Crohn Disease: Zeitz M

Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Häuser W, Herrlinger K, Höhne W, Koletzko S, Krieglstein CF, Kruis W, Matthes H, Moser G, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Sido B, Siegmund B, Stallmach A, Bokemeyer B, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus, Ludwigshafen. · Z Gastroenterol. · Pubmed #18810679 No free full text.

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Hoffmann J, Zeitz M, Anonymous00107. · Klinik für Gastroenterologie, Universitätsklinikum Benjamin Franklin, Berlin. · Z Gastroenterol. · Pubmed #12541171 No free full text.

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Schreiber S, Campieri M, Colombel JF, van Deventer SJ, Feagan B, Fedorak R, Forbes A, Gassull M, Gendre JP, van Hogezand RA, Lofberg R, Modigliani R, Pallone F, Petritsch W, Prantera C, Rampton D, Seibold F, Vatn M, Zeitz M, Rutgeerts P, Anonymous00293. · Department of Medicine I, University Hospital Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany. · Int J Colorectal Dis. · Pubmed #11317691 No free full text.

Abstract: The introduction of novel anti-tumor necrosis factor (TNF) agents has not only led to impressive new therapeutic opportunities but also resulted in uncertainty regarding their optimal use and possible side effects. Guidelines are presented here for the use of anti-TNF agents in gastrointestinal disorders. Experts were chosen from different European countries by an algorithm to avoid bias. An expert consensus on guidelines was established using a two-stage procedure of systematic Medline and abstract search for evidence and a qualifying meeting to derive recommendations. Detailed guidelines were developed for the use and the future clinical development of anti-TNF agents in inflammatory bowel disease. Grading of available evidence and grading of recommendations were performed according to AHCPR guidelines. At present infliximab is the only registered agent for Crohn's disease. Infliximab should be always used at a dose of 5 mg/kg. The guidelines define the indications both in refractory and in fistulating disease for the readministration and before surgery. Guidelines for safety and for concomitant treatments are given. Prospects, potential clinical use, and future directions for the clinical development of other anti-TNF agents are detailed. Clinical use of anti-TNF agents will be influenced by a large number of clinical trials being concluded in 2001 and 2002. It is likely that anti-TNF therapies will become an important long-term therapy for a proportion of patients with Crohn's disease. Biological agents will be followed by smaller and more stable, orally available compounds. These guidelines will be succeeded by a formal public consensus in 2002/2003.

Hoffmann JC, Autschbach F, Bokemeyer B, Buhr HJ, Herrlinger K, Höhne W, Krieglstein C, Kruis W, Moser G, Preiss JC, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Siegmund B, Stallmach A, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus Ludwigshafen. · Dtsch Med Wochenschr. · Pubmed #18788069 No free full text.

This publication has no abstract.

Siegmund B, Zeitz M. · Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. · Langenbecks Arch Surg. · Pubmed #15449064 No free full text.

Abstract: Crohn's disease is a condition of chronic inflammation potentially involving any location of the alimentary tract from mouth to anus but with a propensity for the distal small bowel and proximal large bowel. Frequent complications include stricture and fistula. Numerous extra-intestinal manifestations may also be present. The aetiology of Crohn's disease is incompletely understood, and therapy, although generally effective in alleviating the symptoms, is not curative. Due to the heterogeneity of the disease a major need for the therapeutic approach is the ability to define subgroups with distinct characteristics. However, with regard to the heterogeneity of demographic, anatomic and disease behaviour characteristics, distillation of the numerous possible phenotypes in simple categories is a formidable task. In the present review the focus will be on clinically relevant situations providing therapeutic algorithms according to international guidelines.

Wittig BM, Stallmach A, Zeitz M, Günthert U. · Medical Clinic I, Benjamin Franklin University Hospital, Free University of Berlin, Berlin, Germany. · Pathobiology. · Pubmed #12571424 No free full text.

Abstract: A major problem in inflammatory bowel disease (IBD) is the accumulation of highly activated T-helper cells that are refractory to apoptosis induction. Hence, persistent inflammatory lesions are prevalent and are the basis of chronic disease. In IBD upregulation of costimulatory molecules on lamina propria lymphocytes has been described leading to apoptosis resistance. CD44 is a cell adhesion molecule and a signalling receptor that functions as a costimulatory molecule in T-cell activation. Several variant isoforms of CD44 (CD44v) are expressed by alternative splicing of variant exons encoding extracellular regions. Particularly isoforms containing CD44v7 are expressed on T cells and macrophages in T-helper-1 (Th1)-mediated chronic inflammation and autoimmune diseases. In this review recent data on the functional involvement of CD44v7 isoforms in IBD are discussed. In a mouse model of experimental colitis blockade or deletion of CD44v7 protects mice from severe intestinal inflammation by inducing apoptosis in lamina propria mononuclear cells. Recently, we observed that in lamina propria mononuclear cells from the inflamed but not uninflamed mucosa of patients with Crohn's disease, blockade of CD44v7 isoforms also induces apoptosis. The finding that obstruction of CD44v7 isoforms can antagonize Th1-cytokine-dependent immune pathology identifies CD44v7 as a target in the treatment of inflammatory diseases such as IBD, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases in which CD44v7 isoforms are upregulated.

Stange EF, Schreiber S, Fölsch UR, von Herbay A, Schölmerich J, Hoffmann J, Zeitz M, Fleig WE, Buhr HJ, Kroesen AJ, Moser G, Matthes H, Adler G, Reinshagen M, Stein J, Anonymous00103. · Abteilung Innere Medizin 1, Robert-Bosch-Krankenhaus, Stuttgart. · Z Gastroenterol. · Pubmed #12541167 No free full text.

This publication has no abstract.

Hoffmann JC, Zeitz M. · Medizinische Klinik I, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin. · Internist (Berl). · Pubmed #12524918 No free full text.

This publication has no abstract.

Wittig BM, Zeitz M. · Medizinische Klinik I (Gastroenterologie, Infektiologie, Rheumatologie), Universitätsklinikum Benjamin Franklin, Freie Universität Berlin. · Dtsch Med Wochenschr. · Pubmed #11450615 No free full text.

This publication has no abstract.

Wittig BM, Duchmann R, Stallmach A, Zeitz M. · Innere Medizin II, Universitätskliniken des Saarlandes, 66421 Homburg/Saar. · Internist (Berl). · Pubmed #11271620 No free full text.

This publication has no abstract.

Hoffmann JC, Zeitz M. · Innere Medizin II, Universitätskliniken des Saarlandes, Homburg, Germany. · Hepatogastroenterology. · Pubmed #10690589 No free full text.

Abstract: The treatment of Crohn's disease depends on disease location and disease activity. It can be divided into medical and surgical treatment. While surgery is reserved for complications such as abscesses or failure of pharmacological treatment (fistulae, perianal disease, or strictures) medical treatment aims at induction and maintenance of remission. In order to achieve these goals supportive and therapeutic strategies must be used. Supportive measures include substitution of vitamins, particularly fat-soluble vitamins, and minerals in deficiencies due to resection or disease involvement of the small bowel. All patients on long-term steroids should receive calcium and vitamin D in order to prevent osteoporosis. Therapeutic options include drug treatment (corticosteroids, antibiotics, salicylates, and immunosuppressives), nutrition (parenteral or enteral), and endoscopy (dilatation of strictures). Depending on disease location different pharmacologic preparations of salicylates or corticosteroids should be used, e.g., enemas for distal colitis. The most potent drugs for long-term control are immunosuppressive agents, particularly azathioprine. It is the most widely investigated immunosuppressive agent in Crohn's disease and should be the first line treatment for patients with steroid refractory, chronic steroid dependent, fistulating, and stenosing courses. In the future, more potent drugs and better risk stratification criteria should improve the treatment of Crohn's disease.

Lochs H, Adler G, Beglinger C, Duchmann R, Emmrich J, Ewe K, Gangl A, Gasché C, Hahn E, Hoffmann P, Kaskas B, Malchow H, Pohl C, Raedler A, Renner E, Schölmerich J, Schreiber S, Stange E, Tilg H, Vogelsang H, Weigert N, Zeitz M. · Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie, Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin. · Z Gastroenterol. · Pubmed #10427657 No free full text.

Abstract: The chimeric anti-TNF antibody Remicade (Infliximab) has recently been approved for human use by the FDA and is now available on the market. Since there is considerable interest in this kind of treatment among patients with Crohn's disease, an international working group has summarized the presently available information about efficacy, side effects and possible problems of this treatment. Studies show that Remicade is effective in the treatment of active Crohn's disease, maintaining remission and fistulae. The working group does not see Infliximab as a first-line treatment for Crohn's disease. It may be used in active phase recurrent disease, chronic active disease and fistulae if standard treatment was not successful. For the surveillance special attention has to be given to the unknown malignancy rate of Infliximab. Infusion should be performed in an institution, routinely performing intravenous infusions and a two-hour surveillance of the patients should be guaranteed to recognize anaphylactic reactions or acute side effects. There is presently no information indication that the combination with immunosuppressants might increase risks or side effects of this treatment. Due to the limited information available the working group would prefer to use Remicade in studies only and recommends central collection and documentation of all data on efficacy and side effects for the next year.

Schumann M, Preiss JC, Loddenkemper C, Günther U, Somasundaram R, Siegmund B, Zeitz M. · Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité Universitätsmedizin Berlin. · Dtsch Med Wochenschr. · Pubmed #18788068 No free full text.

Abstract: HISTORY: A 48-year-old patient with Crohn's disease was admitted to our hospital with fatigue, icterus, hepatosplenomegaly and ascites. INVESTIGARTIOS: The whole blood count revealed a pancytopenia, hyperbilirubinemia and slightly elevated transaminases. Examination of the liver histology showed areas of enlarged hyperplastic hepatocytes adjacent to areas of atrophic hepatocytes and dilated sinusoids. DIAGNOSIS, TREATMENT AND COURSE: Pancytopenia was most likely azathioprine-related. Analysis of the liver histology was highly suggestive of an azathioprine-related, nodular regenerative hyperplasia (NRH). After discontinuation of azathioprine the patient's condition improved substantially. CONCLUSIONS: NRH is a rare but potentially serious complication of azathioprine therapy. Other causes include various rheumatological, vascular and myeloproliferative diseases. When azathioprine is prescribed it must be borne in mind that it can cause NRH as a potential adverse effect, and liver enzymes should be measured at regular follow-up examinations.

Niesner U, Albrecht I, Janke M, Doebis C, Loddenkemper C, Lexberg MH, Eulenburg K, Kreher S, Koeck J, Baumgrass R, Bonhagen K, Kamradt T, Enghard P, Humrich JY, Rutz S, Schulze-Topphoff U, Aktas O, Bartfeld S, Radbruch H, Hegazy AN, Löhning M, Baumgart DC, Duchmann R, Rudwaleit M, Häupl T, Gitelman I, Krenn V, Gruen J, Sieper J, Zeitz M, Wiedenmann B, Zipp F, Hamann A, Janitz M, Scheffold A, Burmester GR, Chang HD, Radbruch A. · German Rheumatism Research Center Berlin, 10117 Berlin, Germany. · J Exp Med. · Pubmed #18663125 links to  free full text

Abstract: The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor kappaB (NF-kappaB)-dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-kappaB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-gamma, IL-2, and tumor necrosis factor-alpha, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

Zeissig S, Bergann T, Fromm A, Bojarski C, Heller F, Guenther U, Zeitz M, Fromm M, Schulzke JD. · Department of Gastroenterology, Infectious Diseases, and Rheumatology, Charité, Campus Benjamin Franklin, Berlin, Germany. · Gastroenterology. · Pubmed #18355814 No free full text.

Abstract: BACKGROUND & AIMS: Crohn's disease (CD) is a chronic inflammatory bowel disease. In this study, we have investigated sodium absorption via epithelial sodium channels (ENaC) in the macroscopically noninflamed colon in active CD. METHODS: Sodium transport via ENaC was investigated in Ussing chambers using biopsy specimens of sigmoid colon from controls and active CD limited to the small intestine. ENaC messenger RNA expression and subcellular localization were studied by real-time polymerase chain reaction and confocal microscopy. Effects of proinflammatory cytokines on ENaC and signaling via mitogen-activated protein kinases were investigated in rat distal colon. Therapeutic inhibition of mitogen-activated protein kinases was studied in CD biopsy specimens. RESULTS: Electrogenic sodium absorption via ENaC was strongly impaired in the macroscopically noninflamed CD colon because of reduced gamma-ENaC transcription, whereas subcellular localization of ENaC was not changed. In contrast to impaired epithelial sodium transport, epithelial barrier function was not altered in noninflamed CD colon, indicating that paracellular leak flux of ions did not contribute to decreased sodium absorption. Exposure of rat distal colon to tumor necrosis factor alpha led to reduced electrogenic sodium absorption because of impaired transcriptional gamma-ENaC induction, which resembled the changes found in CD. Tumor necrosis factor alpha effects were dependent on extracellular signal-regulated kinase 1/2 but not p38 or c-Jun-N-terminal kinase because inhibition of mitogen-activated protein kinase/extracellular regulated kinase (MEK)1/2 but not inhibition of p38 or c-Jun-N-terminal kinase prevented suppression of ENaC. Finally, therapeutic inhibition of MEK1/2 restored electrogenic sodium absorption in CD. CONCLUSIONS: In CD, macroscopically noninflamed colon contributes to diarrhea via impaired ENaC-mediated sodium absorption. Inhibition of extracellular signal-regulated kinase might serve as a potential therapeutic strategy for CD diarrhea.

Hoffmann JC, Heller F, Faiss S, von Lampe B, Kroesen AJ, Wahnschaffe U, Schulzke JD, Zeitz M, Bojarski C. · Medizinische Klinik I mit Schwerpunkt Gastroenterologie, Infektiologie, Rheumatologie, Charité, Campus Benjamin Franklin, 12200 Berlin, Germany. · Int J Colorectal Dis. · Pubmed #18338175 No free full text.

Abstract: BACKGROUND/AIMS: About half of all Crohn's disease (CD) patients undergo surgery at some point, many because of strictures. An alternative possibility is to dilate strictures endoscopically. However, little is known about prognostic factors. PATIENTS AND METHODS: Thirty-two patients with primary CD (n=2), radiogenic strictures (n=1), or postoperative strictures (27 because of CD; 2 after resection because of cancer), were planned to undergo colonoscopic dilatation of which 25 patients were dilated (10 men; 15 women; median age 48). Length of stenosis, diameter of stricture, balloon size, smoking status, ulcer in the stricture, passage postdilatation, hemoglobin level, complications, redilatation, and subsequent surgery were recorded. Only patients with at least 6 months follow up were included. RESULTS: Five out of 32 patients had no stenosis, marked inflammation, or fistulas adjacent to the stricture. One patient each had a long stricture (8 cm) or a filiform stenosis ruling out dilatation [technical success, 25/27 (92.6%)]. Among these 25 patients, 39 colonoscopies with 51 dilatations were performed. After a single dilatation, 52% were asymptomatic while 48% needed another intervention, half of them surgery. Bleeding without need for transfusion occurred in 3 out of 39 colonoscopies and one perforation required surgery. Significant prognostic factors were smoking and ulcers in the stricture (P<0.05 each). Some ulcers led to intussusception requiring surgery in spite of good dilatation results. CONCLUSION: Through the endoscope balloon stricture dilatation is a relatively safe and often effective treatment modality in ileocolonic strictures. The presence of ulcers in the stricture have a worse outcome as do smokers.

Hoffmann U, Heilmann K, Hayford C, Stallmach A, Wahnschaffe U, Zeitz M, Günthert U, Wittig BM. · Medical Clinic 1, Department for Gastroenterology, Infectiology and Rheumatology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin D 12200, Germany. · Cell Death Differ. · Pubmed #17479111 links to  free full text

Abstract: Deletion of exon CD44v7 abrogates experimental colitis by apoptosis induction in intestinal mononuclear cells. Here we show that CD44v7 expression was upregulated upon CD40 ligation in human mononuclear cells, and examined whether ligation of CD44v7 also affects activation and apoptosis in lamina propria mononuclear cells (LPMC) from Crohn's disease (CD) patients. Thirty five patients with chronic inflammatory bowel disease (IBD), fourteen controls and four patients with diverticulitis were evaluated. CD44v7 was upregulated predominantly in the inflamed mucosa of CD patients. Furthermore, incubation with an anti-CD44v7 antibody induced apoptosis in LPMC isolated from inflamed mucosa of CD patients, but not from non-inflamed mucosa, from patients with ulcerative colitis (UC) or from normal controls. CD40 ligation and simultaneous incubation with anti-CD44v7 significantly downregulated CD80 in dendritic cells, thus inhibiting a critical second signal for naive T-cell activation. The apoptotic signal was mediated via the intrinsic mitochondrial pathway with decreased Bcl-2 and increased 7A6 (a mitochondrial membrane protein) expression. It was Fas independent and required caspases-3 and -9 activation. The process is highly specific for macrophage activation via CD40. These findings point to a novel mechanism of apoptosis induction in CD patients mediated by CD44v7 ligation.

Deter HC, Keller W, von Wietersheim J, Jantschek G, Duchmann R, Zeitz M, Anonymous00044. · Department of Psychosomatics and Psychotherapy, Charité Campus Benjamin Franklin, Berlin, Germany. · Inflamm Bowel Dis. · Pubmed #17230495 links to  free full text

Abstract: BACKGROUND: Few published studies examine the influence of psychological treatment on health care utilization in Crohn's disease. METHODS: The present substudy of a prospective, randomized, multicenter trial conducted in 69 of 488 consecutive Crohn's disease (CD) patients was designed to investigate the way in which healthcare utilization is influenced by psychotherapy and relaxation in addition to standardized glucocorticoid therapy. Before and after a 1-year period of standardized somatic treatment the psychotherapy and control groups were compared with regard to hospital and sick-leave days. Predictors of healthcare utilization were analyzed. RESULTS: The comparison between groups before and after psychological treatment showed a significantly higher decrease of mean hospital days (P < 0.03) and sick-leave days in the treatment group compared with the controls. When a covariate analysis was applied to compare the data at randomization, the difference in hospital days remained statistically a trend (P < 0.1). Multivariate regression analysis detected a significant gender and depression effect for hospital days (cor r(2) = 0.114) and a significant gender and age effect for sick-leave days (cor r(2) = 0.112). CONCLUSION: A significant drop in healthcare utilization after psychological treatment demonstrates a clear benefit of this additional therapy. This is important, since the study failed to demonstrate significant changes in the psychosocial status or somatic course of study patients. Clinical and psychological factors influencing these outcomes are discussed.

Visekruna A, Joeris T, Seidel D, Kroesen A, Loddenkemper C, Zeitz M, Kaufmann SH, Schmidt-Ullrich R, Steinhoff U. · Max Planck Institute of Infection Biology, Berlin, Germany. · J Clin Invest. · Pubmed #17124531 links to  free full text

Abstract: Enhanced NF-kappaB activity is involved in the pathology of both forms of inflammatory bowel disease (IBD), Crohn disease (CD) and ulcerative colitis (UC). Here we analyzed the mechanism of proteasome-mediated NF-kappaB activation in CD and UC. Our studies demonstrate that the subunit composition and the proteolytic function of proteasomes differ between UC and CD. High expression of the immunoproteasome subunits beta1i and beta2i is characteristic of the inflamed mucosa of CD. In line with this, we found enhanced processing of NF-kappaB precursor p105 and degradation of inhibitor of NF-kappaB, IkappaBalpha, by immunoproteasomes isolated from the mucosa of CD patients. In comparison with healthy controls and CD patients, UC patients exhibited an intermediate phenotype regarding the proteasome-mediated processing/degradation of NF-kappaB components. Finally, increased expression of the NF-kappaB family member c-Rel in the inflamed mucosa of CD patients suggests that p50/c-Rel is important for IFN-gamma-mediated induction of immunoproteasomes via IL-12-driven Th1 responses. These findings suggest that distinct proteasome subunits influence the intensity of NF-kappaB-mediated inflammation in IBD patients.

Schmidt C, Wittig BM, Moser C, Zeitz M, Stallmach A. · Department of Internal Medicine II, Saarland University Hospital Homburg, Homburg, Germany. · Aliment Pharmacol Ther. · Pubmed #16842461 No free full text.

Abstract: BACKGROUND: In patients with steroid-refractory Crohn's disease, the therapeutic goal is to achieve both rapid remission and maintenance of clinical response. AIM: To evaluate the long-term benefit in patients treated with cyclophosphamide pulse therapy and azathioprine or methotrexate, a combination shown to be effective in a recent pilot study. METHODS: Sixteen patients with acute steroid-refractory Crohn's disease participated in a prospective open-labelled uncontrolled pilot study between December 1998 and June 2003. All had a median number of 4 monthly pulses of intravenous cyclophosphamide (750 mg) and were followed until relapse of the disease. RESULTS: Thirteen of 16 patients (81%) achieved remission within 8 weeks after two pulses of cyclophosphamide in combination with azathioprine or methotrexate, with a Crohn's Disease Activity Index decrease from 294 to 111 (median). Remission sustained for 19 months (median, range: 1-45). Moreover, eight patients with pyoderma gangrenosum and erythema nodosum who responded to cyclophosphamide have maintained their remission for up to 30 months.CONCLUSIONS: In steroid refractory patients with Crohn's disease, cyclophosphamide is highly effective to induce remission. This uncontrolled study indicates that cyclophosphamide-induced remission is long-lasting under standard immunosuppressive therapy.

Zeissig S, Bürgel N, Günzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. · Department of Gastroenterology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. · Gut. · Pubmed #16822808 No free full text.

Abstract: BACKGROUND: Epithelial barrier function is impaired in Crohn's disease. AIM: To define the underlying cellular mechanisms with special attention to tight junctions. METHODS: Biopsy specimens from the sigmoid colon of patients with mild to moderately active or inactive Crohn's disease were studied in Ussing chambers, and barrier function was determined by impedance analysis and conductance scanning. Tight junction structure was analysed by freeze fracture electron microscopy, and tight junction proteins were investigated immunohistochemically by confocal laser scanning microscopy and quantified in immunoblots. Epithelial apoptosis was analysed in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling and 4',6-diamidino-2-phenylindole staining. RESULTS: Patients with active Crohn's disease showed an impaired intestinal barrier function as indicated by a distinct reduction in epithelial resistance. As distribution of conductivity was even, focal epithelial lesions (eg, microerosions) did not contribute to barrier dysfunction. Instead, freeze fracture electron microscopy analysis showed reduced and discontinuous tight junction strands. Occludin and the sealing tight junction proteins claudin 5 and claudin 8 were downregulated and redistributed off the tight junction, whereas the pore-forming tight junctions protein claudin 2 was strongly upregulated, which constitute the molecular basis of tight junction changes. Other claudins were unchanged (claudins 1, 4 and 7) or not detectable in sigmoid colon (claudins 11, 12, 14, 15 and 16). Claudin 2 upregulation was less pronounced in active Crohn's disease compared with active ulcerative colitis and was inducible by tumour necrosis factor alpha. As a second source of impaired barrier function, epithelial apoptosis was distinctly increased in active Crohn's disease (mean (SD) 5.2 (0.5)% v 1.9 (0.2)% in control). By contrast, barrier function, tight junction proteins and apoptosis were unaffected in Crohn's disease in remission. CONCLUSION: Upregulation of pore-forming claudin 2 and downregulation and redistribution of sealing claudins 5 and 8 lead to altered tight junction structure and pronounced barrier dysfunction already in mild to moderately active Crohn's disease.

Sina C, Schreiber S, Hoffmann JC, Rogler G, Schölmerich J, Zeitz M, Fölsch UR. · Klinik für Allgemeine Innere Medizin, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel. · Med Klin (Munich). · Pubmed #16501914 No free full text.

Abstract: The competence network chronic inflammatory bowel disease (KN-CED) is one of 17 networks of competence initiated by the German Federal Ministry of Education and Research (BMBF). These networks are concerned with disease patterns which are characterized by their high frequency, high mortality rate or which present a large expense factor. The project-executing organization is the German Center for Air and Space Travel (DLR e. V.). The central structure of organization is the Telematic Platform for medical Networks (TMF e. V.).Aim of the KN-CED is to investigate, in their complexity, the incurable chronic diseases ulcerative colitis and Crohn's disease, particularly with regard to the causes of disease, the establishment of new therapy standards as well as patient care.To achieve this goal, the competence network is integrated into both national and international research associations and is also backed by the national self-help group DCCV and the pharmaceutical industry.Principal items of the competence network are the core facilities and their main focus on molecular genetics, animal and cell models and serum markers. Having stored the data of more than 4,000 patients so far, the central database of the competence network is one of the largest databases worldwide with regard to inflammatory bowel disease (IBD).The successful cooperation within the network is reflected in numerous publications. Thus, two of the three known genes of Crohn's disease were identified. Also with the participation of the competence network national guidelines for the diagnosis and therapy of IBD were generated.Furthermore, the competence network operates study centers where significant therapeutic developments in the field of biotechnological drugs are taking place.The analysis of existing structures of care as well as the development of standards of organization for patients with IBD top the research within the competence network and emphasize the claim to find comprehensive answers to the questions connected with IBD.

Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Bürgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD. · Department of Gastroenterology, Charité, Campus Benjamin Franklin, Berlin, Germany. · Gastroenterology. · Pubmed #16083712 No free full text.

Abstract: BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by a Th2 immune response with inflammation and epithelial barrier dysfunction. So far, Th2 cytokines have not been shown to directly influence epithelial barrier function. METHODS: Lamina propria mononuclear cells (LPMCs) were stimulated and interleukin (IL)-13 was measured by enzyme-linked immunosorbent assay. Functional IL-13 and IL-4 effects were studied on HT-29/B6 colonic epithelial cells in Ussing chambers and by conductance scanning. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. IL-13/IL-4 receptors were analyzed by reverse-transcription polymerase chain reaction and immunofluorescence. Western blotting combined with immunofluorescence was used to detect tight junction proteins. Furthermore, restitution velocity was measured. Finally, mucosal biopsy specimens from patients with UC were compared with cultured cells for these features. RESULTS: LPMCs from patients with UC produced large amounts of IL-13 (985 +/- 73 pg/mL), much more than from controls or patients with Crohn's disease. IL-13Ralpha1 and IL-4Ralpha receptors were present in HT-29/B6 cells and colonic epithelial cells of control patients and patients with UC. IL-13 had a dose-dependent effect on transepithelial resistance of HT-29/B6 monolayers (reduction to 60% +/- 4%), whereas IL-4 had no effect. This was due to an increased number of apoptotic cells (5.6-fold +/- 0.9-fold) and an increased expression of the pore-forming tight junction protein claudin-2 to 295% +/- 37%, both of which contributed equally. Finally, epithelial restitution velocity decreased from 15.1 +/- 0.6 to 10.6 +/- 0.5 microm/h after treatment with IL-13. Parallel changes were observed in human samples, with an increase in claudin-2 expression to 956% +/- 252%. CONCLUSIONS: IL-13 was identified as an important effector cytokine in UC that impairs epithelial barrier function by affecting epithelial apoptosis, tight junctions, and restitution velocity.

Scherübl H, Wittig BM, Hoffmann JC, Zeitz M. · Charité -- Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik I -- Gastroenterologie, Infektiologie und Rheumatologie. · Dtsch Med Wochenschr. · Pubmed #15368182 No free full text.

This publication has no abstract.

Zeissig S, Bojarski C, Buergel N, Mankertz J, Zeitz M, Fromm M, Schulzke JD. · Medizinische Klinik I, Charitè-Universitary Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany. · Gut. · Pubmed #15306588 links to  free full text

Abstract: BACKGROUND AND AIMS: Barrier dysfunction is an important feature contributing to inflammation and diarrhoea in Crohn's disease (CD). Recently, tumour necrosis factor alpha (TNF-alpha) antibodies were recognised as effective in steroid refractory CD. The aim of this study was to characterise the effects of this therapy on the epithelial barrier. PATIENTS AND METHODS: Forceps biopsies were obtained from the sigmoid colon before and 14 days after TNF-alpha antibody therapy in 11 patients treated for chronic active CD (Crohn's disease activity index >150). Epithelial apoptoses were measured after terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling (TUNEL) and 4',6-diamidino-2-phenylindole staining. Epithelial resistance was determined by alternating current impedance analysis in miniaturised Ussing chambers. Occludin, claudin 1, and claudin 4 expression was quantified in immunoblots. RESULTS: The epithelial apoptotic ratio was 2.1 (0.2)% in controls and increased to 5.3 (1.0)% in CD. TNF-alpha antibody therapy decreased the apoptotic ratio to 2.9 (1.0)% (normalised in 10 of 11 patients). In parallel, epithelial resistance was lower in CD than in controls (24 (3) v 42 (3) Omegaxcm(2)) and improved to 34 (3) Omegaxcm(2) after therapy. Occludin, claudin 1, and claudin 4 were not affected by TNF-alpha antibody therapy. In support of a functional role of epithelial apoptoses in CD, a similar decrease in resistance of -40% was observed when the apoptotic rate was selectively upregulated from 2.6% to 5.4% with camptothecin in HT-29/B6 cells. CONCLUSIONS: Epithelial apoptoses were upregulated in the colon in CD and restored to normal in 10 of 11 patients by TNF-alpha antibody therapy. This is the structural correlate of epithelial barrier dysfunction measured as epithelial resistance while expression of tight junction proteins did not contribute to this therapeutic effect.