Management of Constipation in Hospitalized Patients.

Constipation is frequently encountered in hospital settings and can have potentially serious consequences yet is often underrecognized and undertreated. Opioid-induced constipation is a common cause of constipation in hospitalized patients. Opioids induce constipation through agonistic effects on enteric µ-opioid receptors. This review aims to provide insight on the identification and management of constipation in inpatient settings, with a particular focus on opioid-induced constipation. Constipation assessment should be routinely initiated at hospital admission and can be facilitated by thorough symptom assessments; relevant patient history, including recent medication use; physical examination; and patient assessment tools developed to evaluate the impact of constipation. Management of opioid-induced constipation should begin with ensuring adequate hydration and electrolyte balance and encouraging patient mobilization. Other treatments may include laxatives, enemas, intestinal secretagogues, peripherally acting µ-opioid receptor antagonists, and manual disimpaction. Surgical intervention may be required for some patients as a salvage therapy in severe, refractory cases.

The TNF family member TL1A induces IL-22 secretion in committed human Th17 cells via IL-9 induction.

TL1A contributes to the pathogenesis of several chronic inflammatory diseases, including those of the bowel by enhancing TH1, TH17, and TH2 responses. TL1A mediates a strong costimulation of these TH subsets, particularly of mucosal CCR9+ T cells. However, the signaling pathways that TL1A induces in different TH subsets are incompletely understood. We investigated the function of TL1A on human TH17 cells. TL1A, together with TGF-ß, IL-6, and IL-23, enhanced the secretion of IL-17 and IFN-γ from human CD4+ memory T cells. TL1A induced expression of the transcription factors BATF and T-bet that correlated with the secretion of IL-17 and IFN-γ. In contrast, TL1A alone induced high levels of IL-22 in memory CD4+ T cells and committed TH17 cells. However, TL1A did not enhance expression of IL-17A in TH17 cells. Expression of the transcription factor aryl hydrocarbon receptor, which regulates the expression of IL-22 was not affected by TL1A. Transcriptome analysis of TH17 cells revealed increased expression of IL-9 in response to TL1A. Blocking IL-9 receptor antibodies abrogated TL1A-induced IL-22 secretion. Furthermore, TL1A increased IL-9 production by peripheral TH17 cells isolated from patients with Crohn's disease. These data suggest that TL1A differentially induces expression of TH17 effector cytokines IL-17, -9, and -22 and provides a potential target for therapeutic intervention in TH17-driven chronic inflammatory diseases.

TLR8-mediated activation of human monocytes inhibits TL1A expression.

TLR play important roles in inflammation and innate immune response to pathogens. TLR8 recognizes ssRNA and induces NF-kappaB via MyD88 signaling. TL1A is a member of the TNF superfamily that markedly enhances IFN-gamma production by IL-12/IL-18-stimulated peripheral and mucosal CD4(+) T cells. TL1A expression is increased in the mucosa of patients with inflammatory bowel disease and is considered a key mediator of Crohn's disease (CD). We have previously shown that TL1A is strongly induced by immune complexes (IC) but not TLR ligands in antigen-presenting cells. However, a potential interaction between these pro-inflammatory signaling pathways has not been investigated. IC-induced TL1A expression of monocytes was potently inhibited by a TLR8 or TLR7/8 ligand (R848) in a dose-dependent manner. Furthermore, when co-cultured with CD4(+) T cells, TLR8 ligands inhibited TL1A production, resulting in almost complete inhibition of IFN-gamma production by the CD4(+) T cells. Furthermore, we demonstrate that IFN-alpha is not required for this suppressive effect by TLR8 signaling. Our data demonstrate for the first time a direct interaction between TLR and TL1A signaling pathways. TLR8 activation may be an important, novel pathway for targeted treatment of Th1-mediated diseases, such as CD.

IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein.

BACKGROUND: The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts. METHODOLOGY AND PRINCIPAL FINDINGS: Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P< or =0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcgammaR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype. CONCLUSIONS AND SIGNIFICANCE: These findings suggest that TL1A gene variation exacerbates induction of TL1A in response to FcgammaR stimulation in Jewish CD patients and this may lead to chronic intestinal inflammation via overwhelming T cell responses. Thus, TL1A may provide an important target for therapeutic intervention in this subgroup of IBD patients.

Visilizumab induces apoptosis of mucosal T lymphocytes in ulcerative colitis through activation of caspase 3 and 8 dependent pathways.

Visilizumab, a humanized low-Fc receptor binding anti-CD3 antibody, induces rapid clinical response in patients with steroid-refractory ulcerative colitis (UC). Several effective treatments in IBD have been linked to the induction of mucosal T cell apoptosis. The aim of the present study was to evaluate the effect of visilizumab on the apoptosis of lamina propria (LP) and peripheral blood (PB) lymphocytes isolated from patients with UC. Visilizumab induced dose- and time-dependent apoptosis of LP T cells isolated from non-IBD individuals, UC or CD patients. Maximal effect was seen at a concentration of 100 ng/ml and it was 33% for normal, 34% for UC and 23% for CD LP T cells following 24 h stimulation. Visilizumab induced apoptosis predominantly of CD4(+) LP T cells, whereas CD8(+) LP T cells were relatively resistant to apoptosis. Visilizumab did not induce apoptosis of PB T cells from UC patients. Visilizumab-induced apoptosis of LP T cells was dependent on caspase 3 and 8, but not caspase 9 activation and did not involve the Fas/FasL pathway. Low-Fc receptor binding Abs such as visilizumab may be highly effective for the treatment of UC through induction of apoptosis of LP T cells and rapid elimination of lesional pathogenic T cells in the gut mucosa.

Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease.

FOXP3(+)CD4(+) regulatory T cells (T(R)) have emerged as important regulators of immune responses. The aim of our study was to assess the frequency and functional characteristics of FOXP3(+)CD4(+) T(R) in Crohn's disease (CD). We report that FOXP3(+)CD4(+) T(R) cells are expanded in mucosal lymphoid tissues (lamina propria and MLN) but are decreased in the PB in active CD. Patients treated with thiopurines, but not steroids or anti-TNF-alpha inhibitors, have a lower frequency of PB FOXP3(+)CD4(+) T(R) (7.8+/-2.4% vs. 9.9+/-1.8%, p=0.01). FOXP3(+) cells were localized in the lamina propria (LP), muscularis mucosa and serosa and accumulated in granulomas, whereas in MLN they localize in the T cell rich areas. MLN CD4(+)CD25(+) T cells from both CD and normal intestine efficiently suppress the proliferation of effector CD4(+)CD25(-) T cells. T cell activation of MLN in vitro with anti-CD3 plus anti-CD28 Abs enhances the expression of FOXP3, both at the protein and transcriptional level, which is further enhanced by the addition of TGF-beta. In summary, there is an expansion of FOXP3(+)CD4(+) T(R) cells in mucosal lymphoid tissues in CD; they accumulate in areas of active inflammation, including granulomas and retain potent regulatory activity ex vivo.

The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells.

The recently described TL1A/DR3 ligand/receptor pair mediates strong costimulation of Th1 cells. Activation of T and NK cells induces DR3 expression, permitting soluble recombinant TL1A to increase IFN-gamma production and proliferation of these cells. Gut T cells and macrophages express TL1A, especially in Crohn's disease (CD), and there is a strong association between CD and tl1a single nucleotide polymorphisms. Murine studies implicate TL1A in gut inflammation. To determine whether professional T cell-activating cells can express TL1A, fresh blood monocytes and monocyte-derived dendritic cells were stimulated with various activating ligands, including TLR agonists, IFN-gamma, and immune complexes. FcgammaR stimulation strongly induced TL1A mRNA in both cell types, which correlated with the detection of TL1A on the cell surface and in cell culture medium. TLR agonists capable of inducing IL-6 and TNF-alpha in monocytes and dendritic cells did not induce surface nor soluble TL1A. Furthermore, we demonstrate that TL1A production in monocytes leads to enhancement of T cell responses. The induction of TL1A on APCs via specific pathway stimulation suggests a role for TL1A in Th1 responses to pathogens, and in CD.

Phenotype and effector function of CC chemokine receptor 9-expressing lymphocytes in small intestinal Crohn's disease.

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-gamma 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-gamma, 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 TCRVbeta analysis of CCR9(+) T cells revealed a diverse TCRVbeta 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.

Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis.

BACKGROUND: CD4+CD25+ regulatory T cells (TR) can prevent or treat experimental murine colitis but little is known about their potential role in human inflammatory bowel disease (IBD). FOXP3 is a transcription factor that plays a critical role in the development and function of CD4+CD25+ TR. The aim of this study was to examine the presence and functional characteristics of TR cells in colonic lymphoid tissues in patients with ulcerative colitis (UC). METHODS: FOXP3 expression was assessed by flow cytometry, immunohistochemistry, and reverse-transcriptase polymerase chain reaction (RT-PCR). Functional characterization of CD4+CD25+ cells was analyzed by suppression of proliferation and secretion of cytokines by cocultured effector CD4+CD25- T cells. RESULTS: FOXP3 +CD4+ T cells are increased in the lamina propria (LP) of inflamed and noninflamed areas of UC colon compared to normal colon. CD4+CD25+ T cells in UC mesenteric lymph nodes (MLN) express FOXP3 mRNA and protein and suppress the proliferation of autologous MLN CD4+CD25 T cells. The suppressor activity of MLN CD4+CD25+ T cells is cell contact-dependent but cytokine-independent. In addition, CD4+CD25+ T cells potently suppress the production of both Thl (IFN-gamma, IL-2) and Th2 (IL-5, IL-13) cytokines by cocultured CD4+CD25 T cells. FOXP3' cells localized in the T-cell-rich areas of MLN and occasionally present in the follicles. CONCLUSIONS: 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.