The expansion of CD4+CD28- T cells in patients with chronic kidney graft rejection.
ABSTRACT CD4+CD28- T cells are oligoclonal lymphocytes rarely found in healthy subjects, but are present in high frequencies in patients with inflammatory diseases. Contrary to paradigm, they are functionally active and produce interferon gamma and cytolytic proteins, are cytotoxic in vessels and may contribute to tissue damage. The size of the peripheral blood CD4+CD28- T cell compartments was determined in 20 healthy individuals, 20 patients after renal transplantation with stable graft function, and 20 with chronic graft rejection by two-color FACS analysis. In patients with stable graft function, the median frequency of CD4+CD28- T cells was 3.1% and was significantly higher in comparison to the control group (1.4%) (P <.01). The highest subset CD4+CD28- cells was detected in patients with chronic graft rejection (10.65%). The amount of CD4+CD28- cells was significantly higher in this group in comparison to patients with stable graft function (P <.01). The evaluated number of CD4+CD28- cells in patients after renal transplantation, especially in graft recipients with chronic graft rejection, suggests a role of these cells in chronic graft destruction.
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ABSTRACT: Unstable angina (UA) is associated with systemic inflammation and with expansion of interferon-gamma-producing T lymphocytes. The cause of T-cell activation and the precise role of activated T cells in plaque instability are not understood. Peripheral blood T cells from 34 patients with stable angina and 34 patients with UA were compared for the distribution of functional T-cell subsets by flow cytometric analysis. Clonality within the T-cell compartment was identified by T-cell receptor spectrotyping and subsequent sequencing. Tissue-infiltrating T cells were examined in extracts from coronary arteries containing stable or unstable plaque. The subset of CD4(+)CD28(null) T cells was expanded in patients with UA and infrequent in patients with stable angina (median frequencies: 10.8% versus 1.5%, P<0.001). CD4(+)CD28(null) T cells included a large monoclonal population, with 59 clonotypes isolated from 20 UA patients. T-cell clonotypes from different UA patients used antigen receptors with similar sequences. T-cell receptor sequences derived from monoclonal T-cell populations were detected in the culprit but not in the nonculprit lesion of a patient with fatal myocardial infarction. UA is associated with the emergence of monoclonal T-cell populations, analogous to monoclonal gammopathy of unknown significance. Shared T-cell receptor sequences in clonotypes of different patients implicate chronic stimulation by a common antigen, for example, persistent infection. The unstable plaque but not the stable plaque is invaded by clonally expanded T cells, suggesting a direct involvement of these lymphocytes in plaque disruption.Circulation 06/2000; 101(25):2883-8. · 15.20 Impact Factor
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ABSTRACT: Recombinant erythropoietin (Epo) therapy is well established as an effective treatment for the anaemia of end-stage renal disease. However, 5-10% of such patients do not respond adequately and an important contributory factor to this is chronic inflammation. The present study compares the circulating T-cell phenotypes of haemodialysis patients who respond poorly to Epo with those who respond well, along with normal controls. Isolated peripheral blood mononuclear cells were labelled with immunofluorescent monoclonal antibodies to surface antigens and analysed by flow cytometry. In vitro mononuclear cell cytokine secretion was also studied in the three subject groups. The cells were cultured for 48 h either without stimulus, with lipopolysaccharide or with monoclonal antibodies to CD3 and CD28. C-reactive protein levels were increased in poor responders to Epo (18.6 +/- 20.7 mg/l) compared with good responders (8.7 +/- 8.0 mg/l) and normal controls (3.8 +/- 1.1 mg/l). Patients responding poorly to Epo had increased circulating levels of CD4+/CD28- and CD8+/CD28- T-cells compared with patients responding well to Epo and normal controls. Unstimulated mononuclear cells from poor responders showed increased in vitro generation of interleukin-10 (IL-10) compared with both patients responding well to Epo and normal controls. Additionally, IL-10 generation stimulated by monoclonal antibodies to CD3 and CD28 was increased in poor responders compared with normal controls. These findings suggest that patients responding poorly to Epo may show enhanced immune activation as manifest by changes in both T-cell function and phenotype.Nephrology Dialysis Transplantation 02/2003; 18(1):133-40. · 3.37 Impact Factor
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ABSTRACT: CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood. Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4(+)CD28(null) T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161(+) and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4(+)CD28(null) T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4(+) T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I-recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4(+)CD28(null) T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion. In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability. Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell-mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes.Circulation 03/2002; 105(5):570-5. · 15.20 Impact Factor