title: Anti-IL-6 receptor antibody (tocilizumab): a B cell targeting therapy.
abstract: BACKGROUND
  IL-6 mediated inflammation is induced by binding to IL-6 receptor (IL-6R) or IL-6/IL-6R complex binding gp130. Tocilizumab, a recombinant humanised monoclonal antibody that acts as IL-6R antagonist has been recently introduced for the treatment of rheumatoid arthritis (RA).
  
  
  OBJECTIVE
  To evaluate whether tocilizumab therapy may induce B cells to undergo phenotypic changes compatible with regulatory function.
  
  
  METHODS
  B cells from treated RA patients were isolated before and after 3 months of treatment with tocilizumab and were stained for the expression of intracellular TGF-β, IL-10, membrane CD69, and MHCII. These markers were assessed in CD25(high) B cells considered to belong to a regulatory/suppressive subset of B cells. All markers were expressed in mean flow cytometry intensity (MFI), with results given in mean ± SEM. Data was compared before and after tocilizumab treatment.
  
  
  RESULTS
  Clinical improvement was noted three months following the initiation of tocilizumab, namely: DAS improvement from 6.8 ± 0.3 at baseline to 3.1 ± 0.4, p<0.002, and ESR decrease from 44.4 ± 8.6 at baseline to 7.4 ± 2.3, p<0.006. This clinical benefit was found to occur in association with the expansion of a B cell subset with regulatory properties namely: the expression of intracellular TGF-β in CD25-high B cells was significantly increased (from 5.2 ± 2.3 at baseline to 8.1 ± 2.8; p<0.02); In addition, the expression of MHC-II and of CD69 on B cells were significantly reduced (from 9.1 ± 2.2 at baseline to 4.2 ± 0.4; p<0.04), and (from 7.6 ± 2.4 at baseline to 2.7 ± 0.7; p<0.03) respectively.
  
  
  CONCLUSIONS
  The present finding of a shift in B cell properties following tocilizumab treatment, namely the increase in TGF-β expression and the alteration in the activation status (CD69 expression) and APC properties (MHC-II expression) in CD25(high) B cells, suggests that the induction/expansion of B regulatory cells may be one of the mechanisms by which tocilizumab may possibly produce its beneficial clinical effects.
authors.affiliation: Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Snir
authors.forename: A
authors.initials: A
authors.lastname: Kessel
authors.forename: T
authors.initials: T
authors.lastname: Haj
authors.forename: I
authors.initials: I
authors.lastname: Rosner
authors.forename: G
authors.initials: G
authors.lastname: Slobodin
authors.forename: E
authors.initials: E
authors.lastname: Toubi
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007557:Israel; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome; D000099192:CD69 Antigens
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018501:Antirheumatic Agents; D015415:Biomarkers; D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D019947:Receptors, Interleukin-6; D016212:Transforming Growth Factor beta; D000099192:CD69 Antigens; C508609:IL10 protein, human; C508017:IL2RA protein, human; C502936:tocilizumab