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THU0393 IL-17 Producing Pathogenic T Lymphocytes Co-Express CD20 and are Depleted by Rituximab in Primary sjögren's Syndrome: A Novel Target for an Old Weapon
  1. A. Alunno1,
  2. F. Carubbi2,
  3. O. Bistoni1,
  4. S. Caterbi1,
  5. E. Bartoloni1,
  6. P. Di Benedetto2,
  7. P. Cipriani2,
  8. R. Giacomelli2,
  9. R. Gerli1
  1. 1Department of Medicine, Rheumatology Unit, University of Perugia, Perugia
  2. 2Department of Biotechnological and Applied Clinical Sciences, Rheumatology Unit, University of L'Aquila, L'Aquila, Italy

Abstract

Background Compelling evidence suggests that IL-17 and IL-17 producing T lymphocytes play a pivotal role in the pathogenesis of primary Sjögren's syndrome (pSS). In particular, IL-17 producing CD3+CD4-CD8- (double negative, DN) T cells are expanded in the peripheral blood (PB), infiltrate minor salivary glands (MSGs), and are associated with ectopic lymphoneogenesis (1, 2). It has been demonstrated that, besides its B-cell tropism, the anti-CD20 antibody rituximab (RTX) is also able to interfere with IL-17 axis in the PB and synovial tissue of patients with rheumatoid arthritis by depleting the CD20+ cell fraction of IL-17-producing T lymphocytes. Similarly, RTX is able to reduce glandular IL-17 in pSS (3) but, to date, no data are available about its possible role on IL-17-producing T-cell subsets in this disease.

Objectives Aim of the study was to investigate phenotypic and functional effects of RTX on circulating and glandular IL-17 producing T cells in pSS.

Methods MSGs and PB samples were obtained from patients with early and active pSS at different time-points during the treatment with either RTX (n. 22) or disease modifying anti-rheumatic drugs (DMARDs) (n. 16). These patients were part of a previously published trial (4). Flow cytometry was employed for phenotypic analysis of PB and MSG T cells. Hematoxilin-eosin and double immunofluorescence staining were employed on MSG tissue specimens to assess cellular infiltrate, T/B-cell compartmentalization, and lymphoid organization.

Results RTX was able to deplete IL-17-producing DN T, but not CD4+Th17 cells, in the PB at month 3 (T3). At month 6 (T6), both cell subsets were significantly increased in the PB compared to baseline. After 2 courses of RTX (month 12, T12), glandular DN T cells and CD4+ Th17 cells were markedly depleted. No modifications in IL-17+DN T and CD4+Th17 cells were observed in PB and MSGs of patients treated with DMARDs at T3, T6 and T12. A subset of IL-17-producing DN T cells and CD4+Th17 cells isolated from PB and MSGs co-expresses CD20 on the cell surface explaining the T-cell depleting activity of RTX. The exposure to RTX did not rescue the already characterized in vitro corticosteroid (CS)-resistance of circulating pSS IL-17+DN T cells (1). Similarly to PB, also glandular DN T cells did not reduce IL-17 production in presence of CS in vitro. Of interest, unlike circulating CD4+Th17 cells (1), those isolated from pSS-MSGs were resistant to CS in vitro.

Conclusions In this study, we provided evidence that RTX is able to affect IL-17-producing T cells also in pSS by depleting the CD20+ cell fraction. Taken the well-established pathogenic role of IL-17 axis in pSS, our results further support the therapeutic role of RTX that, despite its B-cell specificity, appears able to hamper also IL-17-producing pathogenic T cells in this disease.

References

  1. Alunno A et al. Ann Rheum Dis 2013;72:286-92

  2. Alunno A et al. J Autoimmun 2014;51:38-43

  3. Ciccia F et al. Rheumatology (Oxford) 2014;53:1313-20

  4. Carubbi F et al. Arthritis Res Ther 2013;15:R172

Disclosure of Interest None declared

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