Modulation of CD4 + CD28 null T Lymphocytes by Tumor Necrosis Factor-α Blockade in Patients With Unstable Angina

Abstract

Background— Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that favors the expansion of CD4 ⁺ CD28 ^null T cells, an aggressive and unusual proinflammatory lymphocyte subset frequently observed in patients with unstable angina (UA). The purpose of the present ex vivo study was to evaluate whether inflammation in patients with UA may be modulated by selective blockade of TNF-α. Methods and Results— Peripheral blood samples were collected from 17 patients with UA (Braunwald’s class IIIB). CD4 ⁺ CD28 ^null T cells were assessed by flow cytometry and expressed as a percentage of all CD4 ⁺ T cells after 24 hours of incubation of whole blood with and without increasing doses (0.1, 1, 10, and 100 μg/mL) of infliximab, an anti–TNF-α monoclonal antibody. In addition, CD28 expression was assessed and expressed as mean fluorescence intensity (geometric mean of the CD28 fluorescence value on all CD4 ⁺ T cells). CD4 ⁺ CD28 ^null T-cell percentage decreased from a median of 6.2% (range, 1.2% to 23.9%) to 4.9% (range, 1.1% to 21.9%), 4.5% (range, 1.1% to 21.6%), and 4.1% (range, 0.4% to 21.4%) after incubation with 1, 10, and 100 μg/mL of infliximab ( P for trend=0.043). Analysis of CD28 mean fluorescence intensity showed that the expression of CD28 on cell surface significantly increased after incubation with increasing doses of infliximab ( P for trend=0.03). Conclusions— The findings of this ex vivo study show that CD4 ⁺ CD28 ^null T-cell expansion in patients with UA may be reduced by selective TNF-α blockade. Further studies are warranted to evaluate the clinical benefit of CD4 ⁺ CD28 ^null T-cell modulation.