Ulcerative Colitis: Loddenkemper C

Bojarski C, Günther U, Rieger K, Heller F, Loddenkemper C, Grünbaum M, Uharek L, Zeitz M, Hoffmann JC. · Medical Department I Gastroenterology, Infectious Diseases, Rheumatology, Charité Campus Benjamin Franklin, Berlin, Germany. · Endoscopy. · Pubmed #19418398 No free full text.

Abstract: BACKGROUND AND STUDY AIMS: Conventional histology with hematoxylin and eosin (H&E) staining is the accepted standard for diagnosing acute intestinal graft-versus-host disease (GvHD). Confocal endomicroscopy (CEM) is a noninvasive method that allows in vivo histology to be performed during endoscopy. The aim of this study was to evaluate CEM for the diagnosis of acute intestinal GvHD. PATIENTS AND METHODS: This observational pilot study conducted between September 2006 and August 2008 included patients with acute diarrhea after stem cell transplantation, infectious diarrhea, or active ulcerative colitis. CEM (EC-3870CIFK, Pentax, Tokyo, Japan) was performed after intravenous injection of fluorescein 10% and topical application of acriflavine 0.05%. RESULTS: A total of 35 patients with acute diarrhea after stem cell transplantation were examined. In 16 patients, CEM and histology showed no evidence of GvHD. In 14/19 patients with histologically confirmed GvHD, the diagnosis could already be established by CEM during ongoing endoscopy. In GvHD grade IV, near complete destruction of the colonic crypts ("flat mucosa") was visible. Control patients with infectious colitis (N = 15) or ulcerative colitis (N = 15) displayed inflammatory changes but no evidence of GvHD. Altogether, sensitivity of CEM was 74% and specificity was 100 %. CONCLUSIONS: CEM improves rapid diagnosis of acute intestinal GvHD with high accuracy while performing endoscopy. Platelet transfusions and unnecessary biopsy acquisition can be avoided once acute intestinal GvHD has been diagnosed in vivo.

Frericks BB, Wacker F, Loddenkemper C, Valdeig S, Hotz B, Wolf KJ, Misselwitz B, Kühl A, Hoffmann JC. · Department of Radiology and Nuclear Medicine, Universitätsmedizin Berlin-Charité Campus Benjamin Franklin, Berlin, Germany. · Invest Radiol. · Pubmed #18836385 No free full text.

Abstract: OBJECTIVES: To quantitatively and qualitatively characterize the MR findings of inflammatory bowel disease in a rat model after i.v. injection of the reticuloendothelial system cell specific ultrasmall iron oxide SHU 555 C. MATERIALS AND METHODS: Colitis was induced in 15 rats using dinitrobenzene sulfonic acid instillation. Five rats served as controls. T1- and T2-weighted spin-echo- and T2*-weighted gradient-echo-sequences were acquired at 2.4 Tesla before and immediately, 15, 45, 60, and 90 minutes, and 24 hours after i.v.-injection of SHU 555 C (0.1 mmol Fe/kg). MR images were evaluated quantitatively regarding thickness and signal-to-noise ratio (SNR) of the bowel wall and qualitatively regarding overall bowel wall signal intensity and the occurrence of bowel wall ulcerations. MR findings were correlated to histology. RESULTS: The inflamed bowel wall was significantly thicker than the noninflamed bowel wall and 90 minutes after contrast injection it showed a significant reduction of SNR in T1- (94 +/- 27 vs. 61 +/- 29; P < 0.01), T2- (67 +/- 26 vs. 28 +/- 17; P < 0.05), and T2*- (92 +/- 57 vs. 10 +/- 7; P < 0.05) weighted images as compared with unenhanced images. At 24 hours, the respective SNR values remained significantly reduced. The signal loss was homogeneous in 12 and focal in 3 of the 15 rats with colitis. Nine rats showed colonic wall ulcerations. In all but one animal (missed focal ulceration) MR findings correlated to the histologic findings. CONCLUSIONS: SHU 555 C leads to a significant signal intensity loss of the inflamed bowel wall in T1-, T2- and T2*-weighted images. SHU 555 C enhanced MRI findings correlate well with histologic findings.

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.

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.

Kühl AA, Loddenkemper C, Westermann J, Hoffmann JC. · Medizinische Klinik I, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Deutschland. · Pathobiology. · Pubmed #12571419 No free full text.

Abstract: gammadelta T cells have previously been shown to play a protective role in various animal models of chronic inflammation (e.g., experimental autoimmune encephalomyelitis, collagen-induced arthritis, and non-obese diabetes). This immunoregulatory potential is exerted by synthesizing various anti-inflammatory cytokines and growth factors (e.g., transforming growth factor-beta). As the normal balance between inflammatory and regulatory cytokines is perturbed in inflammatory bowel disease (IBD) a protective effect of gammadelta T cells seems likely. This notion is supported by our finding of increased mortality of rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis following gammadelta T cell depletion. In contrast, no effect was observed after depletion of gammadelta T cells in a Crohn's disease animal model with terminal ileitis (TNF(DeltaARE) mice). Therefore, future studies must further define where in the intestinal immune system gammadelta T cells exert their protective function and how this can be used in the treatment of IBD.