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.

Clonal expansions in selected TCR BV families of rheumatoid arthritis patients are reduced by treatment with the TNFα inhibitors etanercept and infliximab

“….Whether remaining, mainly BV14 family clonal expansions contribute to the flare up of disease after discontinuation of TNFα inhibiting therapies remains to be studied. Similarly, the failure of TNFα inhibiting therapies to significantly decrease CD4+CD28 null T cells in our study cohort could indicate persistence of autoreactivity in the T cell pool despite good clinical response, although conflicting results have also been reported [5,6,20].…”

Inflammatory biomarkers and coronary heart disease: from bench to bedside and back

“…In particular, Rizzello et al [28] show that blockade of TNF-alpha inhibitor may modulate inflammation: the percentage of CD4? CD28null cells is significantly reduced after incubation with infliximab, an anti TNF-alpha monoclonal antibody.…”

Cytotoxic human CD4+ T cells

“…Numbers of cytotoxic CD4 + T cells are increased in chronic inflammatory conditions such as auto-immune [58 ,59-61], vascular [62][63][64][65] and inflammatory bowel disease [61]. Therefore, these cells are thought to have, next to their presumed anti-microbial function, a pathogenic role in inflammatory diseases.…”

“…Therefore, these cells are thought to have, next to their presumed anti-microbial function, a pathogenic role in inflammatory diseases. Indeed, in autoimmune diseases such as rheumatoid arthritis and ankylosing spondylitis the amount of cytotoxic CD4 + T cells is related to disease severity, whereas interfering with the chronic inflammatory status, for instance by treatment with anti-TNFa therapy, reduces their numbers [63,66,67]. It should be stressed that there is no proof that the expanded cytotoxic CD4 + T cells are specific for auto-antigens such as myelin basic protein or collagen type II.…”