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There is limited data about the safety of colorectal surgery after immune checkpoint inhibitors (ICI). We aimed to share our experience about postoperative outcomes of colorectal surgery for patients treated with ICI. Overall, 31 patients were identified, 22 (71%) underwent elective and nine (29%) underwent emergent/urgent surgery. The 30-day Clavien Dindo class ≥ III complication rates were 27.3% (n = 6) for elective and 55.5% (n = 5) for emergent/urgent cases. Four patients underwent emergency surgery for immune-related colonic perforation and developed postoperative septic shock; two died. Considering patients' comorbidities, cancer stage, and surgical complexity, elective colorectal surgery after ICI seems relatively safe. However, emergent/urgent colorectal surgery was associated with high postoperative morbidity. Indeed, colonic perforation in the setting of ICI treatment has a significant risk of postoperative mortality. Therefore, for patients on ICI with any acute abdominal symptoms, surgical consult should be involved, and colon perforation should be ruled out., Competing Interests: Declaration of competing interest This research did not receive external funding. Authors declare no conflict of interest., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4 -/- ) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-β was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.

Diseases of the colon are a big health burden in both men and women worldwide ranging from acute infection to cancer. Environmental and genetic factors influence disease onset and outcome in multiple colonic pathologies. The importance of inflammation in the onset, progression and outcome of multiple colonic pathologies is gaining more traction as the evidence from recent research is considered. In this review, we provide an update on the literature to understand how genetics, diet, and the gut microbiota influence the crosstalk between immune and non‑immune cells resulting in inflammation observed in multiple colonic pathologies. Specifically, we focus on four colonic diseases two of which have a more established association with inflammation (inflammatory bowel disease and colorectal cancer) while the other two have a less understood relationship with inflammation (diverticular disease and irritable bowel syndrome).

Primary classic Hodgkin lymphoma of the gastrointestinal tract represents a rare occurrence. A full patient's work-up is essential in order to exclude a secondary intestinal involvement. Histologically Epstein-Barr virus mucocutaneous ulcer closely resembles Hodgkin lymphoma. The differential diagnosis between these two entities is relevant, since both the therapeutic approach and the clinical behavior are different. Herein, we describe a case of primary classic Hodgkin lymphoma arising in the ileum and a case of Epstein-Barr virus mucocutaneous ulcer of the colon, focusing on the main clinicopathological differences.

In vivo an ecological network of polysaccharides utilization by gut microbiota is not only an intense competition but also an impressive cooperation pattern. The present study evaluated the in vivo protective effect of combined fungal polysaccharides (CFP) from Cordyceps sinensis and Ganoderma atrum on colon immune dysfunction, induced by 150mg/kg cyclophosphamide (CP). The results showed that C. sinensis polysaccharides (CSP) significantly promoted microbial-derived butyrate to improve histone h3 acetylation mediating regulatory T (Treg) cell specific Foxp3, as well as significantly restored CP-induced elevation of interleukin (IL)-17 and IL-21. Additionally, G. atrum polysaccharides (PSG) significantly down-regulated MyD88, as well as significantly increased IL-10 and TGF-β3. Furthermore, CFP balanced the disequilibrium of cytokines secretion and Foxp3/RORγt ratio related Treg/T helper 17 (Th17) balance, as well as down-regulated the TLR-mediated inflammatory signaling pathway and promoted secretory immunoglobulin A (sIgA) secretion to suppress colonic inflammation. Therefore, our results typically contribute to understand the in vivo immunoregulatory function of fungal polysaccharides compounds, involving microbial-associated inflammatory signals and specific metabolic products., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I-like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A-/- and MR1-/- mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT.

Aim: To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy., Methods: We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used., Results: A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported., Conclusion: In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course., Competing Interests: Conflict-of-interest statement: Jain A and Lazarev MG have no declarations. Lipson EJ has served as a consultant for Bristol-Myers Squibb, EMD, Serono, Merck and Novartis; He has received research funding from Genentech and AstraZeneca. Sharfman WH has served as a consultant for Merck, Genentech, and Castle Biosciences, and he has received research funding from Bristol-Myers Squibb, Glaxo Smith Kline, and Novartis. Brant SR has served as an advisory board member for Asana Medical Inc., and he has received research funding from Johnson and Johnson.

Introduction: Invasive Aspergillus commonly involves the lungs, but can also affect other organs such as the skin, adrenal glands, central nervous system, liver, spleen and the gastrointestinal tract. Gastrointestinal aspergillosis is rare and is most often discovered in immunocompromised patients. There is only one other case report to our knowledge that describes the diagnosis being discovered on histopathological analysis of endoscopic biopsies of necrotic ulcers., Case Presentation: A 36-year-old Hispanic woman presented with septic shock secondary to extensive Fournier gangrene that required multiple surgical debridement of the perineal and retroperitoneal area. Her vital signs on admission were a temperature of 39.4°C and blood pressure of 85/56 mmHg, pulse rate of 108/min and respiratory rate of 25. An examination of the perineum/genital area revealed bilateral gluteal and perilabial edema, erythema and focal areas of necrotic tissue with purulent discharge. Other surgeries included small bowel resections with ileoileal anastomosis that later developed an anastomotic leak that required and diverting end ileostomy. Eleven weeks after admission, our patient developed hematochezia from the colostomy associated with a decrease in hemoglobin and hematocrit to 6.4 g/dL and 20.2% respectively. Colonoscopy through the ostomy revealed blood throughout the colon and a 3 cm necrotic ulcer with an adherent clot in the transverse colon. Biopsies were taken from the edge of the ulcer. Histopathological analysis of the specimen with Grocott's methenamine silver stain revealed septated hyphae with the 45-degree-angle branching that is morphologically consistent with Aspergillus species. Our patient was treated with intravenous voriconazole for 30 days with a prolonged hospitalization but no recurrent bleeding., Conclusions: Gastrointestinal aspergillosis is an unusual presentation of invasive Aspergillus associated with a high mortality rate. Characteristic features of gastrointestinal aspergillosis include invasion of the mesenteric arteries, intravascular thrombosis and subsequent tissue ischemia. Clinical manifestations of invasive Aspergillus of the gastrointestinal tract can include fever, abdominal pain, ileus, peritonitis, bloody diarrhea or hematochezia. In an autopsy series of patients with invasive Aspergillus, 37 of 107 patients had Aspergillus involvement of the gastrointestinal system; the most common pathological findings included ulcers and abscesses. Although rare, invasive aspergillosis may present with gastrointestinal bleeding associated with necrotic ulcers on endoscopic examination.

Background: Intestinal tuberculosis (TB) and Crohn's disease closely resemble each other clinically and morphologically. Little is known of cytokine regulation in intestinal TB., Objective: To compare cytokine gene expression in colonic mucosa and peripheral blood mononuclear cells (PBMC) in TB with that in Crohn's disease., Methods: Biopsies were obtained from normal and ulcerated colonic mucosa of 12 intestinal TB and 11 Crohn's disease patients, and PBMC from 15 intestinal TB and 12 Crohn's disease patients and 11 healthy volunteers. RNA was extracted, and the expression of selected cytokines, chemokines and pattern recognition receptors quantified by reverse transcriptase real-time polymerase chain reaction using SYBR green., Results: The mRNA expression of interleukin-8 (IL-8), induced protein-10, tumour necrosis factor-alpha, IL-23 p19 and IL-12 p40, and Toll-like receptors (TLR) 1 and 2 in the ulcerated mucosa was increased in both intestinal TB and Crohn's disease. Expression of growth-related oncogene-alpha was increased in intestinal TB, while expression of interferon-gamma (IFN-) and TLR 4, 5 and 9 was increased in Crohn's disease. Expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) was decreased in Crohn's disease. Secretion of IFN- or IL-10 from PBMC was not significantly altered in either disease. PBMC mRNA expression of IL-1, IL-6 and IL-8 mRNA was upregulated in Crohn's disease, while that of IL-17 was upregulated in intestinal TB., Conclusions: Cytokine gene expression patterns in intestinal mucosa and PBMC of intestinal TB were remarkably similar to Crohn's disease, and demonstrated innate immune activation and T-helper 1 polarisation.

Background: Histoplasmosis is a common opportunistic fungal infection that is observed almost exclusively in immunodeficient patients, especially those with AIDS. Immunocompetent individuals that suffer from histoplasmosis are rarely reported, especially those with disseminated lesions, such as disseminated histoplasmosis. The observation of disseminated histoplasmosis with prominent gastrointestinal involvement, no respiratory symptoms (which is presumed to be the portal of infection), gastrointestinal pathological changes, and minor digestive system disorders make this case study exceedingly rare., Case Presentation: We report the case of a 33-year-old immunocompetent male who presented with fever and weight loss. Based on investigations, the patient showed pancytopenia, hepatosplenomegaly, bone marrow involvement and marked colonic involvement. Finally, disseminated histoplasmosis was diagnosed and confirmed by stained smears of fine needle aspirates and biopsy from lesions in the bone marrow and colon. The patient showed appreciable regression of lesions following prompt treatment with amphotericin B deoxycholate, and was treated thereafter with oral itraconazole following discharge from hospital., Conclusion: Disseminated histoplasmosis could be underestimated in immunocompetent patients. A high degree of clinical suspicion is essential in both immunocompromised and immunocompetent patients, regardless of pulmonary symptoms, and whether in endemic or non-endemic areas. Early and accurate diagnosis is extremely important for the appropriate treatment of infection and to improve disease outcome.

Citrobacter rodentium, which colonizes the gut mucosa via formation of attaching and effacing (A/E) lesions, causes transmissible colonic hyperplasia. The aim of this study was to evaluate whether prophylactic treatment with Bifidobacterium breve UCC2003 can improve the outcome of C. rodentium infection. Six-week-old albino C57BL/6 mice were pre-treated for 3 days with B. breve, challenged with bioluminescent C. rodentium and administered B. breve or PBS-C for 8 days post-infection; control mice were either administered B. breve and mock-infected with PBS, or mock-treated with PBS-C and mock-infected with PBS. C. rodentium colonization was monitored by bacterial enumeration from faeces and by a combination of both 2D bioluminescence imaging (BLI) and composite 3D diffuse light imaging tomography with µCT imaging (DLIT-µCT). At day 8 post-infection, colons were removed and assessed for crypt hyperplasia, histology by light microscopy, bacterial colonization by immunofluorescence, and A/E lesion formation by electron microscopy. Prophylactic administration of B. breve did not prevent C. rodentium colonization or A/E lesion formation. However, this treatment did alter C. rodentium distribution within the large intestine and significantly reduced colonic crypt hyperplasia at the peak of bacterial infection. These results show that B. breve could not competitively exclude C. rodentium, but reduced pathogen-induced colonic inflammation.

Background: Glycoprotein 2 (GP2) was discovered as the major autoantigen of Crohn's disease (CD)-specific pancreatic autoantibodies (PAB). We investigated anti-GP2 IgA and IgG antibodies as novel serological parameters in CD and assessed their association with distinct disease phenotypes., Methods: Anti-GP2 and anti-Saccharomyces cerevisiae (ASCA) IgA and IgG were detected by ELISA employing recombinant human GP2 and phosphopeptidomannan, respectively and PAB by indirect immunofluorescence (IIF) in 271 sera, 169 with CD and 102 with ulcerative colitis (UC). As healthy controls 160 adult blood donors and 65 children were included., Results: Anti-GP2 IgG and/or IgA were more prevalent in CD (51/169, 30.2%) than in UC (9/102, 8.9%) patients and in controls (9/225, 4%) (p < 0.001 respectively). ASCA IgG and/or IgA were present in 60/169 (35.5%) in CD and in 7/102 (6.9%) in UC patients (p < 0.001). CD patients with ileocolonic location (L3) showed a significantly higher prevalence of anti-GP2 and ASCA IgA and/or IgG (40/113 and 48/113, respectively; p < 0.05 for both comparisons), whereas CD patients with colonic location (L2) revealed a significantly diminished prevalence for these autoantibody specificities (2/32 and 5/32, respectively, p < 0.05 for both). Anti-GP2 IgG were significantly more prevalent in CD patients with stricturing behaviour (B2) and perianal disease (7/11, p < 0.02) and less prevalent in those with penetrating behaviour (B3) and perianal disease (4/31, p < 0.05). The occurrence of anti-GP2 IgA and/or IgG was significantly more prevalent in CD patients with age at diagnosis of ≤16 years (16/31, p < 0.009). Prevalence of one or more anti-GP2 or ASCA IgA and/or IgG was significantly higher in L3, B2, and A1 and lower in L2 (68/113, 27/41, 23/31, 6/32; p < 0.04, respectively)., Conclusions: Anti-GP2 IgG and IgA, constituting novel CD specific autoantibodies, appear to be associated with distinct disease phenotypes identifying patients at a younger age, with ileocolonic location, and stricturing behaviour with perianal disease.

Objective: To assess the effects of ischemia and reperfusion on indicators of oxidative stress, activation of eosinophils, and apoptosis in the large colonic mucosa of horses., Animals: 40 horses., Procedures: In 1 or two 20-cm-long segments of the pelvic flexure, ischemia was induced for 1 or 2 hours followed by no reperfusion or 30 minutes and 18 hours of reperfusion in anesthetized horses. Mucosal specimens were collected before (controls; n = 20 horses) and after each period of ischemia, and full-thickness tissue samples were collected after each period of reperfusion. Sections of colonic tissues were stained for histomorphometric analysis or assessment of eosinophil accumulation. Nitrotyrosine was identified immunohistochemically, and severity of apoptosis was determined via the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method., Results: Numbers of mucosal eosinophils were similar before induction of ischemia, after ischemia, and after ischemia-reperfusion. Eosinophil nitrotyrosine production increased significantly during ischemia and continued through 30 minutes of reperfusion; production was decreased at 18 hours of reperfusion but remained greater than that of the controls. In other leukocytes, nitrotyrosine generation peaked at 1 hour of ischemia and again at 18 hours of reperfusion. Compared with control findings, epithelial apoptosis increased gradually at 1 through 2 hours of ischemia with no further progression after reperfusion., Conclusions and Clinical Relevance: Results suggested that resident eosinophils in the large colon of horses react to mucosal injury from ischemia and reperfusion and may undergo oxidative stress under those conditions. Epithelial apoptosis could contribute to tissue damage.

Background: The local and systemic humoral response after colorectal surgery is thought to affect postoperative recovery. It is commonly claimed that laparoscopic surgery elicits a diminished inflammatory response than equivalent open surgery. Despite these claims, the evidence is conflicting. Therefore, we aimed to systematically review the results from randomized controlled clinical trials comparing the humoral response associated with laparoscopic versus open colorectal surgery., Materials and Methods: A high-sensitivity search was conducted independently by two of the authors with no language restriction. Studies were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), Cochrane Library, Medline (January 1966 to January 2009), PubMed (1950 to January 2009), and Embase (1947 to January 2009). Relevant meeting abstracts and reference lists were manually searched. Data analysis was performed using Review Manager ver. 5.0., Results: Thirteen randomized controlled trials were included. Meta-analysis demonstrated a significantly higher serum IL-6 on d 1 after open colorectal resection for neoplasia (n = 97) compared with laparoscopic resection (n = 76, P = 0.0008) without significant heterogeneity. Data for plasma IL-6 were heterogeneous, with no apparent difference between groups. No other significant differences were identified, and there were not enough data on local peritoneal humoral factors to allow meta-analysis., Conclusion: Open colorectal resection for neoplasia is associated with higher postoperative serum levels of IL-6 on d 1 than equivalent laparoscopic surgery. The aetiology and clinical significance of this finding is uncertain, and further studies are required to elucidate any differences in the local humoral response which may be more clinically relevant in surgery for this indication., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Allogeneic stem cell transplantation is the most potent form of effective adoptive immunotherapy. The graft-versus-leukemia (GVL) effect mediated by the allogeneic graft, however, is typically coexpressed with graft-versus-host disease (GVHD), which is the major complication of allogeneic stem cell transplantation. In this study, we used genetic and antibody-based strategies to examine the effect that blockade of interleukin 23 (IL-23) signaling had on GVH and GVL reactivity in murine transplantation recipients. These studies demonstrate that the selective protection of the colon that occurs as a consequence of inhibition of IL-23 signaling reduces GVHD without loss of the GVL effect. The separation of GVH and GVL reactivity was noted in both acute and chronic hematologic malignancy models, indicating that this approach was not restricted by the kinetic profile of the underlying leukemia. Furthermore, a potent GVL response could be mounted in the colon under conditions where tumor cells migrated to this site, indicating that this organ did not serve as a sanctuary site for subsequent systemic relapse in GVHD-protected animals. These studies demonstrate that blockade of IL-23 signaling is an effective strategy for separating GVH and GVL responses and identify IL-23 as a therapeutic target for the regulation of alloresponses in humans.

Background: Gangrene of stomach or intestines owing to non-occlusive bowel infarction (NOBI) is a rare event with unknown etiology. Since B19 may cause vasculitis, arteritis, angiopathy and more importantly, localized microvascular thrombi formation hence patients with bowel gangrene were investigated for B19 infection., Methods: Twelve patients (8 male and 4 females; median age 40 yr) of ischemic unexplained gangrene of bowel underwent emergency laparotomy. Eight cases had NOBI while four had occlusive bowel infarction (OBI). Anti-B19 antibodies in sera by ELISA and Western-blot and B19 DNA by PCR in sera and resected tissues were analysed., Results: All patients underwent resection of gangrenous bowel; with exteriorization followed by restoration wherever appropriate. Histopathology showed loss of bowel mucosa and crypts with inflammatory cell infiltration besides fibrin thrombus in gastric vessels. Sera of all 8 patents of NOBI had B19 genome by nested-PCR (VP1 unique) and in 6 by PCR (VP1-VP2). In three patients resected bowel tissues also had B19 DNA besides anti-B19 IgM and IgG antibodies. NOBI patients were reticulocytopenic and anaemic while one had necrotizing vasculitis of skin a year ago. No IgM antibodies to agents causing vasculitis (HTLV-I, HIV-1+2, CMV, HSV1+2, mumps virus and Mycobacterium tuberculosis) nor any abnormality in coagulation profiles were detected. In four OBI cases's sera and resected bowel tissues and in control bowel tissues (n=36) no anti-B19 IgM antibodies or B19 DNA were detected., Conclusions: Novel finding of active B19 infection in non-occlusive gangrene of the bowel may be causal rather than casual.

We report three cases of ileocolic mucormycosis in adult immunocompromised patients presenting as acute abdomen. All patients underwent laparotomy but two of them died from multiorgan failure before the diagnoses were confirmed. The diagnosis of gastrointestinal mucormycosis is rarely suspected, and antemortem diagnosis is made in only 25%-50% of cases. These cases illustrate the difficulty encountered by surgeons in managing acute abdomen in neutropenic patients with hematological malignancy. The management of colonic mucormycosis in the published literature is also reviewed.

Purpose: Although some studies have reported favorable effects of direct hemoperfusion with polymyxin-B-immobilized fiber columns (PMX) for the treatment of septic shock, few studies have demonstrated the efficacy of PMX in studies with a uniform case definition and without any other blood purification techniques., Materials and Methods: Fifty-two patients with severe sepsis or septic shock secondary to colorectal perforation were treated with PMX. Hemodynamic alterations and plasma concentrations of endotoxin, interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-8, and IL-10 were evaluated following PMX treatment., Results: We observed a significant reduction in plasma endotoxin in the nonsurvivors immediately after PMX treatment compared to before treatment. Systolic blood pressure was markedly increased and circulating levels of IL-1beta, IL-1Ra, and IL-8 were significantly reduced during a 2-h interval of PMX., Conclusions: Our findings suggested that PMX treatment appears to adsorb endotoxin and also modulates circulating cytokine during a 2-h interval of direct hemoperfusion in septic patients with such condition.

Physiological techniques can be used to detect novel autoantibodies causing alteration of autonomic function after passive transfer to mice. Previously, such antibodies have been detected in patients with type I diabetes mellitus, myasthenia gravis, and Sjogren's syndrome. We now describe a patient with an idiopathic nondiabetic neuropathy with prominent autonomic symptoms, including bladder and bowel dysfunction. Physiological assays of whole colon and bladder were used to determine the presence in the patient serum of functional autoantibodies capable of mediating autonomic dysfunction. Immunoglobulin G (IgG) from this patient was able to disrupt bladder and bowel function on passive transfer to mice. This is a new pattern of autoantibody-mediated abnormality. Although the target antigen is unknown, it is likely to be a cell-surface receptor or ion channel. This case highlights the usefulness of passive transfer studies in detecting functional antibodies in patients with autonomic neuropathy.

The purpose of this study was to observe and characterize colonic and lung lesions in horses subjected to experimental distension and decompression of the small colon. Sixteen healthy adult horses were divided into 2 groups: 9 horses that were subjected to distension of the small colon by means of a latex balloon surgically implanted in the lumen and inflated to a pressure of 40 mm Hg for 4 h, and 7 horses in which the balloon was implanted but not inflated. Colonic biopsy specimens were collected before balloon implantation, at the end of the period of obstruction, and 1.5 and 12 h after decompression and were examined for hemorrhage, edema, and neutrophil infiltration; myeloperoxidase (MPO) activity and hemoglobin concentration were measured as well. At the end of the experiment, lung samples were also collected and examined for neutrophil accumulation and MPO activity. The mucosa was not affected by luminal distension; lesions were restricted to the seromuscular layer. Neutrophil accumulation and edema were observed in the samples from both groups of horses but were greater in those from the distension group, in which there was also hemorrhage, fibrin deposition, and increased MPO activity in the seromuscular layer. Similarly, there was greater accumulation of neutrophils in the lung samples from the distension group than in those from the sham-operated group, as determined by histologic evaluation and MPO assay. These findings provide new evidence of reperfusion injury and a systemic inflammatory response, followed by remote lesions, in horses with intestinal obstruction.

Objectives: To characterise mucins in cancer of the colon and compare these with controls using stringent biochemical measures to avoid endogenous proteolysis., Design: Crude mucus scrapings were collected from 12 specimens obtained by colectomy. Specimens from 3 traumatic colectomies and 1 sigmoid volvulus were used as controls, and compared with 6 specimens from colons resected for adenocarcinoma and 2 irradiated colons., Subjects: The median age of the 4 female patients was 76 years (range 49 - 82 years), and of the 8 male patients 46.5 years (range 16 - 74 years)., Results and Conclusions: The crude mucus scrapings in the 9 specimens ranged in weight from 353 mg to 7 697 mg (median 4 928 mg). The median of purified mucin in the 9 specimens was 0.72 microg/mg wet weight of scraped material. Eight samples gave non-extractable pellet material, and were treated with DTT to reduce disulphide bonds for further analysis. One of these 8 pellets was resistant to reduction and had to be digested with papain before analysis. Only 5 of these pellets had mucin. Gel filtration and SDS-PAGE (sodium dodecyl sulphate polyacrylamide gel electrophoresis) analysis revealed different populations of mucin based on size and extent of degradation. Western blotting and immunohistochemical analysis confirmed the presence of MUC2 in all samples, MUC5AC in 2 and MUC5B in 5 diseased specimens. Immunohistochemical analysis showed that there was no MUC1 in the normal specimens, MUC1 apoprotein (MUC1 core) in 2 cancer specimens and MUC1 in 1 cancer specimen. Histochemical analysis showed that normal tissue expressed neutral and acidic mucins and diseased specimens predominantly expressed acidic mucins. The electrophoretic behaviour of MUC2 in sigmoid volvulus was different from that in cancer of the colon.

Lactating rats experience a breakdown of immunity to parasites, i.e. they carry larger worm burdens after re-infection compared to their non-lactating counterparts. Feeding high-protein foods to lactating rats results in reduced worm burdens. This could be attributed to changes in gastrointestinal environment or to overcoming effects of nutrient scarcity on host immunity. The latter hypothesis was addressed through a manipulation of nutrient demand by manipulating litter size. Twenty-three rats were immunized prior to mating and re-infected on day 2 of lactation with 1600 infective Nippostrongylus brasiliensis larvae. From parturition onwards, rats received ad libitum low-protein food (100 g crude protein/kg). Litter size were standardised to nine (LS9), six (LS6) or three (LS3) pups, by day 2 of lactation. After a further 10 d, LS9 and LS6 rats carried more worms than LS3 rats. However, feeding treatment did not affect concentrations of mucosal inflammatory cells. Achieved feed intake did not differ consistently between the treatment groups. However, LS9 and LS6 rats lost weight, whilst LS3 rats gained weight during lactation. The results support the view that resistance to N. brasiliensis is sensitive to changes in nutrient demand, and the improved resistance to N. brasiliensis is likely due to effects of overcoming nutrient scarcity on host immunity.

Spirochaetes are organisms that can infect the colon of people with normal or compromised immune systems. Infected patients can present with a variety of gastrointestinal symptoms, including diarrhoea and rectal bleeding. However, some report a lack of association between specific symptoms and the presence of spirochaetes. It is therefore unclear whether the spirochaetes colonising the colon are true pathogens. Diagnosis is typically made by histological examination, with the biopsy specimen showing a band-like growth of spirochaetes adherent to the colonic luminal surface, giving an accentuated brush-border appearance. A course of metronidazole can eliminate the spirochaetes, but treatment might not lead to improvement of symptoms. Owing to the lack of a definite association between symptoms and the presence of spirochaetes, observation without specific antibiotic treatment can be pursued in most patients.

Background & Aims: Although inflammatory and immune cells are present in the gut in the absence of pathology, their presence does not result in sensitization of sensory nerves, implying the existence of a local antinociceptive influence. We hypothesized that a component of the immune system exerts an antinociceptive influence, thus enabling the gut to function in the absence of undue pain or discomfort., Methods: Visceromotor responses to colorectal distention were measured in mice with severe combined immune deficiency (SCID) and their wild-type controls., Results: SCID mice exhibited significantly lower pain thresholds. Transfer of CD4(+) T, but not B lymphocytes, normalized visceral pain in these mice. The restoration of normal visceral nociception following T-cell reconstitution in SCID mice was blocked by naloxone methiodide. Using an enzyme immunoassay and immunohistochemistry for beta-endorphin, we showed that in vitro stimulation of T lymphocytes induced the synthesis and release of beta-endorphin and that transfer of T cells into SCID mice increased the expression of beta-endorphin in the enteric nervous system., Conclusions: These findings indicate that the immune system is a critical determinant of visceral nociception and that T lymphocytes provide an important opioid-mediated antinociceptive influence in the gut.

Background: The role of the vagal nerve in the autonomic nervous system is widely well known. Recently, an additional function was revealed serving as a connector between the nervous and immune system. This connection is called the "cholinergic inflammatory pathway." Through stimulation of the acetylcholine receptors located upon the macrophages, the "unspecific" immune system can be directly influenced., Methods: The vagal nerve was completely transected directly posterior to its passage through the diaphragm. The effect of complete vagotomy was analyzed using a murine model of polymicrobial peritonitis (colon ascendens stent peritonitis, CASP). Survival and clinical course of vagotomized or sham-operated mice were analyzed in the CASP model., Results: After CASP surgery, vagotomy led to a significantly increased mortality (64.7%) in comparison to sham-vagotomized animals (34%). No difference in the bacterial load of various tissues (lung, liver, spleen, blood, lavage fluid, and kidney) from septic animals with or without vagotomy was observed. Vagotomized animals reveal elevated serum cytokine levels (TNF, IL-6, IL-10, and MCP-1) 20 h after the induction of polymicrobial peritonitis., Conclusion: The vagal nerve is therefore an important modulator of the immune system.

The major classes of enteric bacteria harbour a conserved core genomic structure, common to both commensal and pathogenic strains, that is most likely optimized to a life style involving colonization of the host intestine and transmission via the environment. In pathogenic bacteria this core genome framework is decorated with novel genetic islands that are often associated with adaptive phenotypes such as virulence. This classical genome organization is well illustrated by a group of extracellular enteric pathogens, which includes enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic E. coli (EHEC) and Citrobacter rodentium, all of which use attaching and effacing (A/E) lesion formation as a major mechanism of tissue targeting and infection. Both EHEC and EPEC are poorly pathogenic in mice but infect humans and domestic animals. In contrast, C. rodentium is a natural mouse pathogen that is related to E. coli, hence providing an excellent in vivo model for A/E lesion forming pathogens. C. rodentium also provides a model of infections that are mainly restricted to the lumen of the intestine. The mechanism's by which the immune system deals with such infections has become a topic of great interest in recent years. Here we review the literature of C. rodentium from its emergence in the mid-1960s to the most contemporary reports of colonization, pathogenesis, transmission and immunity.

B cells present BCR V region-derived Id-peptides on their MHC class II molecules to Id-specific CD4+ T cells. Prolonged Id-driven T-B collaboration could cause autoimmune disease, but this possibility is difficult to test in normal individuals. We have investigated whether mice doubly transgenic for an Id+ Ig L chain and an Id-specific TCR develop autoimmune disease. Surprisingly, T cell tolerance was not complete in these mice because a low frequency of weakly Id-reactive CD4+ T cells accumulated with age. These escapee Id-specific T cells provided chronic help for Id+ B cells, resulting in a lethal systemic autoimmune disease including germinal center reactions, hypergammaglobulinemia, IgG autoantibodies, glomerulonephritis, arthritis, skin affection, and inflammatory bowel disease. Inflamed tissues contained foci of Id-driven T-B collaboration, with deposition of IgG and complement. The disease could be transferred with B and T cells. The results demonstrate a novel mechanism for development of autoimmune disease in which self-reactive Id+ B cells receive prolonged help from Id-specific T cells, thus bypassing the need for help from T cells recognizing conventional Ag.

Immune-mediated blistering diseases are rare in childhood, with the subset of IgA pemphigus being extremely uncommon. A child with a bullous disorder of the oral mucosa, skin, and colon is reported because of the unusual nature of the clinical and laboratory findings. Immunofluorescence studies demonstrated both intercellular epidermal and basement membrane zone deposition of IgA and IgG antibodies, as well as intercellular colonic deposition of IgA antibodies. IgA and IgG ELISA tests were positive for desmoglein 3 as the intercellular epidermal antigen. The generation of multiple antibodies against several potential antigenic targets suggests epitope spreading may play a role in this disease. We believe this represents a novel variant of IgA pemphigus.

The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK (p38) has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38alpha(+/-) donor graft induced more acute GVHD-related mortality and more severe gut injury. The survival of p38alpha(+/-) donor-derived intestinal intraepithelial lymphocytes (IEL) was prolonged in vitro and in vivo, and TNF-alpha expression in the p38alpha(+/-) donor-derived IEL was also increased compared with wild-type cells. In contrast, the p38alpha(+/-) grafted mice resulted in decreased expansion of donor lymphocytes in mesenteric lymph nodes, and the up-regulation of IL-12p40 and IL-18 was diminished. These findings suggest that p38 has dichotomous effects for inflammatory response in vivo; not only regulates inflammatory cytokine expression and lymphocyte expansion, but also has distinct regulatory functions for IEL in intestinal GVHD. In conclusion, the inhibition of p38 may not be a suitable anti-inflammatory strategy for GVHD due to the associated intestinal injury.

Background & Aims: The treatment of irritable bowel syndrome (IBS), characterized by abdominal pain and bloating, is empirical and often poorly efficient. Research lacks suitable models for studying the pathophysiologic mechanisms of the colonic hypersensitivity and new pharmacologic targets. The present study aimed to develop a novel model of colonic hypersensitivity possessing several of the characteristics encountered in patients with IBS., Methods: Rats received enemas of a butyrate solution (8-1000 mmol/L) twice daily for 3 days. A time course was determined for colonic hypersensitivity (colorectal distention test) and referred cutaneous lumbar hyperalgesia (von Frey hairs). Macroscopic and histologic analyses were performed on colonic mucosa. The efficacy of morphine, U50488H (a kappa opioid agonist), and trimebutine on the 2 pain parameters was determined. Finally, the involvement of peptidergic C-fibers was evaluated using capsaicin-pretreated animals and treatments with calcitonin gene-related peptide (CGRP) and neurokinin 1 receptor antagonists., Results: Butyrate enemas induced a sustained, concentration-dependent colonic hypersensitivity and, to a lesser extent, a referred cutaneous mechanical hyperalgesia, particularly in female rats, but no macroscopic and histologic modifications of the colonic mucosa, as observed in patients with IBS. Both pain parameters were sensitive to morphine, U50488H, trimebutine, neonatal capsaicin treatment, and the CGRP receptor antagonist but not to the neurokinin 1 receptor antagonist., Conclusions: These results present our noninflammatory model of chronic colonic hypersensitivity as a useful novel tool for studying IBS. The CGRP receptor antagonist-induced reduction of colonic hypersensitivity suggests that CGRP receptors may provide a promising target for treatment of IBS.

Fungal infections occur in patients who are severely immunocompromised with profound and prolonged neutropenia. We report a patient of acute lymphoblastic leukemia who developed nonspecific abdominal symptoms within two days after the onset of neutropenia in the early induction phase of chemotherapy, which was later found to be due to intestinal mucormycosis and resulted in a fatal outcome.

Symptoms of secondary immune deficiency were revealed in 37 out of 84 wounded with colonic fistulas and colostomas. During the preparation of the patients to restorative operations for the improvement of the immune system functions the patients were given transfusions of donor leuko-suspension taken from subjects with high titer of antibody in blood serum to colon bacillus and intravenous infusions of immunoglobulin. Such immunocorrection allowed restoration of immune potential of organism during a short time and improvement of the operation results.

Campylobacter jejuni is a common cause of serious food-borne illness. In an experimental model of human infection, germfree pigs were given C. jejuni, the whipworm Trichuris suis, dual infections with C. jejuni and T. suis, or no infection. In dual-infected pigs, a synergistic effect between C. jejuni and T. suis was observed 27 days after infection, when T. suis fourth-stage larvae were found in the proximal colon. In dual-infected pigs, lymphoglandular complexes (LGCs) in the distal colon were substantially enlarged, and C. jejuni was detected in cells of the follicle-associated epithelium (FAE) and in cells with macrophage morphology within these follicles. In the study reported here, cell types in colonic tissues from these pigs were analyzed by use of immunohistochemical and morphometric analyses for cell surface markers (IgM, IgG, IgA, CD4, CD8, MHC Class II, and macrophage SWC3a). To our knowledge, we provide the first description of cell types in mammalian LGCs, document that they have all elements necessary for antigen processing, and demonstrate the appearance of IgA germinal centers (GC) in LGCs from C. jejuni-infected pigs (single or dual infected). Ileocecal Peyer's patches (ICPP) and mesenteric lymph nodes (MLN) also had IgA GC development if C. jejuni was present, but LGCs had the greatest amount of anti-C. jejuni staining, and appreciable increase in overall follicle size and size and number of GCs committed to IgA production. LGCs are present in humans and other mammals and are important in other enteric infections.

Adults and children have differences in their susceptibility to schistosomiasis. Whether this age-dependent innate susceptibility influences parasite-caused granulomogenesis is difficult to assess in humans. Therefore, we exposed juvenile and adult female rhesus monkeys to primary infection with Schistosoma mansoni. Hepatic and intestinal granuloma formation was observed in both pre-pubescent and adult monkeys. Two distinct stages of granulomas were discerned, the exudative and the productive stage. In the intestine, more granulomas were generated in the colon than in the ileum. In contrast to the adult animals, the juvenile rhesus monkeys had higher numbers of colonic granulomas, these higher numbers being predominantly of the more advanced productive stage. Juvenile animals had a statistically non-significant increased worm burden. These results suggest that juvenile rhesus monkeys have a significantly more intense and advanced colonic response towards entrapped S. mansoni eggs after primary schistosome infections and, thereby, are more susceptible to parasite infection.

Aim: To study the effect of angelica sinensis polysaccharide (ASP) on immunological colon injury and its mechanisms in rats., Methods: Immunological colitis model of rats was induced by intracolon enema with 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) and ethanol. The experimental animals were randomly divided into normal control, model control, 5-aminosalicylic acid therapy groups and three doses of ASP therapy groups. The 6 groups were treated intracolonically with normal saline, normal saline, 5-aminosalicylic acid (100 mg.kg(-1)), and ASP daily (8:00 am) at the doses of 200, 400 and 800 mg.kg(-1) respectively for 21 days 7 d following induction of colitis. The rat colon mucosa damage index (CMDI), the histopathological score (HS), the score of occult blood test (OBT), and the colonic MPO activity were evaluated. The levels of SOD, MDA, NO, TNF-alpha, IL-2 and IL-10 in colonic tissues were detected biochemically and immunoradiometrically. The expressions of TGF-beta and EGF in colonic tissues were also determined immunochemically., Results: Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in colitis rats, which manifested as significant increases of CMDI, HS, OBT, MPO activity, MDA and NO contents, as well as the levels of TNF-alpha and IL-2 in colonic tissues, although colonic TGF-beta protein expression, SOD activity and IL-10 content were significantly decreased compared with the normal control (P<0.01). However, these parameters were found to be significantly ameliorated in colitis rats treated intracolonically with ASP at the doses of 400 and 800 mg.kg(-1) (P<0.05-0.01). Meantime, colonic EGF protein expression in colitis rats was remarkably up-regulated., Conclusion: ASP has a protective effect on immunological colon injury induced by TNBS and ethanol enema in rats, which was probably due to the mechanism of antioxidation, immunomodulation and promotion of wound repair.

We present the case of a young male patient admitted for weight loss, diarrhea and rectal bleeding. The patient belonged to a low social class and had associated hypogammaglobulinemia. The endoscopy revealed different localized ulcerations of he rectum and a stenosis. By barium enema and hydrosonography multiple stenotic lesions were observed. The pathological examinations detected lesions suggestive for intestinal tuberculosis. A specific therapy led to the improvement of his general state and to the disappearance of diarrhea and rectal bleeding.

Actinomycosis is caused by gram-positive filamentous organisms of the genus Actinomyces, which may spread through trauma. Most commonly, it is a cervicofacial disease due to dental infection or a thoracic disease secondary to aspiration of foreign bodies. Primary abdominal infection usually follows some form of mucosal disruption. Any organ of the human body may be involved so that a wide range of symptoms may be present. We report a rare form of actinomycosis involving the lung, pleura and colon concomitantly in an immunocompromised patient. A fine needle aspiration from a lung lesion detected the characteristic sulfur granules, and a pleural effusion culture confirmed the diagnosis. Clinical manifestations and treatment are discussed. Actinomycetes are rarely opportunistic agents in immunocompromised patients; thus the disease deserves special attention in those patients., (Copyright 2003 S. Karger AG, Basel)

Inhibition of TNF/TNFR2 interactions ameliorates intestinal graft-vs-host disease (GVHD) and Th1 cytokine responses induced by transfer of B6 CD4(+) spleen cells into irradiated MHC class II disparate B6.C-H-2(bm12) (bm12) x B6 F(1) recipients. The present studies examined whether these effects of TNF are IL-12 dependent. T cell proliferative responses of B6.129S1-IL-12rb2(tm1Jm) (B6.IL-12R(-/-)) responder spleen cells were found to be comparable to those of control B6 spleen cells. TNF inhibition reduced T cell proliferation and IFN-gamma production in supernatants of MLC using either B6.IL-12R(-/-) or control B6 responder cells. GVHD induced wasting disease in recipients of B6.IL-12R(-/-) CD4(+) spleen cells that received a TNF inhibitor-encoding adenovirus (5.4 +/- 6.5% weight loss (n = 7)) was significantly reduced compared with levels of weight loss observed in recipients that had received a control adenovirus (25.7 +/- 12.2% weight loss (n = 11), p = 0.001). Furthermore, TNF inhibition was associated with a reduction in colonic GVHD scores (p = 0.039) and in the percentage of the splenic CD4(+) T cells that expressed IFN-gamma (16 vs 6%). These findings indicate that TNF promotes CD4(+) T cell alloproliferation, IFN-gamma responses, and intestinal GVHD by IL-12-independent mechanisms.

Campylobacter jejuni, a leading cause of bacterial gastroenteritis, has different age distribution and disease expression in developing and developed countries, which may be due to the endemnicity of infection and the age of acquisition of immunity. Differences in disease expression are not solely dependent on the C jejuni strain or virulence attributes. Another modulating factor in developing countries may be endemic nematode infections such as Trichuris, which drive type 2 cytokine responses and down-regulate type 1 immune responses. In this study, three-day-old germ-free pigs given dual infections with Trichuris suis and C jejuni had more frequent, more severe diarrhea and severe pathology than pigs given no pathogens, only T. suis, or only C jejuni. These pigs had significant hemorrhage and inflammatory cell infiltrates in the proximal colon where adult worms were found, and abscessed lymphoglandular complexes in the distal colon with intracellular C jejuni. Pigs given only C jejuni had mild clinical signs and pathology, and bacteria in feces or extracellular sites. Pigs given T. suis or no pathogens had no disease and minimal pathology. Thus, these agents synergized to produce significant disease and pathology, which was site specific.

Gastrointestinal tract involvement in Langerhans'cell histiocytosis (LCH) is unusual. It is most often observed in children, is usually asymptomatic, diagnosed at post mortem examination and associated with a disseminated disease. We report 2 cases of LCH large bowel involvement occuring in a 50-year- old man and in a 71-year-old woman, who presented with digestive symptoms. Histiocytic proliferation with reniform nuclei was demonstrated in colonic biopsies it was located in the lamina propria, and dissociating the mucosa glands. Immunohistochemical study revealed a strong positivity of these cells with anti-CD1a and anti-PS100 antibodies. Ultrastructural study performed in one case showed large cells with reniform and indented nuclei, numerous tubuloreticular structures and Birbeck granules. Digestive localization of LCH is exceptional in adult, and may be underestimated.

Mice infected with Citrobacter rodentium represent an excellent model in which to examine immune defenses against an attaching-effacing enteric bacterial pathogen. Colonic tissue from mice infected with C. rodentium harbors increased transcripts for IL-12 and IFN-gamma and displays mucosal pathology compared with uninfected controls. In this study, the role of IL-12 and IFN-gamma in host defense and mucosal injury during C. rodentium infection was examined using gene knockout mice. IL-12p40(-/-) and IFN-gamma(-/-) mice were significantly more susceptible to mucosal and gut-derived systemic C. rodentium infection. In particular, a proportion of IL-12p40(-/-) mice died during infection. Analysis of the gut mucosa of IL-12p40(-/-) mice revealed an influx of CD4(+) T cells and a local IFN-gamma response. Infected IL-12p40(-/-) and IFN-gamma(-/-) mice also mounted anti-Citrobacter serum and gut-associated IgA responses and strongly expressed inducible NO synthase (iNOS) in mucosal tissue, despite diminished serum nitrite/nitrate levels. However, iNOS does not detectably contribute to host defense against C. rodentium, as iNOS(-/-) mice were not more susceptible to infection. However, C57BL/6 mice infected with C. rodentium up-regulated expression of the mouse beta-defensin (mBD)-1 and mBD-3 in colonic tissue. In contrast, expression of mBD-3, but not mBD-1, was significantly attenuated during infection of IL-12- and IFN-gamma-deficient mice, suggesting mBD-3 may contribute to host defense. These studies are among the first to examine mechanisms of host resistance to an attaching-effacing pathogen and show an important role for IL-12 and IFN-gamma in limiting bacterial infection of the colonic epithelium.

A T helper cell type 1-mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RB(high) CD4(+) T cells and can be prevented by cotransfer of the CD45RB(low) subset. The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population. This population isolated from IL-10-deficient (IL-10(-/-)) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti-murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RB(low) CD4(+) cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RB(high) CD4(+) cells, as CD45RB(low) CD4(+) cells from WT mice were able to inhibit colitis induced by IL-10(-/-) CD45RB(high) CD4(+) cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.