Expression of the chemokine decoy receptor D6 mediates dendritic cell function and promotes corneal allograft rejection.

PURPOSE: To identify the role of chemokine receptor 6 (D6) expression by dendritic cells (DCs) and its role in corneal transplant immunity. METHODS: Flow cytometry analysis was used to assess the expression level of the D6 chemokine receptor in different leukocyte populations and DC maturation following lipopolysaccharides (LPS) stimulation of bone marrow-derived DCs isolated from wild-type (WT) or D6(-/-) mice (C57BL/6 background). Mixed-lymphocyte reactions and delayed-type hypersensitivity assays were performed with bone marrow-derived DCs from WT or D6(-/-) mice to evaluate T-cell alloreactivity. Adoptive transfer experiments with T cells from WT or D6(-/-) hosts with BALB/c corneal allografts were performed. Graft opacity was assessed over an 8-week period, and graft survival was plotted using Kaplan-Meier survival curves. RESULTS: Expression of the D6 chemokine receptor was significantly higher in DCs compared to other leukocyte subpopulations, including neutrophils, lymphocytes, and monocytes/macrophages. LPS challenge of D6(-/-) bone marrow-derived DCs elicited significantly lower levels of major histocompatibility complex II and costimulatory molecules (CD40, CD80, and CD86) compared to WT bone marrow-derived DCs, indicating the role of the D6 chemokine receptor in DC maturation. Further, DCs isolated from D6(-/-) mice induced less T-cell proliferation (p≤0.001) and interferon-gamma production in T cells of draining lymph nodes compared to WT mice following corneal transplantation (p≤0.001). Moreover, adoptively transferred T cells from D6(-/-) corneal transplanted mice to WT mice led to impaired graft rejection, compared to the hosts that received T cells from the WT transplanted mice. CONCLUSIONS: We demonstrated D6 chemokine receptor expression by DCs and identified its critical function in multiple aspects of DC biology, including maturation and consequent elicitation of alloreactive T-cell responses that are responsible for corneal allograft rejection.

Remifentanil decreases sevoflurane requirements to block autonomic hyperreflexia during transurethral litholapaxy in patients with high complete spinal cord injury.

BACKGROUND: An inhaled anesthetic concentration required to block autonomic hyperreflexia (AHR) is high enough to cause severe hypotension in patients with high spinal cord injury (SCI). We determined the effects of remifentanil on the sevoflurane requirement to block AHR in SCI. METHODS: The study involved 96 patients with chronic, complete SCI scheduled to undergo transurethral litholapaxy during general anesthesia. Anesthesia was induced with thiopental, and sevoflurane concentrations in 50% nitrous oxide were adjusted to maintain a bispectral index of 40 to 50. Whether the patient develops an AHR [an increase of systolic blood pressure (SBP) >20 to 40 mm Hg] was first examined by distending the bladder with glycine solution (the first trial). Patients who developed AHR were then allocated to receive no remifentanil infusion (control, n = 31), a target-controlled plasma concentration of 1 ng/mL (n = 25), or 3 ng/mL remifentanil (n = 24). After baseline hemodynamics had recovered, the target sevoflurane and remifentanil concentrations were maintained for at least 20 minutes and the procedure was resumed (the second trial). Each target sevoflurane concentration was determined by the up-and-down method based on changes (15% increase or more) of SBP in response to the bladder distension. SBP, heart rate, and bispectral index were measured before and during the bladder distension during the trials, and plasma concentrations of catecholamines during the first trial. RESULTS: Eighty-two (85.4%) of 96 patients developed AHR during the first trial, in which 2 were excluded because of hypotension (mean arterial blood pressure <50 mm Hg) developed during target-controlled drug administration. During the second trial, the end-tidal concentrations of sevoflurane to prevent AHR were reduced to 2.6% (95% confidence interval 2.5% to 2.8%, P < 0.01) and 2.2% (2.1% to 2.4%, P < 0.0001) in the groups receiving 1 and 3 ng/mL remifentanil, respectively, in comparison with 3.1% (2.9% to 3.3%) in the control. When considering minimum anesthetic concentration (MAC) values and the contribution of 50% nitrous oxide (0.48 MAC), the combined MAC values, expressed as multiples of MAC, were 2.27, 1.98, and 1.75 in the control, 1 ng/mL remifentanil, and 3 ng/mL remifentanil groups, respectively. CONCLUSIONS: Target-controlled concentrations of 1 and 3 ng/mL remifentanil would reduce the requirement of sevoflurane combined with 50% nitrous oxide to block AHR by 16% and 29%, respectively, in SCI patients undergoing transurethral litholapaxy.

Urinary trypsin inhibitors afford cardioprotective effects through activation of PI3K-Akt and ERK signal transduction and inhibition of p38 MAPK and JNK.

BACKGROUND: We determined the effect of urinary trypsin inhibitors (UTI) in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases such as phosphatidylinositol-3-OH kinases (PI3K)-Akt and extracellular signal-regulated kinases (ERK 1/2) and apoptotic kinases such as p38 and JNK. METHODS: The rats were anesthetized and subjected to an I/R insult consisting of 30-min left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size was measured after 120 min of reperfusion. UTI was given alone or along with wortmannin (inhibitor of PI3K) or PD098059 (inhibitor of ERK1/2) before LAD occlusion. The phosphorylation of Akt, ERK1/2, p38 and JNK was determined by immunoblotting after 5 min of reperfusion. UTI was administered 10 min before LAD occlusion, and wortmannin and PD098059 were administered 20 min before LAD occlusion. RESULTS: UTI significantly reduced the infarct size compared with the control. Wortmannin or PD098059 alone did not affect the infarct size, but they abolished the UTI-induced cardioprotective effect. UTI significantly reduced the phosphorylation of p38 and JNK, while it enhanced that of Akt and ERK1/2. CONCLUSIONS: UTI has a protective effect against regional myocardial I/R injury through activation of survival kinases PI3K-Akt and ERK1/2 and attenuation of p38 and JNK.

Levels of Foxp3 in regulatory T cells reflect their functional status in transplantation.

Foxp3 expressing CD4(+)CD25(+) regulatory T cells (Tregs) have been shown to prevent allograft rejection in clinical and animal models of transplantation. However, the role of Foxp3 in regulating Treg function, and the kinetics and mechanism of action of Tregs in inducing allograft tolerance in transplantation, are still not fully understood. Thus, we investigated the kinetics and function of Tregs in a mouse model of orthotopic corneal transplantation, the most common form of tissue grafting worldwide. In this study, using in vitro functional assays and in vivo Treg adoptive transfer assays, we show that far more relevant than Treg frequency is their level of Foxp3 expression, which is directly associated with the potential of Tregs to prevent allograft rejection by producing regulatory cytokines and suppressing effector T cell activation. In addition, our data clearly demonstrate that Tregs primarily suppress the induction of alloimmunity in regional draining lymph nodes rather than suppressing the effector phase of the immune response in the periphery. These findings provide new insights on Treg dynamics in transplantation, which are crucial for designing therapeutic strategies to modulate Treg function and to optimize Treg-based cell therapies for clinical translation.

Purified high-dose anthocyanoside oligomer administration improves nocturnal vision and clinical symptoms in myopia subjects.

The aim of the present study was to determine the effect of purified high-dose anthocyanoside oligomer administration on nocturnal visual function and clinical symptoms in low-to-moderate myopia subjects. The study was a randomized, double-blind, placebo-controlled trial and involved sixty subjects with asthenopia and refractive errors between -1.00 and -8.00 diopters in both eyes. Thirty subjects were administered a purified high-dose anthocyanoside oligomer (100 mg tablet comprising 85 % anthocyanoside oligomer), and thirty were given a placebo in tablet form twice daily for 4 weeks. Prior to the treatment, the placebo and anthocyanoside groups were similar in terms of age and contrast sensitivity. Before and after treatment, subjects completed a questionnaire to determine their clinical symptoms and were also assessed for nocturnal visual function using contrast sensitivity testing. Questionnaire data analysis showed that, following treatment, twenty-two (73.3 %) anthocyanoside subjects showed improved symptoms, whereas only one placebo subject showed an improvement (Fisher's exact test, P<0.0001). Contrast sensitivity levels according to each cycle per degree significantly improved in the anthocyanoside group and remained stable in the placebo group. The mean contrast sensitivity change in the anthocyanoside group was 2.41 (SD) 1.91, compared with -0.66 (SD) 2.66 dB for the placebo group (unpaired Student's t test, P<0.0001). At all cycle per degree levels, contrast sensitivity changes in the anthocyanoside group were better than in the placebo group (unpaired Student's t test, P<0.05). The present data show that the administration of anthocyanoside oligomer appears to improve subjective symptoms and objective contrast sensitivity in myopia subjects with asthenopia.