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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