Joerg Emmrich

Randomized, Double Blind Controlled Trial of Subcutaneous Recombinant Human Interleukin-11 Versus Prednisolone in Active Crohn's Disease

BACKGROUND: Interleukin-11 has shown benefit in animal inflammatory bowel disease models. Recently, recombinant human interleukin-11 (rhIL-11) has been observed to induce remission in a subset of patients with mild to moderate Crohns disease (CD). The present study compared the efficacy of rhIL-11 versus prednisolone in remission induction in CD.METHODS: Patients with active CD were randomly assigned to receive either subcutaneous rhIL-11 (1 mg once weekly) and prednisolone placebo tablets, or active prednisolone (60 mg/day) and rhIL-11 placebo, for 12 weeks. Prednisolone/placebo was tapered after week 1, and patients were assessed every second week.RESULTS: Fifty-one patients received medication: 13/27 (rhIL-11) and 17/24 (prednisolone) completed 12 weeks of treatment. Remission rates (intent to treat) for rhIL-11 versus prednisolone were 4%versus 46% at week 4 (p < 0.001) and 19%versus 50% at week 6 (p < 0.05). Response to treatment (ΔCDAI > 100) was seen in 19% (rhIL-11) versus 63% (prednisolone) after 4 weeks (p < 0.002) and 37%versus 63% after 6 weeks (p= 0.1). After 12 weeks of treatment, it was observed that 22% (rhIL-11) versus 21% (prednisolone) had remained in remission. Frequent side effects of rhIL-11 included fever (n = 3), rash (4), arthralgia/arthritis (3), nausea/vomiting (3), and headache (6).CONCLUSION: rhIL-11 is well tolerated but significantly inferior when compared to prednisolone in short-term remission induction in patients with active CD. In this patient cohort, both treatments appeared to be poor in maintaining remission over a period of 3 months.

Pancreatic cancer regression by intratumoural injection of live Streptococcus pyogenes in a syngeneic mouse model

Background: This study addressed the potential of bacteriolytic therapy using Streptococcus pyogenes in a syngeneic pancreatic carcinoma mouse model. Methods: Panc02 tumours were either infected with S pyogenes or were treated with the equivalent volume of vehicle. In addition to assessment of tumour histology and immunohistochemistry, isolated splenocytes were analysed by flow cytometry. Interferon (IFN) γ secretion as a reaction of splenocytes against tumour cells was shown through the ELISpot technique. A cytotoxic effect of lymphocytes against tumour targets was detected by lactate dehydrogenase (LDH) release. Cytokine levels in serum were measured. Results: A single application of live bacteria into established Panc02 tumours resulted in complete tumour regression. This antitumoural effect was accompanied by massive leucocyte infiltration into the tumours as well as a significant and sustained elevation of systemic levels of the proinflammatory cytokines IFNγ, tumour necrosis factor α and interleukin 6. Lymphocytes obtained from treated mice specifically recognised syngeneic tumour cells in IFNγ-ELISpot, and most importantly in cellular cytotoxicity assays, indicating a tumour-specific immune response. Conclusions: We provide data that both the direct lytic activity of S pyogenes towards tumour cells and the infection-driven infiltration of tumours by cells of the innate immune system lead to damage of tumour cells followed by a dissemination of tumour components. This last outcome allows for the activation of tumour-specific effector cells, most probably in draining lymph nodes, promoted by the proinflammatory context. Taken together, these data indicate that the application of live S pyogenes may be a promising new treatment strategy for advanced pancreatic cancer patients that warrants further investigation.

Prophylactic Application of Bovine Colostrum Ameliorates Murine Colitis via Induction of Immunoregulatory Cells

Epidemiologic studies suggest a relationship between early weaning and the incidence of inflammatory bowel disease. Herein, we addressed the question whether bovine colostrum, the first milk produced by mammals, is able to prevent dextran sulfate sodium (DSS)-induced colitis in mice. Prior to induction of colitis with 5% DSS, Naval Medical Research Institute mice were fed bovine colostrum [BV-20 or 200 mg/kg body weight (BW)], BSA (20 mg/kg BW), or water (100 μL) daily by oral gavage for 2 wk. The clinical severity of colitis was determined by scoring changes in BW and colon length reduction. Following 2 wk of observation, the colons were removed for histologic and immunohistochemical evaluation of inflammation. Flow cytometric phenotyping of leukocyte subsets was performed from peripheral blood, mesenteric lymph nodes, and spleens. Administration of bovine colostrum improved the clinical and histologic severity of colorectal inflammation. Compared with BSA-fed and water-fed controls, BV-20 pretreated mice had significantly less severe weight loss and decreased colon shortening. Beneficial effects were accompanied by redistribution of immunoregulatory, peripheral and splenic γδ TCR(+) cells, and CD11b(+)Gr1(+) cells. Higher colostrum doses did not affect disease activity. In summary, prophylactic administration of colostrum improved clinical symptoms of colorectal inflammation in a well-established mouse model of DSS-induced colitis. Further investigations will target the underlying immunomodulatory mechanisms to our approach.

Immunologic characterization of acute pancreatitis in rats induced by dibutyltin dichloride (DBTC).

There is little information available regarding the role of inflammatory cells and cytokines in the pancreatic tissue during acute interstitial pancreatitis. The single intravenous application of dibutyltin dichloride (DBTC) induces a pancreatitis in rats with a dosage dependent course. We analyzed the infiltrating leukocytes and the cytokine expression profile in the experimental model of DBTC-initiated mild interstitial pancreatitis during a time course of 4 weeks. Macrophages dominated among the infiltrating inflammatory cells detected by immunohistochemistry. The expression of IL-1&bgr;, IL-10, and TGF&bgr;1 was shown to be elevated 24 hours after onset of pancreatitis reaching a maximum during the first week. Positive immunostaining of IL-1&bgr;, IL-10, or TGF&bgr;1 was not restricted to infiltrating leukocytes but was found to various degrees in pancreatic cells. Transcripts of collagen type 1 reached high levels in the first week, but were down regulated thereafter. There was no significant expression of IL-2, IL-2 receptor, IL-4, TNF&agr;, or IFN&ggr;. Our data show that the experimental interstitial pancreatitis was characterized by macrophage infiltration accompanied by elevated cytokine expression that lasted longer than the visible morphologic lesions. These inflammatory processes might create the environment that makes the pancreas more susceptible to further damaging effects.

Bacterial Immunotherapy-Antitumoral Potential of the Streptococcal Toxin Streptolysin S-

Chronic infections can lead to cancer. However, acute infection has beneficial effects often contributing to complete eradication of tumors. In the wake of this, bacteria and their related products were applied therapeutically for experimental immunotherapy. They exhibit direct antitumoral potential and are recognized by the host’s immune system via Toll-like receptors (TLRs) finally promoting pro-inflammatory, often Th1-directed immune responses.

Autoimmune Diseases in Gastroenterology

There are several different diseases in gastroenterology with an important role of immunological mechanisms in their pathogenesis. We know autoimmune diseases with immunological reactions against liver or pancreatic tissue. In addition there are diseases like chronic inflammatory bowel diseases representing inappropriate immunological reactions followed by inflammation and tissue destruction. The research of the last decade has contributed significantly to the understanding of the pathogenesis of diseases based on immunological mechanisms and consequently to the development of novel therapeutic strategies targeting molecules. Chronic inflammatory bowel diseases, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune pancreatitis, and celiac disease are the most important diseases with immunological pathogenesis in Gastroenterology. Especially in chronic inflammatory bowel diseases ulcerative colitis and Crohns disease with immunosuppressive drugs and monoclonal antibodies new preparations are used in therapy. Autoimmune pancreatitis was characterized as an own entity in the last years. Therefore, this review will focus on these diseases.

A Short Time Rat Model of Mucosal Inflammation by in Situ Perfusion of an Intestinal Segment

Background: The extent to which numerous strains of genetically engineered mice, including mice lacking toll-like receptor 5 (T5KO), display colitis that is environment-dependent with the gut microbiota underlying much of the variance in phenotype. Accordingly, embryonic rederivation of T5KO mice ameliorated their spontaneous colitis despite only partially correcting elevations in pro-inflammatory gene expression. We postulated that absence of overt inflammation in these mice required activation of endogenous anti-inflammatory pathways. Consequently, we hypothesized that neutralization of the anti-inflammatory cytokine IL-10 might induce uniform colitis in T5KO mice and thus provide a practical means to study mechanisms underlying their inflammation. Methods: Two distinct strains of noncolitic T5KO mice, mice lacking MyD88, TLR4 and IL-1R as well as various double-KO were treated weekly for 4 weeks with 1 mg/mouse of IL-10 receptor neutralizing antibody (IL-10R mAb) and colitis assayed 1 week after the final injection. Results: Anti-IL-10R mAb treatment led to severe uniform intestinal inflammation in both strains of T5KO mice. Such neutralization of IL-10 signaling did not cause colitis in WT littermate mice nor mice lacking TLR4, Myd88 or IL-1R. The susceptibility of T5KO mice to this colitis model was not rescued by absence of TLR4 in that TLR4/T5-DKO mice displayed severe colitis in response to anti-IL-10R mAb treatment. Finally, we observed that ablation of IL-1β signaling was crucial for this colitis model as IL-1R/TLR5-DKO were completely protected from colitis in response to IL-10RmAb treatment. Conclusion: Regardless of whether they harbor a “colitiogenic microbiota,” loss of TLR5 predisposes mice to colitis triggered by immune dysregulation via an IL-1β-dependant pathway.

T1196 Reduced Clinical Activity During the Course of Ulcerative Colitis

Background: There are limited data available concerning the course of ulcerative colitis (UC) beyond a 10 year history. Clinical experience shows decreased disease activity of UC over time. Therefore, the aim of the study was to obtain data from a 15-year UC period to verify this clinical observation. Methods: 49 adult patients suffering from UC at least 15 years were included in the study. They were evaluated for age, gender, disease extension, the frequency of acute flares, surgical interventions, the highest clinical activity index (CAI according to Rachmilewitz), medication, and the number of hospitalizations. Assessment was performed comparing 5-year episodes of disease history. The patients were treated using 5-aminosalicylates, glucocorticoids and azathioprin. Results: We found a highly significant (p= 0.001) reduction of acute flare number during the course of UC. In the first 5 years 86.4% of the patients had 1-5 acute flares, 11.4% had more than 5 episodes. In the time period of 11-15 years 57.1% of pats. had 1-5 acute flares, but 32.7% of pats. were in remission without acute flares. Moreover, there was a significant (p=0.001) reduction of the highest CAI during the course of disease. 88.9 % of the patients had an CAI>4 in the first 5 years. In contrast, only 41.5% of the patients had a CAI>4 in the years 11-15 after diagnosis. Furthermore, the number of patients without hospitalization was increased significantly from 28.9% (year 1-5) to 83.0% (year 11-15). There was no relation of these data to age, gender, disease extension, and the medication. Conclusion: During the long time course of UC disease activity was reduced independent of the other investigated disease parameters.