Ulcerative Colitis: Manns MP

Bischoff SC, Mayer JH, Manns MP. · Department of Gastroenterology and Hepatology, Medical School of Hannover, Hannover, Germany. · Int Arch Allergy Immunol. · Pubmed #10828717 No free full text.

Abstract: There have frequently been doubts as to the relevance of food allergy, in particular as far as the involvement of the intestinal tract is concerned. Several studies, however, have confirmed the existence of allergic reactions in the gut, with an estimated prevalence of about 1-2% in adults. Clinical symptoms are unspecific and include nausea, vomiting, abdominal pain, cramping and diarrhea. Intestinal mast cells, as well as intestinal eosinophils, have been shown to be involved in the pathogenesis of food-allergy-related enteropathy. In addition to classical IgE-dependent degranulation, further agonists have been demonstrated for mast cell activation, for example IL-4. The methods used to confirm the diagnosis of intestinal allergy are still insufficient. Until now, blinded oral challenge procedures with food antigens have been accepted as the 'gold standard' in diagnosing food allergy, although these tests have practical problems. Therefore, new test systems have been developed, such as endoscopic provocation tests, that may improve diagnostic procedures. Elimination diet still presents the main basis of therapy. Aspects to be focused on in the future are the role fo IgE-independent allergic mechanisms in intestinal allergy, the impact of cross-reactivity with other allergens and the relationship to other inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, celiac disease and irritable bowel syndrome.

Haile LA, von Wasielewski R, Gamrekelashvili J, Krüger C, Bachmann O, Westendorf AM, Buer J, Liblau R, Manns MP, Korangy F, Greten TF. · Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany. · Gastroenterology. · Pubmed #18674538 No free full text.

Abstract: BACKGROUND & AIMS: CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) have been shown to cause T-cell tolerance in tumor-bearing mice; however, little is known about the role of MDSCs in chronic inflammation. Here, for the first time, we have identified and analyzed their role in inflammatory bowel disease (IBD). METHODS: Repetitive adoptive transfer of clone 4/T-cell receptor (CL4-TCR) transgenic CD8(+) T cells into VILLIN-hemagglutinin (HA) transgenic mice was performed on days 1, 12, and 27. Recipient mice were analyzed for immunopathology, HA-specific CD8(+) T-cell responses, and CD11b(+)Gr-1(+) MDSCs (frequency, phenotype, expression analysis, and in vitro as well as in vivo function). In addition, peripheral blood from patients with active Crohn's disease and ulcerative colitis was examined for the presence and function of human MDSCs denoted as CD14(+)HLA-DR(-/low) cells. RESULTS: Repetitive transfer of HA-specific CD8(+) T cells prevented VILLIN-HA recipient mice from development of severe enterocolitis, which is seen after a single transfer of T cells. Repeated transfer of antigen-specific T cells led to an increase in the frequency of nitric oxide synthase 2 and arginase-expressing CD11b(+)Gr-1(+) MDSCs in spleen and intestine of VILLIN-HA mice with immunosuppressive function. Cotransfer of MDSCs with HA-specific CD8(+) T cells into naive VILLIN-HA mice ameliorated enterocolitis, indicating a direct immune regulatory effect of MDSCs on induction of IBD by antigen-specific T cells. Finally, an increase in the frequency of human MDSCs with suppressor function was observed in peripheral blood from patients with IBD. CONCLUSIONS: These results identify MDSCs as a new immune regulatory pathway in IBD.

Hafer A, Krämer S, Duncker S, Krüger M, Manns MP, Bischoff SC. · Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. · BMC Gastroenterol. · Pubmed #17784949 links to  free full text

Abstract: BACKGROUND: The prebiotic potential of lactulose is well established and preclinical studies demonstrated a protective effect of lactulose in murine models of colitis. The aim of the present study was to investigate the clinical and histological efficacy of lactulose in patients with inflammatory bowel disease (IBD), for which probiotic therapy yielded promising results. METHODS: Patients were treated with standard medication alone or combined with 10 g lactulose daily as adjuvant therapy for 4 months. Clinical efficacy of treatment was assessed using clinical activity indices, a quality of life index (IBDQ), endoscopic scores, defecation frequency and monitoring corticosteroid medication. Orsomucoid, alpha1-antitrypsin and other laboratory parameters were determined. In addition, in some participants colonic biopsies were analyzed with haematoxylin-eosin staining or with antibodies against HLA-DR, CD68, IgA and CD3, and evaluated systematically. All measurements were performed both at enrollment and at the end of the trial. RESULTS: 14 patients presenting ulcerative colitis (UC) and 17 patients presenting Crohn's disease (CD), most of them in a clinically active state, were enrolled in this pilot study. After 4 month no significant improvement of clinical activity index, endoscopic score or immunohistochemical parameters was observed in CD or UC patients receiving lactulose in comparison to the control group. However, significant improvement of quality of life was observed in UC patients receiving lactulose compared to the control group (p = 0.04). CONCLUSION: The findings of the present pilot study indicate that oral lactulose has no beneficial effects in IBD patients in particular with regard to clinical activity, endoscopic score or immunohistochemical parameters. The importance of the beneficial effect of lactulose in UC patients regarding the quality of life needs further evaluation in larger controlled clinical trials.

Ockenga J, Borchert K, Stüber E, Lochs H, Manns MP, Bischoff SC. · Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Germany. · Eur J Clin Nutr. · Pubmed #16077744 No free full text.

Abstract: BACKGROUND: Studies in animal models of inflammatory bowel disease (IBD) suggest that supplementation of total parenteral nutrition with glutamine (gln), a conditionally essential amino acid in catabolic conditions, increases gln plasma concentrations, reduces intestinal damage, improves nitrogen balance and may improve the course of the disease. However, human data supporting this assumption are missing. METHODS: A total of 24 consecutive patients with an acute exacerbation of IBD (19 Crohn's disease; five ulcerative colitis) and scheduled for total parenteral nutrition (TPN) (>7 days) were randomised. Parallel to a standardised anti-inflammatory therapy, the patients received either a TPN with 1.5 g/kg body weight of a standard amino acid or an isonitrogenic, isocaloric TPN with 1.2 g/kg body weight of a standard amino acid and 0.3 g/kg L-alanine-L-glutamine. Primary end points were gln plasma concentrations and intestinal permeability assessed by urinary lactulose and D-xylose ratio. RESULTS: Gln plasma levels did not differ significantly in either group throughout the study. Intestinal permeability did not change within 7 days either with or without gln supplementation (Delta-lactulose/xylose ratio: 0.01+/-0.05 (gln+) vs 0.02+/-0.1 (gln-)). The observed changes in inflammatory and nutritional parameters, and also disease activity, length of TPN and hospital stay, were independent of glutamine substitution. Five (41%) patients in the gln+ group and three (25%) patients in the gln- group needed surgical intervention. CONCLUSION: Although limited by the sample size, these results do not support the hypothesis that glutamine substitution has an obvious biochemical or clinical benefit in patients with active IBD scheduled for total parenteral nutrition.

Streetz KL, Buhr T, Wedemeyer H, Bleck J, Schedel I, Manns MP, Göke MN. · Dept. of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany. · Scand J Gastroenterol. · Pubmed #12608474 No free full text.

Abstract: A symptomatic cytomegalovirus (CMV) infection usually occurs in patients with debilitating diseases, immunosuppression, transplantations and acquired immunodeficiency syndrome (AIDS). Gastrointestinal infections with CMV, especially colitis, are usually found in immunocompromised patients and rarely affect immunocompetent subjects. Here we report the case of a young female patient with a history of ulcerative colitis (UC) who presented with an acute attack of colitis caused by CMV infection. This was documented by the presence of CMV early antigen, antibodies and evidence of CMV in the colonic mucosa. After combined anti-inflammatory and antiviral treatment the patient recovered completely. As most attention is given to CMV-pathogeneity in immunocompromised patients, here we discuss the relationship to inflammatory bowel diseases.

Bischoff SC, Mayer J, Nguyen QT, Stolte M, Manns MP. · Department of Gastroenterology and Hepatology, Medical School of Hannover, Germany. · Am J Gastroenterol. · Pubmed #10606314 No free full text.

Abstract: OBJECTIVE: To assess the activation grade of intestinal eosinophils in patients with eosinophilic gastroenteritis (EOG), ulcerative colitis (UC), Crohn's disease (CD), and controls by immunohistochemistry. METHODS: Cecal biopsies were collected from healthy controls and from patients with EOG, CD, UC, and other noninflammatory GI diseases. Immunohistochemistry was performed in sequential sections stained with monoclonal antibodies directed against eosinophil cationic protein (ECP) or eosinophil protein X (EPX) stored in eosinophil granules (EG1) and that secreted by activated eosinophils (EG2). The ratio of EG1 to EG2-positive eosinophils expressed as percentage of lamina propria cells was calculated. ECP and EPX were measured in serum and feces. RESULTS: The percentage of EG1 and EG2-positive lamina propria cells was elevated in EOG and slightly, but not significantly, in UC. The ratio of EG1 to EG2-positive cells was decreased in CD, UC, and other patients as compared to healthy controls. Particularly low EG1 to EG2 ratios were found in EOG. Correspondingly, fecal and serum levels of ECP and EPX, respectively, were highest in patients with EOG. The EG1 to EG2 ratio was negatively correlated with fecal ECP and EPX levels. At sites of actively inflamed mucosa, the EG1 to EG2 ratio was lower than in noninflamed tissue. CONCLUSIONS: Our data strongly suggest that the EG1 to EG2 ratio may be a marker of tissue eosinophil activation. Low ratios (<1) indicate eosinophil activation, whereas ratios > or =1 are found in healthy controls. Furthermore, we show that EOG is characterized by a pronounced intestinal eosinophil accumulation and activation, whereas in CD and UC, eosinophils seem to be activated but their number is not or only slightly elevated compared to controls.

Lorentz A, Schwengberg S, Mierke C, Manns MP, Bischoff SC. · Department of Gastroenterology and Hepatology, Medical School of Hannover, Germany. · Eur J Immunol. · Pubmed #10359103 No free full text.

Abstract: IL-5, known to be produced by T lymphocytes and eosinophils, is a key regulator of intestinal diseases such as parasitosis or eosinophilic gastroenteritis. Here we examined if mast cells contribute to the IL-5 production in human intestinal mucosa. The number of IL-5-positive lamina propria cells was substantially higher in patients with intestinal inflammatory diseases (5.3 +/- 4.6%, n = 17) compared to healthy controls (0.5 +/- 0.9%, n = 8, p < 0.01). In patients, the IL-5-positive cells were eosinophils (70 +/- 13%) and mast cells (29 +/- 14%), whereas in controls all IL-5-positive cells were eosinophils. IL-5-positive T cells were not detected, likely because they do not store IL-5. In vitro studies with isolated human intestinal mast cells and eosinophils showed that mast cells do not produce IL-5 constitutively, but release high amounts of IL-5 (315 +/- 115 pg/10(6) cells) following IgE receptor cross-linking, compared to activated eosinophils (24 +/- 5 pg/10(6) cells). Inhibitor studies suggest a regulation of IL-5 production at the transcriptional level. In conclusion our data demonstrate that activated mast cells are a potent source of IL-5 in the human intestinal mucosa.

Bischoff SC, Lorentz A, Schwengberg S, Weier G, Raab R, Manns MP. · Department of Gastroenterology and Hepatology, Medical School of Hannover, D-30623 Hannover, Germany. · Gut. · Pubmed #10205200 links to  free full text

Abstract: BACKGROUND: Several inflammatory disorders of the intestine are characterised by enhanced expression of tumour necrosis factor alpha (TNF-alpha). Monocytes and macrophages have been suggested as a major cellular source of TNF-alpha in human gut, whereas mast cells, although known to be capable of producing TNF-alpha, have been poorly examined in this respect. AIMS: To investigate whether human intestinal mast cells can produce TNF-alpha, and which factors regulate TNF-alpha production in these cells. METHODS: Mast cells were isolated from surgery tissue specimens of patients undergoing bowel resection because of cancer. Immunohistochemical studies were performed in biopsy specimens derived from 13 patients (two healthy controls, four with Crohn's disease, four with ulcerative colitis, three others). TNF-alpha mRNA and protein expression were studied in vitro by polymerase chain reaction, RNAse protection assay, western blot, and enzyme linked immunosorbent assay in isolated purified human intestinal mast cells stimulated by IgE receptor crosslinking, intestinal bacteria, and lipopolysaccharide. Cellular localisation of TNF-alpha was examined by immunohistochemistry. RESULTS: TNF-alpha mRNA and protein were expressed constitutively in isolated human intestinal mast cells. Expression of TNF-alpha mRNA and release of TNF-alpha protein were substantially enhanced by IgE receptor crosslinking and by coculture of mast cells with intestinal bacteria; lipopolysaccharide had only marginal effects. Immunohistochemical studies revealed that approximately 60% of the lamina propria cells with immunoreactivity for TNF-alpha were mast cells. CONCLUSIONS: The data show that mast cells are an important source of TNF-alpha in the human intestinal mucosa.