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Anti-IL-6 receptor antibody (tocilizumab): a B cell targeting therapy
  1. A Snir1,
  2. A Kessel1,
  3. T Haj1,
  4. I Rosner2,
  5. M Rozenbaum2,
  6. G Slobodin2,
  7. E Toubi1
  1. 1Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel
  2. 2Rheumatology Unit, Bnai Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel


Background and objectives B cells function as regulatory cells by producing inhibitory cytokines such as transforming growth factor β (TGF-β) and interleukin 10 (IL-10). Human CD25high B cells were shown to secrete higher levels of IL-10 versus CD25low B cells, suggesting this subset of cells to be immune-regulatory. Tocilizumab, a monoclonal antibody that acts as an IL-6R antagonist thus inhibiting IL-6 activity, and its autocrine growth activity on B cells is currently used for treatment of rheumatoid arthritis (RA). Following this treatment, one might expect a reduction in B cell activity status, and on the other hand increase of their regulatory properties.

Methods Freshly purified B lymphocytes were isolated from 10 active RA patients, with inadequate response to methotrexate, at baseline and 3 months following add on tocilizumab. Clinical status was assessed by DAS 28 score and erythrocyte sedimentation rate (ESR). Using flow cytometry, B cells were stained for the expression of intracellular TGF-β, IL-10, membrane CD69, and MHC-II. These markers were assessed in primary (no-stimulated) CD25high B cells and expressed in MFI, with results given in mean ± SEM.

Results Three months following initiation of tocilizumab, the expression of intracellular TGF-β in CD25high B cells was significantly increased (from 5.2 ± 2.3 at baseline to 8.1 ± 2.8; p < 0.02); the expression of MHC-II on B cells was significantly reduced (from 9.1 ± 2.2 at baseline to 4.2 ± 0.4; p < 0.04). In addition, the expression of CD69 also decreased (from 7.6 ± 2.4 at baseline to 2.7 ± 0.7; p < 0.03). The expression of intracellular IL-10 was too low for comparison. These phenotypic B cell changes namely, the alteration in B cell activity and antigen presenting cell (APC) properties and the shift and/or expansion of the B cell subset with regulatory properties were found to occur in association with beneficial clinical outcome, 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.

Conclusions Our unique finding of a shift in B cell properties following tocilizumab treatment, namely the increase in TGF-β expression and the alteration in their activation status and APC properties in CD25high 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.

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