Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. SUMMARY: Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged ≥ 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non-major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19-2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.

TCR-mediated activation of allergen-specific CD45RO(+) memory T lymphocytes results in down-regulation of cell-surface CXCR4 expression and a strongly reduced capacity to migrate in response to stromal cell-derived factor-1.

The selective migration of functional T(h) lymphocyte subsets with different cytokine production profiles into inflamed tissue is likely to depend on the state of activation of the cells, as well as on the differential expression of various adhesion molecules and chemokine receptors. In this study, we have analyzed the effect of allergen-specific activation on the expression of the chemokine receptor CXCR4 on T lymphocytes. We show that stimulation of peripheral blood mononuclear cells from atopic patients with the allergen Der p results in down-regulation of CXCR4 surface expression on Der p-activated CD25(+)CD45RO(+) antigen-specific memory cells which was caused by a decrease in CXCR4 gene transcription and did not seem to be mediated by endogenous cytokines, such as IFN-gamma. In contrast, however, CXCR4 surface expression was enhanced on naive CD25(-)CD45RO(-) and resting CD25(-)CD45RO(+) memory T cells, as a result of the presence of endogenous IL-4, most likely produced by Der p-activated memory T cells. Antigen-specific CD25(+)CD45RO(+) T lymphocytes, purified 7 days after stimulation with Der p, had a strongly reduced capacity to migrate in response to stimulation with stromal cell-derived factor (SDF)-1, the ligand for CXCR4. Together, these results suggest that differential expression of CXCR4 on activated and resting T cells is due to the counteracting effects of TCR-mediated down-regulation and IL-4-mediated up-regulation of this chemokine receptor respectively, and furthermore indicate that antigen-activated memory T cells are unlikely to migrate into inflamed tissue in response to SDF-1.

Effect of bronchial allergen challenge on in vitro cytokine release by peripheral blood mononuclear cells of atopic patients.

BACKGROUND: During the pollen season, peripheral blood mononuclear cells (PBMC) from allergic patients produce increased levels of Th2 cytokines after stimulation with allergen in vitro. We have studied the effect of a single bronchial provocation test (BPT) of allergic patients to determine whether allergen challenge in vivo modulates cytokine production by PBMC, after subsequent stimulation with the same allergen in vitro. METHODS: Twelve atopic asthmatic patients were challenged with the relevant allergen, and their PBMC, isolated before (T0) or 6 (T6) or 24 h (T24) after BPT, respectively, were cultured for 120 h in the presence or absence of the same allergen, after which cytokine production was measured by ELISA. RESULTS: Allergen-specific activation of the PBMC at T0 resulted in interleukin (IL)-5 and IL-13 production, but not in detectable levels of interferon-gamma and IL-4. BPT did not induce the secretion of the latter cytokines. However, IL-5 and IL-13 production was significantly decreased at T24, as compared to T0. No statistically significant differences were found between the production of IL-10 before and after BPT. CONCLUSIONS: In contrast to the effects of natural challenge with allergen, a decrease in the production of some Th2 cytokines by peripheral blood T cells was observed 24 h after BPT, suggesting a concomitant decrease in the frequency of allergen-specific T cells in the circulation.

IL-4 induces functional cell-surface expression of CXCR4 on human T cells.

Here we report that IL-4 specifically enhances cell surface expression of CXCR4 on resting peripheral and cord blood T cells. Whereas polarized Th2 clones express variable levels of CXCR4, expression of this receptor is undetectable on polarized Th1 clones but can be induced on the latter cells as well, following short-term culture in the presence of IL-4. The IL-4-induced CXCR4 is functional since interaction with its ligand, stromal-derived factor (SDF)-1, activates the p42 MAP-kinase ERK-2. In addition, although CXCR4 expression is down-regulated following stimulation of T cells and T cell clones via CD28 or CD3 and CD2 cell surface molecules, respectively, it is re-induced by IL-4. These data indicate an important role for IL-4 in rendering CD4+ T cells susceptible to infection with HIV via CXCR4, as well as in promoting SDF-1-induced migration of these cells.

The role of IgE in asthma.

Asthma is a multifactorial and complex disease in which allergic factors and non-allergic triggers interact and result in bronchial obstruction and inflammation. Allergenic sensitization is important in the development of asthma and, although links between inhalant allergy and asthma have been known for many years, they have recently been re-emphasized. Indoor allergens are associated with asthma prevalence, severity and exacerbations whereas outdoor allergens such as pollens are associated with exacerbations. Moreover, there is a link between total IgE and asthma which appears to be independent of allergen sensitization. One of the typical aspects of airway inflammation of asthma is the infiltration of the airway wall by T helper type 2 (Th2) cells. These cells are attracted to inflammatory sites by adhesion molecules and chemokines among which CCR3 and CXCR4 receptors appear to be of importance. Differentiation of B cells into IgE-secreting plasma cells is a complex cascade of events in which cytokines play a crucial role. Both IL-4 and IL-13 are inducing IgE synthesis whereas IFN-gamma and IL-12 are blocking IgE synthesis. IgE production by B cells not only requires the presence of IL-4 or IL-13, but also a physical interaction between T and B cells, involving a number of surface and adhesion molecules such as CD40-CD40L and CD28/CD80. Production of TH2-cytokines is not restricted to T cells as basophils and mast cells can produce them indicating that these cells may be of importance in the synthesis of IgE.