Atsuo Kitano

Type 1 T helper cell predominance in granulomas of Crohn's disease

OBJECTIVE:The pathogenesis of Crohns disease (CD) is thought to be associated with production of several cytokines, especially type-1 cytokines. To elucidate the in situ cytokine profiles in CD, cytokine-containing cells were localized by immunohistochemistry, with special attention to noncaseating granulomas. The results were compared with those from studies of ulcerative colitis (UC).METHODS:We adopted the biotin-streptavidin-peroxidase method on frozen sections obtained at surgery from patients with CD or UC, and we immunohistochemically examined the expression of several cytokines (interferon-gamma, interleukin-2, -4, -10, and -12).RESULTS:In normal colonic tissue, expression of these cytokines was rare except for interleukin-4. In actively inflamed areas of CD, increased expression of all cytokines by mononuclear cells was observed. In contrast, granulomas in CD involved interferon-gamma+ lymphocytes and interleukin-12+ macrophage-lineage cells (epithelioid cells and multinucleated giant cells) but few interleukin-4+ or -10+ cells. Actively inflamed areas of UC also showed an increase in the number of cytokine-containing cells; however, quantitative analysis revealed that there was more expression of interferon-gamma and interleukin-12, and less of interleukin-10, in CD than in UC, indicating the presence of more type 1 T-helper cells in CD tissue than in UC.CONCLUSIONS:The findings of the present study suggest that granulomas of CD are coupled with type 1 T-helper responses; these responses may contribute to the pathogenesis of this disease.

Ulcerative colitis with skip lesions at the mouth of the appendix: a clinical study

Objective: We examined the clinical characteristics of ulcerative colitis patients who demonstrated endoscopically discontinuous lesions at the mouth of the appendix. Methods: Of patients with initial or recurrent active ulcerative colitis who underwent total colonoscopy during the past 3 yr at Osaka City General Hospital, we selected those who had skip lesions in the mouth of the appendix before treatment, and examined their gender, age, disease type, sites of lesions, inflammatory reaction, severity of disease, effects of treatment, and posttreatment course. Results: Discontinuous lesions at the mouth of the appendix were found in 10 patients, who had the following common clinical features: the major lesion was usually present in the lower part of the large bowel including the rectum, many of the patients had suffered an initial attack only, all patients had mild disease, and many of the patients responded quite satisfactorily to treatment with salicylazosulfapyridine. Conclusion: Numerous patients with ulcerative colitis with discontinuous lesions at the mouth of the appendix were observed and their clinical characteristics were examined. Determination of the clinical significance of skip lesions in the appendix will contribute to elucidation of the pathogenesis of ulcerative colitis.

Adhesion Molecule Expression on Vascular Endothelium and Nitroblue Tetrazolium Reducing Activity in Human Colonic Mucosa

BACKGROUND Expression of adhesion molecules is increased in inflamed colonic mucosa, but little is known about their functional activity in vascular endothelium. METHODS We studied in situ nitroblue tetrazolium reducing activity and expression of E-selectin, ICAM-1, CD31, and VCAM-1 by immunohistochemistry in the same biopsy specimen in controls and patients with ulcerative colitis (UC). RESULTS VCAM-1 expression was negative in mucosal vessels. E-selectin-positive vessels were significantly increased in endoscopically active colitis compared with normal mucosa. ICAM-1-positive vessels were consistently found in normal, quiescent UC and active UC. CD31-positive vessels were not significantly increased in quiescent UC and active UC compared with control. Only E-selectin significantly correlated with the histologic grade of inflammation. Nitroblue tetrazolium reducing vessels were increased in inflamed mucosa, and these vessels expressed ICAM-1 and CD31. E-selectin positivity in association with nitroblue tetrazolium reduction was mainly seen in the large mucosal vessels, but capillaries showing nitroblue tetrazolium reduction were rarely positive for E-selectin. CONCLUSIONS Phenotypic and functional activation of vascular endothelium might be involved in the recruitment of leukocytes and tissue destruction of inflamed colonic mucosa.

Decreased anti-Saccharomyces cerevisiae antibody titer by mesalazine in patients with Crohn's disease.

Saccharomyces cerevisiae may contribute to the pathophysiology of Crohn’s disease. We determined serum anti‐Saccharomyces cerevisiae antibody (ASCA) levels in patients with inflammatory bowel disease.

Prediction of Short-Term Outcome for Patients with Active Ulcerative Colitis

We report results of a retrospective chart review to evaluate factors predicting short-term outcome of patients with ulcerative colitis treated by corticosteroids. Between January 1992 and December 1997, we treated 71 patients with ulcerative colitis (44 with severe and 27 with moderately severe disease). Forty-nine patients were treated by conventional prednisolone therapy and 22 patients by steroid pulse therapy. There were no differences in clinical or endoscopic improvement between the two treatments. Clinical examination showed that 41 patients entered remission, 17 patients improved, and 13 patients did not respond. Endoscopically, 26 patients entered remission, 30 patients improved, and 15 patients did not respond. Extent of disease, type of disease (first attack, relapsing, or chronic active type), and endoscopic findings were factors useful in predicting short-term outcome of medical treatment.

New treatment of ulcerative colitis with K-76

The complement inhibitor K-76 (Otsuka Pharmaceutical Co., Osaka, Japan) was clinically evaluated as a new drug for treatment of active stage ulcerative colitis (UC). As monotherapy, K-76 proved effective in four of five cases. Furthermore, in patients with active stage UC that continued despite administration of corticosteroid hormone and salicylazosulphapyridine (so-called refractory UC), concomitant administration of K-76 was effective in seven of 21 cases. Thus, we believe that the multifunctional agent K-76 will provide clinicians with a new therapeutic approach to inflammatory bowel diseases, including UC and Crohns disease.

IN SITU COMPARISON OF PHENOTYPICAL AND FUNCTIONAL ACTIVITY OF INFILTRATING CELLS IN ULCERATIVE COLITIS MUCOSA

The production of reactive oxygen species may have an important role in the pathogenesis of inflammatory bowel disease, yet the cells responsible in colonic mucosa have not been clearly defined. We studied 28 patients with ulcerative colitis and 13 controls to determine the cells generating reactive oxygen species, using a combined method for determining nitroblue tetrazolium reducing activity and immunohistochemical characterization. In contrast to the proportion of EBM11‐positive cells (tissue macrophages), which did not increase in inflamed mucosa, the proportions of PMN‐13F6 positive cells, CD11b‐positive cells, and eosinophils were significantly increased in inflamed mucosa. PMN‐13F6 positive cell and eosinophil counts were significantly correlated with CD11b positivity. Eosinophils, however, showed a stronger correlation with CD11b positivity than PMN‐13F6‐positive cells. The majority of CD11b‐positive cells were eosinophils. Although some nitroblue tetrazolium reducing leukocytes were positively stained with EBM11 or PMN‐13F6, eosinophils were the major subset of nitroblue tetrazolium reducing leukocytes. Recruitment and activation of eosinophils may play an important role in the pathogenesis of ulcerative colitis.

Clinical and prognostic features of rectal sparing in ulcerative colitis

Thirty patients with ulcerative colitis who had been followed clinically for more than 5 years were studied. Patients with total or left-sided colitis were investigated to evaluate the significance of rectal sparing in the prognosis of the disease. Patients were divided into two groups, one with complete or relative sparing of the rectum and the other with homogeneous lesions ranging from the rectum to the proximal colon based on endoscopic findings. The administration of topical corticosteroids seemed to have little effect on rectal sparing. However, the relapse index was significantly higher in patients with rectal sparing. The intractability index, representing the ratio of the duration of the active stage to the investigation period, was also higher, though not significantly so, in this group. The results suggest that rectal sparing may give information about intractability or a tendency to relapse.

DISTRIBUTION AND ANTI-INFLAMMATORY EFFECT OF MESALAZINE ON CARRAGEENAN-INDUCED COLITIS IN THE RABBIT

1. A controlled‐release preparation of mesalazine microgranules (PentasaR; Ferring AS, Vanlose, Denmark) releases the active ingredient over a wide area from the small intestine to the rectum and is consequently expected to bring about therapeutic benefits to patients with ulcerative colitis and Crohns disease.

Immunoglobulin-containing cells in the colonic mucosa of rabbits with carrageenan-induced colitis

Immunohistochemical analysis of immunocompetent cells in the colonic mucosa was performed with carrageenan-induced experimental colitis in rabbits. Colitis was induced by seven months of oral administration of λ-degraded carrageenan following immunization with the same substances containing Freunds complete adjuvant. In the colonic mucosa with colitis, IgG- and IgM-containing cells were significantly increased in number (IgG: 540±94/mm2 in experimental group,vs. 120±54/mm2 in control,P<.05, IgM: 55.0±19.7/mm2 in experimental group,vs. 6.7±2.4/mm2 in control,P<.05). There was no significant increase of IgA-containing cells either in number or in proportion to the total mononuclear cells. These changes, induced by carrageenan in rabbits, had resembled those in human ulcerative colitis well. These observations suggested an impairment of the IgA-regualted local immune system and an abnormality in the differentiation process of immunoglobulin-secreting cells.