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THU0115 The effects of costimulation blockade performed by abatacept: Decreased production of G-IFN by CD8+ T cells and of IL-17 by CD4+ T cells after in vitro stimulation in good clinical responders
  1. M. Scarsi1,
  2. S. Piantoni1,
  3. M. Chiarini2,
  4. C. Zanotti2,
  5. L. Imberti2,
  6. A. Tincani1,
  7. P. Airò3
  1. 1Rheumatology Unit, Spedali Civili, University of Brescia
  2. 22. Biotechnologies Laboratory, Diagnostic Department
  3. 3Rheumatology Unit, Spedali Civili of Brescia, Brescia, Italy

Abstract

Background The most important costimulatory signal for T cells is delivered by CD28 molecule. After its engagement, different functional T cell properties are enhanced, such as upregulation of surface activatory molecules (including HLA-DR), cytokines production, and cytotoxic activity. Abatacept (ABA) is a chimeric molecule able to down-modulate T-cell costimulation through the competition with CD28 engagement. Previous studies demonstrated a reduction of pro-inflammatory cytokines synthesis and of macrophage functionality after ABA treatment, but little information is available on the effect on T-cell function.

Objectives The aim of the present study is to verify whether ABA might decrease T cell activation and functionality, such as γ-IFN and IL-17 production after T cell in vitro stimulation.

Methods 42 consecutive patients (4 males, 38 females; median age: 55) affected from Rheumatoid Arthritis were enrolled. ABA was given for at least 6 consecutive months. DAS28 (CRP) and EULAR Clinical Response Criteria were used to analyze the disease activity and clinical response to treatment. Phenotypical analysis of peripheral primed T lymphocyte was longitudinally evaluable in 24 patients, before treatment and after 6 and 12 months of therapy. In 14 patients, peripheral blood mononuclear cells (PBMCs) were also obtained from blood sample, and stimulated for 5 hours with PMA+Ionomycin (5+500 ng/ml). T cell γ-IFN and IL-17 production was evaluated by flow-cytometry intra-cytoplasmatic staining.

Results 22 patients (52%) achieved good clinical response after 6 months of therapy. Phenotypical analysis after ABA treatment demonstrated a significant reduction in the number of CD28-negative CD4+ (35 (10-151) vs 15 (1-113) cells/μl; p:0.043) and CD8+ T cells (112 (37-272) vs 39 (13-219) cells/μl; p:0.049), as well as of primed (HLA-DR+) CD4+ (19 (4-59) vs 10 (2-40) cells/μl; p:0.003) and CD8+ T cells (14 (3-43) vs 8 (1-56) cells/μl; p:0.037) and “terminally differentiated effector memory” (TDEM; CD45RA+CCR7-) CD8+ T cells (69 (22-145) vs 28 (14-207) cells/μl; p:0.041). These phenotypic variations were directly related to the variation of clinical disease activity after 6 months of ABA treatment. Among 14 individuals evaluated as far as cytokine production, 8 patients with good clinical response after 6 months of therapy showed a significant reduction of circulating CD4+ T cells producing IL-17 (19 (12-23) vs 9 (4-16) cells/μl; p:0.017) and of CD8+ T cells producing γ-IFN (70 (45-166) vs 55 (43-82) cells/μl; p:0.036) after in vitro stimulation. On the other hand, no significant variation was seen in non responding patients (n=6).

Conclusions Costimulation blockade by ABA may decrease the number of circulating primed and CD28-negative CD4+ and CD8+ T-cells, as well as of TDEM CD8+ T-cells. A reduction in μ-IFN production by CD8+ T cells and of IL-17 production by CD4+ T cells after in vitro stimulation was observed in patients with good clinical response.

Disclosure of Interest None Declared

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