There is an expansion of FOXP3+CD4+ T cells in mucosal lymphoid tissues in UC. CD4+CD25+ isolated from UC MLN express FOXP3 and display features of TR cells in spite of active mucosal inflammation. These data suggest that their suppressor activity may be abrogated in vivo or they are unable to counterbalance the chronic mucosal inflammation in UC.

The TNF-like cytokine TL1A augments IFN-γ production by anti-CD3 plus anti-CD28 and IL-12/IL-18-stimulated peripheral blood (PB) T cells. However, only a small subset of PB T cells respond to TL1A stimulation with IFN-γ production. PB CCR9+ T cells represent a small subset of circulating T cells with mucosal T cell characteristics and a Th1/Tr1 cytokine profile. In the current study, we show that TL1A enhanced IFN-γ production by TCR- or CD2/CD28-stimulated CCR9+CD4+ PB T cells. However, TL1A had the most pronounced effect on augmenting IFN-γ production by IL-12/IL-18-primed CCR9+CD4+ PB T cells. TL1A enhanced both the percentage and the mean fluorescence intensity of IFN-γ in CCR9+CD4+ T cells as assessed by intracellular cytokine staining. IL-12 plus IL-18 up-regulated DR3 expression in CCR9+CD4+ T cells but had negligible effect on CCR9−CD4+ T cells. CCR9+CD4+ T cells isolated from the small intestine showed a 37- to 105-fold enhancement of IFN-γ production when TL1A was added to the IL-12/IL18 cytokine combination. Cell membrane-expressed TL1A was preferentially expressed in CCR9+CD4+ PB T cells, and a blocking anti-TL1A mAb inhibited IFN-γ production by cytokine-primed CCR9+CD4+ T cells by ∼50%. Our data show that the TL1A/DR3 pathway plays a dominant role in the ultimate level of cytokine-induced IFN-γ production by CCR9+ mucosal and gut-homing PB T cells and could play an important role in Th1-mediated intestinal diseases, such as Crohn’s disease, where increased expression of IL-12, IL-18, TL1A, and DR3 converge in the inflamed intestinal mucosa.

CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn’s disease (CD) and an increased frequency of CCR9+ T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9+ T cells in mucosal lymphoid tissues in CD. We show that CCR9+ T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9+ T cells isolated from CD SB lamina propria produced more IFN-γ and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-γ, but not IL-17, by CD lamina propria CCR9+ T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVβ analysis of CCR9+ T cells revealed a diverse TCRVβ repertoire among MLN CCR9+ T cells in patients with SB CD. Our data indicate that CCR9+ T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.

Cyclooxygenase-2 (COX-2) is a prostanoid-synthesizing enzyme that is critically implicated in a variety of pathophysiological processes. Using a COX-2-deficient mouse model, we present data that suggest that COX-2 has an active role in liver ischemia/reperfusion (I/R) injury. We demonstrate that COX-2-deficient mice had a significant reduction in liver damage after I/R insult. The inability of COX-2−/− to elaborate COX-2 products favored a Th2-type response in these mice. COX-2−/− livers after I/R injury showed significantly decreased levels of IL-2, as well as IL-12, a cytokine known to have a central role in Th1 effector cell differentiation. Moreover, such livers expressed enhanced levels of the anti-inflammatory cytokine IL-10, shifting the balance in favor of a Th2 response in COX-2-deficient mice. The lack of COX-2 expression resulted in decreased levels of CXCL2, a neutrophil-activating chemokine, reduced infiltration of MMP-9-positive neutrophils, and impaired late macrophage activation in livers after I/R injury. Additionally, Bcl-2 and Bcl-xL were normally expressed in COX-2−/− livers after injury, whereas respective wild-type controls were almost depleted of these two inhibitors of cell death. In contrast, caspase-3 activation and TUNEL-positive cells were depressed in COX-2−/− livers. Therefore, our data support the concept that COX-2 is involved in the pathogenic events occurring in liver I/R injury. The data also suggest that potential valuable therapeutic approaches in liver I/R injury may result from further studies aimed at identifying specific COX-2-derived prostanoid pathways.

Baclofen's safety and efficacy in improving the clinical condition patients with alcoholic liver disease has been supported. Randomized prospective studies with longer duration of baclofen in this population may further optimize its use and corroborate efficacy.

Context Hyperglycemia in the hospital setting is associated with increased morbidity and mortality. In an attempt to cut costs, some hospitals implement policies to substitute all glargine orders with detemir. Objective To examine how the substitution of glargine with detemir affects inpatient blood glucose control. Methods Medical records were retrospectively analyzed to investigate the effect of a hospital formulary change at a semi-urban underserved hospital that substituted detemir for glargine on a 1:1 dosing basis. The study evaluated blood glucose control from September 6, 2015, to September 5, 2016, before substitution and from September 6, 2016, to September 5, 2017, after the substitution began. Patients were included in the study if they were older than 18 years, received glargine before admission, and had type 1 or 2 diabetes mellitus. Patients were excluded if they were pregnant, did not receive long-acting insulin, or lacked regular blood glucose testing. The medical records were analyzed for mean glucose levels, hypoglycemic events, and short-acting insulin administration amounts. Results A total of 318 patients met criteria and were included in the retrospective analysis—134 patients received detemir and 184 patients received glargine. The mean glucose levels in the morning were 133.8 mg/dL for patients receiving detemir and 145.8 mg/dL for patients receiving glargine (95% CI, 126.972-140.753; P=.013). The mean blood glucose levels in the afternoon were 171.6 mg/dL for patients receiving detemir and 172.1 mg/dL for patients receiving glargine (95% CI, 162.955-180.344; P=.938). The mean blood glucose levels in the evening were 162.5 mg/dL for patients receiving detemir and 163.3 mg/dL for patients receiving glargine (95% CI, 153.654-171.315; P=.897). The mean blood glucose levels at night were 176.1 mg/dL for patients receiving detemir and 174.7 mg/dL for patients receiving glargine (95% CI, 167.797-184.474; P=.788). No significant difference in sliding scale insulin was required between the patient groups (0.16 U/kg insulin aspart in detemir group vs 0.18 U/kg aspart in glargine; 95% CI, 0.154-0.189; P=.297). There was no significant difference between the patient groups in regard to hypoglycemic events (45% glargine vs 49% detemir; P=.59). Conclusion Substituting detemir for glargine did not adversely affect inpatients’ blood glucose control.

openAccessArticle: FalsePage Range: v-vdoi: 10.1016/B978-1-4377-1725-9.10038-3Harvest Date: 2016-01-12 15:15:49issueName:cover date: 2012-01-01pubType

No abstract