cells from responder RA patients were functionally able to suppress the proliferation of conventional T cells.
  
  
  CONCLUSIONS
  In both CIA and RA, the frequency of functionally suppressive CD39+ Treg cells is increased as a result of anti-IL-6R treatment, whereas Th17 cells are unaffected. The modification of Treg cell frequency and phenotype may be one of the mechanisms involved in the therapeutic effect of IL-6 blockade in RA.
authors: INSERM U1125 and Sorbonne Paris Cité Université Paris 13, Bobigny, France.
authors: A
authors: A
authors: Thiolat
authors: L
authors: L
authors: Semerano
authors: Y M
authors: YM
authors: Pers
authors: J
authors: J
authors: Biton
authors: D
authors: D
authors: Lemeiter
authors: P
authors: P
authors: Portales
authors: J
authors: J
authors: Quentin
authors: C
authors: C
authors: Jorgensen
authors: P
authors: P
authors: Decker
authors: M-C
authors: MC
authors: Boissier
authors: P
authors: P
authors: Louis-Plence
authors: N
authors: N
authors: Bessis
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D010641:Phenotype; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D058504:Th17 Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D019947:Receptors, Interleukin-6; D001081:Apyrase; C067869:CD39 antigen; C502936:tocilizumab