Article Text

PDF
OP0273 Tocilizumab Enhances Regulatory T Cell Activation and Proliferation in Giant Cell Arteritis
  1. C. Miyabe,
  2. K. Strle,
  3. Y. Miyabe,
  4. J.H. Stone,
  5. A.D. Luster,
  6. S. Unizony
  1. Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, United States

Abstract

Background Both CD4+ T helper (Th)-type 17 lymphocytes and Th1-type lymphocytes appear to contribute to the pathogenesis of giant cell arteritis (GCA). In addition, regulatory T cell (Treg) responses appear to be suppressed in GCA. Interleukin (IL)-6, highly expressed in GCA patients, is a key mediator in the differentiation of both Th17 and Treg cells. Preliminary experience in GCA with the use of tocilizumab (TCZ), an IL-6 receptor antagonist, has been encouraging. However, it is unknown whether TCZ affects the differentiation and function of these CD4+ T-cell subsets in these patients.

Objectives We aimed to characterize the effector and regulatory CD4+ T-cell compartments in the peripheral blood of GCA patients treated with TCZ.

Methods We evaluated 38 GCA patients classified into one of three categories: 1) active disease (aGCA, n=9); 2) disease remission on corticosteroid (CS) monotherapy (rGCA-CS, n=18); and 3) disease remission on TCZ therapy (rGCA-TCZ, n=11). Nine healthy controls were also included. Using flow cytometry, we determined the percentages (%) of IFNg+IL-17- (Th1), IL-17+IFNg- (Th17), CD25high (Treg), and CD45RA-Foxp3high (activated Treg, aTreg) cells within the CD4+ lymphocyte population. In addition, we determined the % of Foxp3+ cells expressing Ki67 (proliferating Treg). We assessed Treg function in suppression assays. Serum concentrations of IL-12, IFNg, IL-6, IL-1β, IL-23, IL-21, TNF-α, CCL20, IL-17A, and IL-10 were measured by Luminex.

Results The frequencies (mean %) of Th1, Th17, and Treg cells were equivalent across groups. However, the frequency of aTregs was higher in rGCA-TCZ patients (1.3%) compared with rGCA-CS patients (0.6%; p=0.02). Moreover, the number of proliferating Tregs was significantly higher in rGCA-TCZ patients (31.7%) compared to rGCA-CS (16.4%; p=0.003) and aGCA (15.5%; p=0.007) patients. Tregs were functional in all groups. IL-10 levels were significantly increased in the serum of patients with aGCA. There were no significant differences in the serum levels of other cytokines or chemokines measured.

Conclusions The therapeutic effects of tocilizumab in GCA could be mediated by increasing the activation and proliferative potential of Tregs. Further studies are needed to expand these preliminary findings.

References

  1. Unizony S, Arias-Urdaneta L, Miloslavsky E, Arvikar S, Khosroshahi A, Keroack B, Stone JR, Stone JH. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken). 2012; 64(11): 1720-9.

  2. Osman M, Pagnoux C, Dryden DM, Storie D, Yacyshyn E. The Role of Biological Agents in the Management of Large Vessel Vasculitis (LVV): A Systematic Review and Meta-Analysis. PLoS One. 2014;9(12):e115026.

Disclosure of Interest None declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.