Apoptotic Effects of Antilymphocyte Globulins on Human Pro-inflammatory CD4+CD28− T-cells

BACKGROUND: Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro. PRINCIPAL FINDINGS: Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells. CONCLUSION: In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism

Long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis.

CONTEXT: The annual risk of ischemic stroke in patients with asymptomatic carotid artery stenosis is about 2% during the short-term (2-3 years), but the long-term risks of stroke and other vascular events are unknown, although they may affect surgical decision making. OBJECTIVE: To evaluate the long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis. DESIGN: Cohort study with a median follow-up of 10 years (range, 5-18 years). SETTING: The teaching hospital of the University of Toronto, Toronto, Ontario. PATIENTS: From the initial cohort of 500 patients, 106 patients with asymptomatic carotid artery stenosis were selected because they had completed at least 5 years of follow-up. MAIN OUTCOME MEASURES: Ipsilateral stroke, myocardial infarction, and nonstroke vascular death. RESULTS: The 10- and 15-year actuarial risks of ipsilateral stroke were 5.7% (95% confidence interval [CI], 0%-12%) and 8.7% (95% CI, 1%-17%), respectively, in patients with 0% to 49% internal carotid artery stenosis, and 9.3% (95% CI, 1%-18%) and 16.6% (95% CI, 1%-32%) in patients with 50% to 99% internal carotid artery stenosis. The 10- and 15-year risks of myocardial infarction and nonstroke vascular death were 10.1% (95% CI, 4%-16%) and 24.0% (95% CI, 14%-34%). Age (P =.02), diabetes mellitus (P =.02), and internal carotid artery stenosis of 50% or more (P =.04) were predictive of increased risks of myocardial infarction and nonstroke vascular death. Internal carotid artery stenosis of 50% or more did predict the risk of ipsilateral stroke (P =.003) when all 181 asymptomatic carotid arteries were included. CONCLUSIONS: The annual stroke risk in patients with asymptomatic carotid artery stenosis was low and remained stable during long-term follow-up. Any benefit from carotid surgery is therefore unlikely to increase significantly with long-term follow-up. The high long-term risks of myocardial infarction and nonstroke vascular death suggest that prevention strategies should concentrate on coronary risk more than stroke risk

Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation

<div><p>Background</p><p>End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR).</p><p>Methods</p><p>222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31⁺ naive T cells were determined as T-cell ageing parameters.</p><p>Results</p><p>Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4⁺CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8⁺CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4⁺CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001).</p><p>Conclusion</p><p>Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR.</p></div