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Background and Aims: Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy., Methods: This was a randomized, double-blind, placebo-controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CD patients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5nM [n = 3], 25nM [n = 3], and 250nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated., Results: STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis., Conclusion: Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) is not fully understood. The interaction between intestinal environmental factors of food and intestinal microbes and the immunological system of hosts seems to be an important aspect. We have reviewed the relationship of the daily consumption of dietary animal meat and fats, dairy products, sugar, and other factors that may be linked to the occurrence of CD and UC from the literature and Japanese epidemiological data. In the present study, we reviewed the association between food and intestinal microbes and other factors contributing to the occurence of inflammatory bowel disease (IBD) from epidemiological data and case-control studies of IBD in the literature that appeared on Medline, and assessed the reports of intestinal microbes involved in the occurrence of IBD. We found several papers describing the positive association of animal meat and sweets and sugar with the occurrence of CD and UC. An analysis of Japanese epidemiological data suggested that the registered number of patients with CD or UC started to increase more than 20 years after an increased daily consumption of dietary animal meat and fats, and milk and dairy products, and after a decreased consumption of rice. Many studies implied a positive role of intestinal microbes in the occurrence of IBD. Intestinal environmental factors, such as Westernized food and intestinal microbes, seem to be involved in the increased occurrence of IBD.

Ulcerative colitis and Crohn's disease are nonspecific inflammatory diseases of unknown etiology. Recent immunological studies have shown that proinflammatory cytokines and adhesion molecules play an important role in the pathogenesis of ulcerative colitis and Crohn's disease. Therefore, monoclonal antibodies to proinflammatory cytokines and adhesion molecules are used to suppress the mucosal inflammatory response in experimental colitis and ulcerative colitis and Crohn's disease. Anti-TNF alpha antibody and anti-alpha 4 beta 7 integrin antibody are well-tolerated and effective for treatment of patients with Crohn's disease. This review described clinical features and immunopathophysiology of ulcerative colitis and Crohn's disease, proinflammatory cytokines and immunosuppressive cytokines and adhesion molecules involved in the pathogenesis of both disease, and treatment of both diseases with monoclonal antibodies.

Background: Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)-alpha (Infliximab) is extremely valuable in the treatment of Crohn's disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohn's disease., Methods: A 12-week multicenter, open trial of Infliximab was carried out and involved 25 patients with moderate to severe Crohn's disease who were resistant to conventional treatment. Patients received a single 2-h intravenous infusion of Infliximab at a dose of 1, 3, 5 or 10 mg/kg bodyweight. Clinical evaluation of this treatment response was defined as a reduction in the index of the inflammatory bowel disease (IOIBD) and of the Crohn's disease activity index scores (CDAI), and in serum levels of C-reactive protein (CRP) at 2, 4, 8 and 12 weeks, and as an increase in serum levels of rapid turnover proteins as well as improvement of radiologic and endoscopic findings at 4 weeks., Results: The IOIBD score was reduced after 4 weeks in 66.7% of the group receiving 1 mg/kg Infliximab, 71.4% in the group receiving 3 mg/kg, 80.0% in the group receiving 5 mg/kg, and 85.7% in the group receiving 10 mg/kg. Improvement was better maintained over 12 weeks in the 5 and 10 mg/kg groups compared with the 1 and 3 mg/kg groups. Similar results were obtained for the CDAI scores. Serum levels of rapid turnover proteins significantly increased to within the normal ranges after infusion in all groups. Seven of the 11 (63.6%) patients evaluated showed improvement of radiologic and endoscopic findings., Conclusions: A single infusion of Infliximab was effective for the treatment of Japanese patients with Crohn's disease. Serum rapid turnover proteins reflected the clinical response to antibody for TNF-alpha well.

To elucidate the possible role of proinflammatory cytokines in inflammatory bowel disease, the expression and localization of interleukin (IL) -6 and IL-8 mRNAs were examined in colonic biopsy specimens obtained from 10 patients with active ulcerative colitis (UC), 5 with inactive UC, 6 with Crohn's disease (CD), and 5 normal controls. In situ hybridization with digoxigenin-labeled probes and immunohistochemistry for both cytokines were performed. The IL-6 mRNA expression was enhanced in the inflamed mucosa in 4 of 6 CD patients, while that of UC patients stayed at baseline. In contrast, IL-8 mRNA expression was apparently augmented (P = 0.044) in 7 of 10 active UC and 3 of 6 CD patients (NS). The cell count positive for IL-8 mRNA per unit area was definitely increased in moderate/severe UC when compared to mild UC (53.1 +/- 14.4/mm2 vs 9.0 +/- 5.1/mm2, P = 0.028) according to the degree of inflammation. IL-6 mRNA positive cells in CD were preferentially located in deeper lamina propria than IL-8 mRNA positive cells in UC. Interestingly, IL-8 mRNA was expressed in the mucosal epithelial cells in one UC patient. The patients treated by corticosteroids tended to show suppressed expression of each mRNA, except one patient with intractable UC. Our data suggest enhanced expression of mucosal IL-6 mRNA in CD and of IL-8 mRNA in UC by infiltrating mononuclear cells, indicating the distinct participation of each cytokine in the pathogenesis of UC and CD. Moreover, intestinal epithelial cells in UC occasionally exhibit IL-8 mRNA.

Background/aims: We investigated the mRNA expression of spectrum of cytokines in the colonic mucosa in inflammatory bowel disease (IBD)., Methods: The expression of cytokine gene was evaluated by using the reverse transcription-polymerase chain reaction and the radioactivity of amplified cDNA standardized by coamplified beta-actin cDNA., Results: Crohn's disease and ulcerative colitis showed significantly increased expression of IL-1beta, IL-6, IL-8 and TNF-alpha mRNA as compared with controls (p < 0.05)., Conclusion: Proinflammatory cytokines such as IL-1beta, IL-6, IL-8 and TNF-alpha are closely involved in the immune abnormalities of inflammatory mucosal lesions in IBD.

Faecal clearance of alpha 1-antitrypsin was measured in patients with ulcerative colitis and Crohn's disease and compared with disease activity and markers of protein-calorie malnutrition. Patients with active ulcerative colitis and Crohn's disease showed elevated clearance of alpha 1-antitrypsin and clearance declined in most patients with induction of remission. However, even with inactive disease, elevated protein loss persisted in some patients, presumably reflecting residual inflammation in the intestinal mucosa. There was a significant correlation between clearance of alpha 1-antitrypsin and serum levels of retinol-binding protein and transferrin in patients with ulcerative colitis and with retinol-binding protein in patients with Crohn's disease. Clearance of alpha 1-antitrypsin reflects disease activity in inflammatory bowel disease and correlates with serum levels of rapid-turnover proteins such as retinol-binding protein and transferrin, which are markers for the presence of protein-calorie malnutrition.

Lymphocyte proliferative response to phytohemagglutinin (PHA) and relevance of serum factors to the response were studied in 12 patients with Crohn's disease (CD). The lymphocyte proliferative response was markedly reduced in patients with Crohn's disease (S.I. = 38.8 +/- 36.8) (mean +/- SD), as compared with normal controls (S.I. = 100.6 +/- 28.6) (p less than 0.01). In addition, the effect of sera from patients with CD or 10 patients with ulcerative colitis (UC) who had extremely impaired lymphocyte responsiveness to PHA on the proliferative response of normal lymphocytes to PHA was also measured. Sera from CD patients had a marked suppressive effect on the blastogenesis of normal lymphocytes (S.I. = 46.4 +/- 28.5), as compared with normal sera (S.I. = 126.2 +/- 14.7) (p less than 0.001). On the other hand, UC sera did not suppress the blastogenesis of normal lymphocytes (S.I. = 114.9 +/- 27.7). Moreover, serum immunosuppressive acidic protein (IAP) levels in patients' sera were measured by single radial immunodiffusion assay. A marked increase in serum IAP levels was revealed both in CD patients (780 +/- 470 micrograms/ml) and in UC patients (601 +/- 278 micrograms/ml), as compared with normal controls (376 +/- 92 micrograms/ml) (p less than 0.001). But there was no precise correlation between the suppressive effect of sera and serum IAP levels in patients with CD. Thus, we demonstrated an impairment of the lymphocyte responsiveness to PHA in CD patients and the possible existence of immunosuppressive factors which is not identical with IAP in the sera from patients with CD.

A 20-year-old man, who had suffered from ankylosing spondylitis for about 1 year, was admitted to our hospital due to melena and syncope. Physical examination revealed tenderness of abdomen and sacroiliac joint, and decreased spinal mobility. X-ray examination showed sacroiliitis and squaring of vertebral bodies. RA test and RAHA, negative; CRP, strongly positive; HLA-B 27 positive. Intestinal barium enema revealed skipping longitudinal fissure at terminal ileum, and a biopsy specimen of the colon revealed non-caseating granuloma. The association of ankylosing spondylitis and Crohn's disease has widely been known in Europe and United States; but this is the first case reported in detail in Japan, where incidences of both diseases were much lower than those found in Caucasians.

A 16 year old man with complaints of abdominal pain, diarrhea, high fever and loss of body weight was made a diagnosis of Crohn's disease. During the administration, he had intestinal obstruction and several episodes of massive intestinal bleeding. Selective angiography of the superior mesenteric artery demonstrated the bleeding site in the ileum. Microangiography of the surgical specimens revealed abrupt interruptions of arteriae rectae in the submucosa indicating the bleeding site from the diseased intestine.

The effect of sera from 17 patients with Crohn's disease, 8 with ulcerative colitis or 5 with intestinal tuberculosis on the proliferative response of mouse spleen cells induced by phytohemagglutinin (PHA) was studied. Sera from patients with Crohn's disease markedly suppressed the blastogenesis of mouse spleen cells (S.I. = 6.8 +/- 2.0, % suppression = 83%), as compared with normal sera (S.I. = 41.0 +/- 5.2, p less than 0.001, % suppression = 0). Conversely, ulcerative colitis sera did not suppress the blastogenesis of mouse spleen cells (S.I. = 43.5 +/- 8.7, % suppression = -6%), nor the sera of intestinal tuberculosis (S.I. = 38.9 +/- 4.0, % suppression = 6%). Thus, we confirmed the possible existence of immunosuppressive factors in Crohn's disease. Moreover, immunosuppressive factors in Crohn's disease were characterized for biochemical properties. The approximate molecular weight is 45,000 estimated by diafiltration and gel filtration on a Sephadex G-75 column. Analytical isoelectric focusing showed an increased amount of acidic protein in fractionated sera (m.w. ranging 30,000-50,000) from patients with Crohn's disease and ulcerative colitis, in comparison with that in normal sera. Furthermore, the main peak of this acidic protein in Crohn's disease was an isoelectric point (pI) of 2.8, while the pI of that from ulcerative colitis was 3.0. These results suggest that qualitative differences of such acidic protein may serve to discriminate between the sera of Crohn's disease and ulcerative colitis.

We investigated the in vitro immunosuppressive effect of the sera and the culture supernatants of the peripheral blood mononuclear cells obtained from patients with Crohn's disease. Sera from Crohn's disease markedly suppressed the proliferative response of mouse spleen cells, compared with sera from ulcerative colitis, intestinal tuberculosis and normal controls. The culture supernatants of the adherent mononuclear cells from Crohn's disease showed a remarkable suppressive effect (96 +/- 1%), while the culture supernatants of the non-adherent mononuclear cells had no suppressive activity (-10 +/- 16%). The culture supernatants of the adherent and non-adherent mononuclear cells from normal controls had no suppressive activity. The fractionization of the culture supernatants of the adherent cells from the Crohn's disease patients demonstrated that the fractions with high suppressive activity had similar or identical biochemical properties to the serum immunosuppressive fractions which has been reported previously. These results indicate that monocytes may release the serum immunosuppressive factor in Crohn's disease. This factor may contribute to the depression of the immune reactivity in the mucosal lesion and to the persistence of the stimulation of abnormal immune response in the intestinal wall.

Chemiluminescence (CL) analysis of monocytes and polymorphonuclear cells (PMNs) was performed on 13 patients with Crohn's disease (CD) and 10 healthy volunteers. The percentages of monocyte populations in mononuclear cells obtained from the patients with CD were greater than those from the healthy volunteers, but the numbers of PMNs were not different between the two groups. The peak level of phorbol myristate acetate (PMA)-induced CL activity generated by diluted whole blood from the patients with CD was more significantly elevated than that from the healthy volunteers, whereas the peak levels of opsonized zymosan-induced CL activity did not differ between the two groups. In monocytes, the peak levels of both PMA- and opsonized zymosan-induced CL activity were significantly higher in the patients with CD than in the healthy volunteers. CL in PMNs, however, showed no significant difference between CD and controls. It is suggested that monocytes of CD have a large capacity to generate active oxygen species. The present study suggests that excessive active oxygen species released by monocytes and perhaps macrophages may play an important role in formation of the intestinal lesions in CD.

Background: Chronic immune activation in the colon is characteristic of ulcerative colitis (UC). Fas/Fas ligand (FasL) system is a mechanism responsible for activation-induced cell death (AICD), which maintains homeostasis within the immune system. Thus, Fas/FasL expression on activated colonic T cells of UC patients, as well as the susceptibility of such T cells to AICD was investigated in order to determine the role of activated colonic T cells in the long lasting inflammation in UC. Methods: Fas, FasL, and CD45RO expression on peripheral blood and colonic T cells of UC patients were assayed by flow cytometry. Apoptosis of colonic T cells induced by anti Fas antibody was assessed using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay. Results: The majority of colonic T cells expressed both CD45RO and Fas in the colonic mucosa, a situation that was quite different from that in the peripheral blood. The number of CD45RO[sup +]CD8[sup +] and Fas[sup +]CD8[sup +] T cells was significantly lower in UC patients than the controls, unlike the number of Fas[sup +]CD4[sup +] T cells. In contrast, the number of both CD45RO[sup +]CD4[sup +] and CD45RO[sup +]CD8[sup +] T cells in UC mucosa expressing FasL was significantly higher than in the controls. While Fas mediated apoptosis of CD45RO[sup +]CD8[sup +] T cells was higher in UC patients than the controls, the number of apoptotic CD45RO[sup +]CD4[sup +] T cells from UC mucosa was not. Conclusions: In UC patients, CD45RO[sup +]CD4[sup +] T cells are less sensitive to apoptotic signals mediated by Fas. These phenomena may contribute to the pathogenesis of UC. [ABSTRACT FROM AUTHOR]