Impact of Specialized Inpatient IBD Care on Outcomes of IBD Hospitalizations: A Cohort Study.

BACKGROUND: The management of inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) is increasingly complex. Specialized care has been associated with improved ambulatory IBD outcomes. AIMS: To examine if the implementation of specialized inpatient IBD care modified short-term and long-term clinical outcomes in IBD-related hospitalizations. METHODS: This retrospective cohort study included IBD patients hospitalized between July 2013 and April 2015 at a single tertiary referral center where a specialized inpatient IBD care model was implemented in July 2014. In-hospital medical and surgical outcomes as well as postdischarge outcomes at 30 and 90 days were analyzed along with measures of quality of in-hospital care. Effect of specialist IBD care was examined on multivariate analysis. RESULTS: A total of 408 IBD-related admissions were included. With implementation of specialized IBD inpatient care, we observed increased frequency of use of high-dose biologic therapy for induction (26% versus 9%, odds ratio 5.50, 95% confidence interval 1.30-23.17) and higher proportion of patients in remission at 90 days after discharge (multivariate odds ratio 1.60, 95% confidence interval 0.99-2.69). Although there was no difference in surgery by 90 days, among those who underwent surgery, early surgery defined as in-hospital or within 30 days of discharge, was more common in the study period (71%) compared with the control period (46%, multivariate odds ratio 2.73, 95% confidence interval 1.22-6.12). There was no difference in length of stay between the 2 years. CONCLUSIONS: Implementation of specialized inpatient IBD care beneficially impacted remission and facilitated early surgical treatment.

Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort.

BACKGROUND: Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients. METHODS: Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey-Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey-Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey-Bradshaw index ≤4, simple clinical colitis activity index ≤2 and physician assessment of response and remission. RESULTS: Our study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%. CONCLUSIONS: VDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.

Early life environment and natural history of inflammatory bowel diseases.

BACKGROUND: Early life exposures may modify risk of inflammatory bowel diseases (IBD; Crohn's disease (CD), ulcerative colitis (UC)). However, the relationship between early life exposures and natural history of IBD has not been previously examined. METHODS: This single center study included patients with CD or UC recruited in a prospective IBD registry. Enrolled patients completed a detailed environmental questionnaire that assessed various early life environmental exposures. Our primary outcome was requirement for disease-related surgery in CD and UC. Logistic regression models defined independent effect of early life exposures, adjusting for potential confounders. RESULTS: Our study included 333 CD and 270 UC patients. Just over half were female with a median age at diagnosis of 25 years. One-third of the cohort had history of bowel surgery (31%) and nearly half had used at least one biologic agent (47%). Among those with CD, being breastfed was associated with reduced risk of CD-related surgery (34% vs. 55%), while childhood cigarette smoke exposure was associated with increased risk. On multivariate analysis, history of being breastfed (odds ratio (OR) 0.21, 95% confidence interval [CI] 0.09-0.46) and cigarette smoke exposure as a child (OR 2.17, 95% CI 1.10-4.29) remained independently associated with surgery. None of the early life variables influenced disease phenotype or outcome in UC. CONCLUSION: A history of being breastfed was associated with a decreased risk while childhood cigarette smoke exposure was associated with an increased risk of surgery in patients with CD. Further investigation to examine biological mechanisms is warranted.

Impaired innate immune function associated with fecal supernatant from Crohn's disease patients: insights into potential pathogenic role of the microbiome.

BACKGROUND: Although a dysbiosis of the intestinal microbiome plays a role in the pathogenesis of Crohn's disease (CD), the functional implication is unclear. We sought to determine the influence of fecal supernatant from patients with CD on innate immune function in neutrophil, macrophage, and epithelial cells. Metabolomic analysis was subsequently performed in an attempt to identify potential compounds responsible for the effects identified. METHODS: In the fecal samples from 11 pediatric patients with CD and 10 healthy controls, 16S ribosomal and metabolomic analyses were performed. We evaluated the effect of preincubation with fecal supernatant on neutrophil, macrophage, epithelial cell survival, superoxide production, bacterial invasion, and/or bactericidal function using gentamicin protection assay. Ten substances identified as most elevated in CD compared with control samples by metabolomic analysis were similarly tested for effect on bactericidal function. RESULTS: There were no statistically significant differences in microbial membership in fecal samples from patients with CD compared with healthy controls. However, bactericidal function was impaired in neutrophils and monocytes preincubated with supernatant from fecal samples from patients with CD. Although levels of many metabolites were noted to be altered in samples from patients with CD, the combination of the 10 most elevated compounds failed to demonstrate any effect on neutrophil bactericidal capacity. CONCLUSIONS: Fecal supernatant from patients with CD impairs intracellular bactericidal activity in neutrophils and macrophages. The functional consequences of the intestinal microbiome and its associated secreted products on innate immune function may be more critical than microbial membership in understanding the pathophysiology of CD.

Impact of mode of delivery on outcomes in patients with perianal Crohn's disease.

BACKGROUND: Crohn's disease (CD) often affects women during the reproductive years. Although several studies have examined the impact of pregnancy on luminal disease, limited literature exists in those with perianal CD. Decision regarding mode of delivery is a unique challenge in such patients due to concerns regarding the effect of pelvic floor trauma during delivery on preexisting perianal involvement. METHODS: We performed a retrospective chart review of patients with CD with established perianal disease undergoing either vaginal delivery or caesarean section (C-section) at our institutions. We examined the occurrence of symptomatic perianal disease flares within 5 years after delivery in such women compared with nonpregnant CD controls. We also compared the occurrence of such flares between the 2 modes of delivery in women with established perianal CD. RESULTS: We identified 61 pregnant patients with CD with established perianal disease (11 vaginal delivery, 50 through C-section) and 61 nonpregnant CD controls with perianal disease. One-third of the C-sections were primarily for obstetric indications. Six of the vaginal deliveries were complicated. Approximately, 36% of cases had a symptomatic perianal flare within 1 year after delivery. This was similar across both modes of delivery (P = 0.53) and similar to nonpregnant patients with CD. There was no difference in the rates of perianal surgical intervention or luminal disease flares in our population based on mode of delivery or between pregnant patients with CD and nonpregnant CD controls. CONCLUSIONS: We observed no difference in risk of symptomatic perianal flares in patients with established perianal CD delivering vaginally or through C-section.

Natural history of Crohn's disease following total colectomy and end ileostomy.

BACKGROUND: Crohn's disease (CD) requires surgical management in up to two-thirds of patients. Few studies have addressed the issue of ileal recurrence after colectomy and permanent ileostomy. The aims of our study were to assess the rate and predictors of postoperative recurrence of CD in patients with permanent ileostomy. METHODS: In a retrospective study from a tertiary referral center, we analyzed the natural history of patients with CD who underwent total colectomy and permanent ileostomy. Our primary outcomes were (1) overall disease recurrence including luminal recurrence, perianal disease or peristomal lesions requiring therapy, and (2) luminal recurrence alone defined as endoscopic and clinical recurrence within the terminal ileum. We examined if patient characteristics predicted recurrence using multivariate Cox proportional hazard models. RESULTS: Our study included 73 patients with CD followed for a mean of 28 months (range, 0-168 mo) after total colectomy and permanent ileostomy. Twenty patients had overall disease recurrence within 10 years after surgery, at rates of 15% and 50% at 1 and 5 years, respectively. Rate of luminal recurrence was 8% and 35% at 1 and 5 years, respectively. Diagnosis at age less than 18 years (hazard ratio, 2.94; 95% confidence interval, 1.14-7.62) and anti-tumor necrosis factor therapy before surgery (hazard ratio, 4.75; 95% confidence interval, 1.25-18.13) were the only independent predictive factors for overall disease recurrence. CONCLUSIONS: Up to one-third of patients with CD have overall recurrence of disease after treatment with total colectomy and permanent ileostomy. There is need to develop algorithms for surveillance and management of this select subgroup of patients.

Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases.

BACKGROUND: Cigarette smoking is a well-established environmental risk factor for Crohn's disease (CD) and ulcerative colitis (UC). The exact mechanism of its effect remains unexplained. Genetic polymorphisms in metabolizing enzymes may influence susceptibility to the effect of smoking and shed light on its mechanism of action. METHODS: We used a prospective cohort of patients with CD, UC, and healthy controls. Smoking status was defined as current, former, or never smoking. Patients were genotyped for polymorphisms in CYP2A6, glutathione transferase enzymes (GSTP1 and GSTM1), NAD(P)H quinone oxidoreductase (NQO), and heme oxygenase 1 using a Sequenom platform. Multivariate logistic regression models with CD or UC as the outcome, stratified by genotype, were developed and interaction P-values calculated. RESULTS: Our study included 634 patients with CD, 401 with UC, and 337 healthy controls. Ever smokers had an increased risk of CD (odds ratio = 3.88, 95% confidence interval = 2.35-6.39) compared with nonsmokers among patients with AG/AA genotypes at CYP2A6. However, ever smoking was not associated with CD among patients with the AA genotype (Pinteraction = 0.001). Former smoking was associated with an increased risk for UC only in the presence of GG/AG genotypes for GSTP1 but not in those with the AA genotype (Pinteraction = 0.012). Polymorphisms at the NQO and HMOX loci did not demonstrate a statistically significant interaction with smoking and risk of CD or UC. CONCLUSIONS: Genetic polymorphisms in metabolizing enzymes may influence the association between smoking and CD and UC. Further studies of gene-environment interaction in inflammatory bowel disease are warranted.

Venous thromboembolism in patients with inflammatory bowel diseases: a case-control study of risk factors.

BACKGROUND: Inflammatory bowel disease (IBD) is a well-known risk factor for venous thromboembolism (VTE). Existing guidelines for thromboprophylaxis in hospitalized patients do not extend to other clinical scenarios that may also be associated with VTE risk. Our aim was to estimate the fraction of VTE events in patients with IBD that could be prevented. METHODS: A retrospective analysis assessed all patients with IBD diagnosed with VTE at a single academic medical center from 2002 to 2012. Confirmed cases were analyzed for VTE risk factors, inpatient status, the use of deep venous thrombosis prophylaxis, and when applicable the reason for omission of prophylaxis. IBD VTE cases were compared with age- and sex-matched non-IBD VTE controls with regards to risk factors and potential opportunities for VTE prevention. RESULTS: There were 204 patients with IBD (108 ulcerative colitis, 96 Crohn's disease) diagnosed with VTE (110 deep venous thrombosis, 66 pulmonary embolism, 27 intra-abdominal thromboses, and 1 other). One-third of the VTE events occurred in hospitalized patients. Two-third of the medical inpatients and 44% of surgical inpatients who developed VTE did not receive prophylaxis. Importantly, 129 VTE events occurred in outpatients. The proportion of outpatients hospitalized within 4 weeks of developing venous thrombosis was higher in patients with IBD than non-IBD controls (33% versus 15%, P = 0.0003). One-third (36%) of patients were experiencing ambulatory disease flares at the time of VTE diagnosis. CONCLUSIONS: A substantial portion of VTE events in patients with IBD occurred in clinical scenarios is not routinely recommended for thromboprophylaxis. Further investigation of primary prophylaxis for patients with IBD in high-risk outpatients may be warranted.

Differential effect of genetic burden on disease phenotypes in Crohn's disease and ulcerative colitis: analysis of a North American cohort.

OBJECTIVES: Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown. METHODS: The data source for our study was a prospective cohort of CD and UC patients recruited from a tertiary referral center. All patients underwent genotyping on the Illumina Immunochip. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for each of the 163 inflammatory bowel disease (IBD) risk loci was calculated and phenotypic associations examined across GRS quartiles. RESULTS: Our study cohort included 1,105 patients (697 CD, 408 UC). Increasing genetic burden was associated with earlier age of diagnosis of CD (Ptrend=0.008). Patients in the highest GRS quartile were likely to develop disease 5 years earlier than those in the lowest quartile. Increasing genetic burden was also associated with ileal involvement in CD (Ptrend <0.0001). The effect of genetic burden was independent of the NOD2 locus and was stronger among those with no NOD2 variants, and in never smokers. UC patients with an involved first-degree relative had a higher genetic burden, but GRS was not associated with disease phenotype in UC. CONCLUSIONS: Increasing genetic burden is associated with early age of diagnosis in CD, but not UC. The expanded panel of IBD risk loci explains only a fraction of variance of disease phenotype, suggesting limited clinical utility of genetics in predicting natural history.

ß7 integrins are required to give rise to intestinal mononuclear phagocytes with tolerogenic potential.

BACKGROUND AND OBJECTIVE: While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin α4ß7 is required for this process. METHODS: We used a T cell-mediated colitis model to study the role of α4ß7 in the innate immune compartment. We then performed competitive bone marrow (BM) reconstitution experiments to assess the requirement of α4ß7 in the generation of intestinal retinoic acid (RA)-producing CD11c(hi) DC (ALDE(+)DC) and CD64 macrophages. Using mixed BM chimeras we also asked whether α4ß7 is required to give rise to tolerogenic mononuclear phagocytes. RESULTS: Lack of ß7 integrins in the innate immune compartment (ß7(-/-)RAG2(-/-) mice) markedly accelerated T cell-mediated colitis, which was correlated with lower numbers and frequencies of ALDE(+)DC in mesenteric lymph nodes. Consistent with a role of α4ß7 in the generation of intestinal mononuclear phagocytes, BM cells from ß7(-/-) mice poorly reconstituted small intestine ALDE(+)DC and Mφ when compared to their wild type counterparts. In addition, mice lacking ß7 integrins in the CD11c(hi) compartment showed decreased ability to induce Foxp3(+) T(REG) and IL-10-producing T cells. CONCLUSIONS: Mice lacking ß7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of ß7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential.

Pretreatment 25-hydroxyvitamin D levels and durability of anti-tumor necrosis factor-α therapy in inflammatory bowel diseases.

INTRODUCTION: Emerging evidence supports an immunologic role for 25-hydroxyvitamin D (25(OH)D) in inflammatory bowel disease (IBD). Here we examined if pretreatment vitamin D status influences durability of anti-tumor necrosis factor (TNF)-α therapy in patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: All IBD patients who had plasma 25(OH)D level checked <3 months prior to initiating anti-TNF-α therapy were included in this retrospective single-center cohort study. Our main predictor variable was insufficient plasma 25(OH)D (<30 ng/mL). Cox proportional hazards model adjusting for potential confounders was used to identify the independent effect of pretreatment vitamin D on biologic treatment cessation. RESULTS: Our study included 101 IBD patients (74 CD; median disease duration 9 years). The median index 25(OH)D level was 27 ng/mL (interquartile range, 20-33 ng/mL). One-third of the patients had prior exposure to anti-TNF-α therapy. On multivariate analysis, patients with insufficient vitamin D demonstrated earlier cessation of anti-TNF-α therapy (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.39; P = .04). This effect was significant in patients who stopped treatment for loss of response (HR, 3.49; 95% CI, 1.34-9.09) and stronger for CD (HR, 2.38; 95% CI, 0.95-5.99) than UC (P = NS). CONCLUSIONS: Our findings suggest that vitamin D levels may influence durability of anti-TNF-α induction and maintenance therapy. Larger cohort studies and clinical trials of supplemental vitamin D use with disease activity as an end point may be warranted.

Colitis and colon cancer in WASP-deficient mice require helicobacter species.

BACKGROUND: Wiskott-Aldrich syndrome protein-deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which Helicobacter spp. have been implicated in disease pathogenesis. We sought to determine the role of Helicobacter spp. in colitis development in Wiskott-Aldrich syndrome protein-deficient (WKO) mice. METHODS: Feces from WKO mice raised under specific pathogen-free conditions were evaluated for the presence of Helicobacter spp., after which a subset of mice were rederived in Helicobacter spp.-free conditions. Helicobacter spp.-free WKO animals were subsequently infected with Helicobacter bilis. RESULTS: Helicobacter spp. were detected in feces from WKO mice. After rederivation in Helicobacter spp.-free conditions, WKO mice did not develop spontaneous colitis but were susceptible to radiation-induced colitis. Moreover, a T-cell transfer model of colitis dependent on Wiskott-Aldrich syndrome protein-deficient innate immune cells also required Helicobacter spp. colonization. Helicobacter bilis infection of rederived WKO mice led to typhlitis and colitis. Most notably, several H. bilis-infected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls. CONCLUSIONS: Spontaneous and T-cell transfer, but not radiation-induced, colitis in WKO mice is dependent on the presence of Helicobacter spp. Furthermore, H. bilis infection is sufficient to induce typhlocolitis and colon cancer in Helicobacter spp.-free WKO mice. This animal model of a human immunodeficiency with chronic colitis and increased risk of colon cancer parallels what is seen in human colitis and implicates specific microbial constituents in promoting immune dysregulation in the intestinal mucosa.

Impact of coexistent celiac disease on phenotype and natural history of inflammatory bowel diseases.

OBJECTIVES: Inflammatory bowel disease (IBD) and celiac disease are the two most common immune-mediated gastrointestinal diseases. There is limited knowledge regarding the course of IBD in those with coexisting celiac disease. We conducted this study to determine whether patients with coexisting celiac disease present a unique phenotype of IBD and to examine the frequency of co-occurrence of celiac disease and IBD in comparison with other autoimmune disorders. METHODS: This was a case-control study performed at two tertiary referral centers. Cases comprised of patients with known diagnoses of celiac disease and IBD. Two random IBD controls without celiac disease were selected for each case after matching for IBD type. Disease phenotype and natural history for both Crohn's disease (CD) and ulcerative colitis (UC) were noted from medical record review, and were compared between IBD patients with and without celiac disease. RESULTS: We identified a total of 51 patients with IBD (22 UC, 1 indeterminate colitis, 28 CD) and celiac disease. There was no significant difference in the age, gender, or ethnicity between celiac-IBD and controls. Pancolitis was more common in celiac-UC patients as compared with controls (odds ratio (OR) 3.30, 95% confidence interval (CI) 1.05-21.50). There was also a trend toward increased use of immunomodulators (IMMs) among celiac-UC patients than in non-celiac UC controls (OR 2.83, 95% CI 0.95-8.48). No phenotypic differences were found in celiac-CD patients. There were no significant differences in IBD-related medication usage, hospitalizations, or surgeries. CONCLUSIONS: Patients with UC and celiac disease were more likely to have pancolitis and had a trend toward greater use of IMMs. Coexisting celiac disease did not influence natural history of CD.

Older age is associated with higher rate of discontinuation of anti-TNF therapy in patients with inflammatory bowel disease.

BACKGROUND: In increasingly aging populations, awareness of outcomes of older patients treated with biologics is becoming more important. However, few studies to date have investigated the safety and durability of anti-tumor necrosis factor (TNF) therapy in this subgroup. METHODS: This was a retrospective single-center study with cases comprising all IBD patients who began anti-TNF treatment at age >60 years. Cases of Crohn's disease (CD) and ulcerative colitis (UC) were identified from medical record review. Our controls consisted of patients younger than age 60 years on anti-TNF treatment and patients >60 years on treatment with immunomodulators. Kaplan-Meier survival estimates were used to calculate the probability of remaining on anti-TNF therapy. RESULTS: We identified a total of 54 IBD patients who initiated anti-TNF therapy over the age of 60 years (mean 73, range 61-97 years). Among these, a total of 38 patients (70%) discontinued anti-TNF therapy after a mean of 24.1 months. At 12 months after initiation, 75% of patients older than age 60 years were still on anti-TNF agents compared to 93% among younger users and 82% among older AZA users (P < 0.05). Compared to older AZA users, older anti-TNF users remained more likely to require early therapy cessation (hazard ratio 2.21, 95% confidence interval 1.29-3.78). CONCLUSIONS: The IBD population older than age 60 at the time of initiation of anti-TNF therapy is at higher risk for discontinuation of therapy. They may also be particularly vulnerable to infectious complications requiring hospitalization, suggesting the need for careful monitoring during therapy.

Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice.

BACKGROUND & AIMS: Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich syndrome protein (WASP), a hematopoietic cell-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T cell-mediated colitis in mice with WASP-deficient cells of the innate immune system. METHODS: Naïve and/or regulatory CD4(+) T cells were transferred from 129 SvEv mice into RAG-2-deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays. RESULTS: Transfer of unfractionated CD4(+) T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Naïve wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared with RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients and associated with reduced numbers of CD103(+) tolerogenic dendritic cells and levels of interleukin-10. Administration of interleukin-10 prevented induction of colitis following transfer of T cells into WRDKO mice. CONCLUSIONS: Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of interleukin-10, and homeostasis of regulatory T cells.

MyD88-dependent TLR1/2 signals educate dendritic cells with gut-specific imprinting properties.

Gut-associated dendritic cells (DC) synthesize all-trans retinoic acid, which is required for inducing gut-tropic lymphocytes. Gut-associated DC from MyD88(-/-) mice, which lack most TLR signals, expressed low levels of retinal dehydrogenases (critical enzymes for all-trans retinoic acid biosynthesis) and were significantly impaired in their ability to induce gut-homing T cells. Pretreatment of extraintestinal DC with a TLR1/2 agonist was sufficient to induce retinal dehydrogenases and to confer these DC with the capacity to induce gut-homing lymphocytes via a mechanism dependent on MyD88 and JNK/MAPK. Moreover, gut-associated DC from TLR2(-/-) mice, or from mice in which JNK was pharmacologically blocked, were impaired in their education to imprint gut-homing T cells, which correlated with a decreased induction of gut-tropic T cells in TLR2(-/-) mice upon immunization. Thus, MyD88-dependent TLR2 signals are necessary and sufficient to educate DC with gut-specific imprinting properties and contribute in vivo to the generation of gut-tropic T cells.

Low-dose MDCT and CT enterography of patients with Crohn disease: feasibility of adaptive statistical iterative reconstruction.

OBJECTIVE: The purpose of this study was to evaluate the image quality and diagnostic performance of low-dose MDCT and CT enterography with adaptive statistical iterative reconstruction (ASIR) in the evaluation of Crohn disease. SUBJECTS AND METHODS: Forty-eight patients (20 men, 28 women; mean age, 33.3 years; range, 17-83 years) with known or suspected Crohn disease who underwent low-dose MDCT and CT enterography with ASIR between December 2008 and December 2009 were included in the study. Twenty-seven patients had previously undergone standard-dose 64-MDCT and CT enterography with filtered back projection (FBP), and those images were used for comparison. The weight-based i.v. contrast protocol and scan parameters (120 kVp, 5-mm section thickness, 0.5-second rotation, pitch of 1.375, 64 × 0.625 mm detector configuration) were constant for the two techniques except for a higher noise index (×1.3) in the ASIR group. Two blinded readers reviewed 75 randomized MDCT-CT enterographic scans of 48 patients to assess image quality and diagnostic performance in the evaluation of Crohn disease, and the radiation dose for the studies was estimated. RESULTS: All 75 MDCT and CT enterographic scans had acceptable quality for diagnostic interpretation. Findings of Crohn disease were seen on 63 of 75 scans (84%). Low-dose scans in the ASIR group had optimal image quality and were rated comparable to or better than standard-dose FBP images (mean score, 4.2 vs 3.87; p = 0.007). The subjective image noise score (mean, 1.43 vs 1.58; p = 0.2) and objective image noise measurements were lower for ASIR images (p < 0.001). Low-dose studies with ASIR allowed average dose reduction of 34.5% compared with standard-dose scans with FBP (volume CT dose index for ASIR, 7.7 ± 2.1 mGy; for FBP, 12 ± 5.5 mGy; p < 0.01). CONCLUSION: Low-dose MDCT and CT enterographic studies reconstructed with ASIR were of appropriate quality for confident evaluation of the manifestations of Crohn disease while allowing approximately 34% dose reduction in comparison with FBP technique.

Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10-deficient mice.

BACKGROUND & AIMS: The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine interleukin (IL)-10 in this signaling pathway using a mouse model of colitis. METHODS: Clinical, histopathologic, and functional parameters of intestinal inflammation were evaluated in TLR4(-/-), IL-10(-/-), and TLR4(-/-) x IL-10(-/-) mice that were free of specific pathogens and in TLR4(-/-) x IL-10(-/-) mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay. RESULTS: TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4(-/-) x IL-10(-/-) mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3(+)) that secrete interferon-gamma and IL-17 accumulate in the colonic lamina propria of TLR4(-/-) x IL-10(-/-) mice and do not prevent inflammation. Aberrant control of epithelial cell turnover results in the persistence of antigen-presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4(-/-) mice. CONCLUSIONS: In mice that lack both IL-10- and TLR4-mediated signals, aberrant regulatory T-cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation.

Lymphocyte-dependent and Th2 cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome protein.

BACKGROUND & AIMS: Controversy exists as to whether patients with inflammatory bowel disease have an underlying immunodeficiency. We have focused on a murine model of the Wiskott-Aldrich syndrome, an immunodeficiency in which autoimmunity can manifest in the form of an inflammatory bowel disease-like illness. Wiskott-Aldrich syndrome protein (WASP) deficiency in mice results in similar clinical features. Herein, we characterized the colitis in WASP-deficient mice. METHODS: WASP-deficient mice were followed clinically and histologically. Immunologic studies were performed to determine the pathogenic cell population(s), the predominant cytokine expression pattern, and the role of cytokine(s) in colitis pathogenesis. RESULTS: All WASP-deficient mice develop colitis by 6 months of age. Lymphocytes are required for disease induction, and CD4(+) T cells from WASP-deficient mice are sufficient to induce disease in lymphocyte-deficient hosts. Lamina propria preparations from WASP-deficient mice demonstrated elevations in interferon-gamma, interleukin (IL)-4, and IL-13 levels but decreased IL-6 and no difference in IL-17 expression in comparison with wild-type controls. Treatment with neutralizing antibody to IL-4, but not to interferon-gamma, abrogated colitis development. However, mice deficient in both WASP and IL-4 showed no difference in histologic colitis scores at 24 weeks of age compared with WASP-deficient mice. CONCLUSIONS: These results demonstrate a critical role for lymphocytes and a relative T helper 2 cytokine predominance in the colitis associated with WASP-deficient mice. This is the only model of colitis with elevated T helper 2 cytokines and aberrant natural regulatory T cell function and is unique in having a human disease counterpart with similar defects.