IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease.

BACKGROUND: A novel T helper (Th) cell lineage, Th17, that exclusively produces the proinflammatory cytokine interleukin 17 (IL17) has been reported to play important roles in various inflammatory diseases. IL23 is also focused upon for its potential to promote Th17. Here, the roles of the IL23/IL17 axis in inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease (CD) were investigated. METHODS: Mucosal samples were obtained from surgically resected specimens (controls, n = 12; UC, n = 17; CD, n = 22). IL17 production by isolated peripheral blood (PB) and lamina propria (LP) CD4(+) cells was examined. Quantitative PCR amplification was performed to determine the mRNA expression levels of IL17, interferon gamma (IFNgamma), IL23 receptor (IL23R) and retinoic acid-related orphan receptor gamma (RORC) in LP CD4(+) cells, and IL12 family members, such as IL12p40, IL12p35 and IL23p19, in whole mucosal specimens. The effects of exogenous IL23 on IL17 production by LP CD4(+) cells were also examined. RESULTS: IL17 production was higher in LP CD4(+) cells than in PB. Significant IL17 mRNA upregulation in LP CD4(+) cells was found in UC, while IFNgamma was increased in CD. IL23R and RORC were upregulated in LP CD4(+) cells isolated from both UC and CD. IL17 production was significantly increased by IL23 in LP CD4(+) cells from UC but not CD. Upregulated IL23p19 mRNA expression was correlated with IL17 in UC and IFNgamma in CD. CONCLUSIONS: IL23 may play important roles in controlling the differential Th1/Th17 balance in both UC and CD, although Th17 cells may exist in both diseases.

T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn's disease.

BACKGROUND AND AIMS: Many lines of evidence suggest that T helper cell type 1 (Th1) immune responses predominate in Crohn's disease (CD). Recently, a novel transcription factor T-box expressed in T cells (T-bet) has been reported as the master regulator of Th1 development. This study was designed to investigate the role of T-bet and proinflammatory cytokines in Th1 mediated immunopathology in CD. MATERIALS: CD4+ lamina propria mononuclear cells (LPMCs) were isolated from surgically resected specimens (CD, n = 10; ulcerative colitis (UC), n = 10; normal controls (NL), n = 5). METHODS: (1) T-bet expression of CD4+ LPMCs was examined by quantitative real time polymerase chain reaction and western blotting. (2) T-bet expression of LPMCs stimulated by interleukin (IL)-12/IL-18 was analysed by western blotting. (3) Interferon gamma (IFN-gamma) production and T-bet expression of CD4+ peripheral blood mononuclear cells (PBMCs) were examined with or without stimulation by anti-CD3/CD28 monoclonal antibodies and/or IL-12. RESULTS: (1) T-bet expression of CD4+ LPMCs was increased in CD compared with UC and NL. (2) Synergistically, augmentation of IFN-gamma production by IL-12/IL-18 was independent of T-bet expression in LPMCs. (3) T-bet was induced by T cell receptor stimulation in CD4+ PBMCs. T-bet induction correlated with IFN-gamma production and with augmentation of surface expressed IL-12 receptor beta2. CONCLUSIONS: T-bet induction by antigenic stimulation and subsequent stimulation by macrophage derived IL-12/IL-18 are important for establishing Th1 mediated immunopathology in CD.

Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-alpha for Crohn's disease in Japan: evaluation by rapid turnover proteins, and radiologic and endoscopic findings.

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.

Successful resection of ampullary carcinoma in a father and adenoma in a daughter with familial adenomatous polyposis following detection by surveillance: report of two cases.

This report describes the successful resection of ampullary carcinoma in a 58-year-old man and an adenoma in his 28-year-old daughter after they had undergone proctocolectomy for familial adenomatous polyposis (FAP). Both patients had been monitored by surveillance endoscopy once a year since their proctocolectomy. The father was found to have an ampullary adenoma 26 years after proctocolectomy, and ampullary carcinoma was detected 2 years later, for which pancreatoduodenectomy was performed. Histological examination of the specimen revealed an ampullary carcinoma, 2.5 x 1.7 cm, that had invaded the submucosal layer, but no lymph node metastasis was found. The patient's daughter underwent endoscopy, which showed an ampullary polyp 6 years after total colectomy. Endoscopic mucosal resection of the periampullary lesion was performed, and histological examination revealed a dysplastic tubular adenoma 0.6 x 0.4 cm in diameter. This report reinforces the importance of long-term periodic surveillance of patients with FAP by gastroduodenal endoscopy.

The incidence and outcome of pelvic sepsis following handsewn and stapled ileal pouch anal anastomoses.

The incidence and outcome of pelvic sepsis was analyzed in 210 patients who underwent restorative proctocolectomy for ulcerative colitis (UC) in 197 patients, and for familial adenomatous polyposis (FAP) in 13 patients. Pelvic sepsis developed in 18 patients (8.6%) and a significantly higher incidence was seen in men than in women, at 13.6% vs 3.7%, respectively (P < 0.05). The incidence of pelvic sepsis in patients with UC complicated by toxic megacolon and/or fulminant colitis was significantly higher that in those without any preoperative complications, at 36.4% vs 7.4% (P < 0.05). The incidence of pelvic sepsis following handsewn anastomosis was significantly higher than that following stapled anastomosis, at 15.6% vs 5.5% (P < 0.05). The outcome of pelvic sepsis in patients with a stapled anastomosis was better than that in those with a handsewn anastomosis. The prognosis of women who developed pelvic sepsis was better than that of men who developed pelvic sepsis. The risk factors predisposing to pelvic sepsis were UC, especially when complicated by toxic megacolon and/or fulminant colitis, and male sex, while a handsewn anastomosis was more vulnerable than a stapled anastomosis.

Listeria monocytogenes in the colon in a case of fulminant ulcerative colitis.

A case of ulcerative colitis in which the presence of Listeria monocytogenes was confirmed in the resected colon with polymerase chain reaction and subsequent Southern blot analysis and immunohistochemistry using antibody against Listeria is presented. The patient developed ulcerative colitis at the age of 59 years. Prednisolone, 50 mg/day, was given for severe ulcerative colitis. Later the disease became fulminating, indicating colectomy 4 months after the onset. Multiple sealed colonic perforations were observed. Numerous L. monocytogenes were found at the site of perforation, in fissures, and in cracks in the submucosa. This case indicates the possibility that L. monocytogenes contributes to the exacerbation of colitis to fulminating and colonic perforation.

[Preservation of anal transitional zone in restorative proctocolectomy].

Since 1980, restorative proctocolectomy has been established for surgical therapy to ulcerative colitis. The crucial points of this procedure are mucosectomy of the anorectal mucosa and pouch anal anastomosis. Mucosectomy is often difficult due to long standing acute and chronic inflammation and incomplete microscopically and leakage of pouch anal anastomosis is relatively high probably due to steroid given prior to surgery or direct effect of anorectal mucosal inflammation. Regards to postoperative bowel function, nocternal soiling is frequently recognized in the patients who received this operation. To overcome these technical and functional disadvantages, anal transitional zone preservation without mucosectomy and stapled anastomosis between pouch and the upper rim of the puborectalis muscle has been performed. Our series of 84 cases with this modified method, anastomotic leakage was significantly decreased and nocternal soiling was completely disappeared within 7 months postoperatively. And one stage procedure became possible unless severe, or high doses of steroid given prior to surgery. Only one case of mild dysplasia was experienced in the remaining rectal mucosa which was disappeared at the next examination. Medical treatment to the remaining lesion was not necessary in the most of cases. Anal canal preservation is superior to mucosectomy in the points of bowel function and minimizing postoperative complications.

[Prognostic factors of colorectal cancer concerning metastases].

Four prognostics factors were investigated for colorectal cancer metastases. 1) There were statistically more venous invasions using Victoria blue elastic staining in patients with liver or lymph node metastasis than in those without metastasis. 2) The immunohistochemical expression rate of c-erbB-2 in liver metastasis cases was 27%, which was significantly higher than 3% in no metastasis cases. 3) Sialyl Lewis x (SLex) is related with cell adhesion. SLex positive rates in vessel invasion cancer cells were 71.4% with metastasis and 31.0% without metastasis. 4) Matrilysin is one of MMPs and it was significantly increased with Dukes stage by fluorescence intensity.

Surgery for Crohn's anal fistulas.

The aim of this study was to analyze the features of Crohn's anal fistulas and to evaluate the efficacy of seton treatment. In 119 patients with Crohn's disease, the incidence of anal fistula was 56% (67/119), with no significant difference in the incidence among patients with ileitis, colitis, and ileocolitis. "Intractable" anal fistulas were found in 17% of patients with ileitis, compared to 64% of those with colitis (P = 0.051) and 68% of those with ileocolitis (P = 0.014). Seton treatment, i.e., non-cutting, long-term seton drainage, was performed for 21 patients (5 with intersphincteric, and 16 with transsphincteric fistulas). In the 16-month follow up, 9 patients required redrainage for recurrent fistulous abscess, mainly because of progressive colorectal disease. Finally, a good result was obtained in 17 of the 21 patients (81%) and no recurrent fistulous abscess developed in the 8 patients in whom all setons were removed. Anal continence was preserved in all the patients. These results indicate that anal fistulas with Crohn's ileitis were cured more easily than those with colitis or ileocolitis, and that seton treatment was effective for intersphincteric fistula with multiple fistula openings and for transphincteric fistulas in patients exhibiting remission of intestinal Crohn's disease.

Seton treatment for perianal Crohn's fistulas.

In this study, we evaluated the efficacy of long-term seton drainage in the management of 13 patients with severe perianal Crohn's fistulas which had proven to be intractable to conventional therapy. After adequate curettage of the fistulous tracts and infected tissue, either a Penrose drain or a fine polyethylene catheter was inserted to encircle the tracts and tied. Patients were followed up for a mean period of 12.1 months. Perianal pain disappeared or improved in all 13 patients, while the body temperature of all 7 with pyrexia dropped to within the normal range. Discharge disappeared or diminished in 77% (10/13) and tenderness disappeared or improved in 77% (10/13). Induration disappeared or improved in 69% (9/13). Overall, good results were achieved in 10 patients, although 3 required redrainage. In one of these patients, a good result was achieved after colostomy was performed for active intestinal disease. Nevertheless, 2 patients did not improve, one of whom required lay-open surgery after seton treatment. In 8 of the 13 patients, some seton drains were able to be removed, and none of the patients experienced any soiling or leakage. Thus, we conclude that seton treatment is worthwhile in the management of perianal Crohn's fistulas as it alleviates the symptoms and simplifies multiple tracts. Moreover, it preserves sphincter function, is less invasive, and can be managed easily.

Enterolithiasis, refractory anemia, and strictures of Crohn's disease.

In Crohn's disease, multiple areas of small bowel stenosis are relatively common, but there are only 11 reported cases with stenosis complicated by enterolithiasis. We describe three patients with multiple strictures, enterolithiasis, and refractory iron deficiency anemia. The chronic anemia was severe, requiring multiple transfusions in two patients. One patient developed a perforation, and a second had cancer within one of the saccular dilatations between strictures. Management of this stricture-enterolith-anemia triad requires removal of the enteroliths and correction of the strictures by strictureplasty and/or resection. If the operation of choice is strictureplasty, however, meticulous inspection and biopsy of each proposed site of enteroplasty is essential to rule out carcinoma.

[Postoperative recurrence form of Crohn's disease: comparison between perforating and non perforating types].

Postoperative recurrence rate and recurrence form were analyzed in two clinical forms of Crohn's disease at primary resection, one of which was perforating and the other was non perforating. Forty four patients with Crohn's disease were included in this study, 18 of them were perforating type and 26 were non perforating type. Crude recurrence rates were 39% (7/18 cases) in perforating type group and 54% (14/26 cases) in non perforating type group, which were not significantly different. Cumulative recurrence rates 5 years after initial operation were 58% in perforating type group and 47% in non perforating group without statistically significance. The recurrence form was perforating type more frequently in perforating type group (86%) than non perforating group at primary resection (29%) with statistically significance (p = 0.013). Postoperative recurrence form had a tendency to be similar to the form at primary resection. It was suggested from this study that Crohn's disease had two different disease entities; perforating and non perforating types and that postoperative recurrence should be examined carefully from the view of primary resection.