Response In Colitis Research Articles

Chemokine receptor CXCR3 expression in inflammatory bowel disease.

CD4+ T lymphocytes in the lamina propria (LP) of the gut play a central role in the immune response in inflammatory bowel disease (IBD). CXCR3 is a chemokine receptor expressed on activated T lymphocytes, and a key component for the recruitment of T helper (Th1) effector cells to the site of inflammation. To determine if CXCR3 is involved in localization of T cells to the gut in IBD patients, we investigated the expression of CXCR3 on CD4+ T lymphocytes in the LP and in the submucosa of resection specimens from 51 IBD patients and 15 control patients. Positive cells were microscopically scored using a semiquantitative analysis on a five-point scale. We found that CD4+ T cells, CXCR3+ cells, and CD4+CXCR3+ T cells in the LP were slightly increased in both IBD groups compared with control non-IBD specimens. In addition, CD4+ and CXCR3+ cells in the submucosa were significant increased in the CD group compared with the control group. CD4+ and CXCR3+ expression was not statistically different between CD and UC. Flow cytometry was used to analyze the percentage of CXCR3+ cells within the CD4+ T-cell population isolated from biopsy specimens and peripheral blood from IBD patients and control patients. There was no difference in the percentage of CD4+CXCR3+ cells between the different groups in the gut as well as in the circulation. These results suggest that CD4+CXCR3+ T cells migrate to the normal and inflamed intestinal mucosa, indicating a role in maintaining normal gut homeostasis. The selective expression of CXCR3+ cells in the submucosa of CD patients might also indicate that these cells play a role in inflammation.

Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease.

Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLR4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders.

Role of the intestinal flora in gastrointestinal diseases

B ecause of their high incidence and potential severity, adenocarcinoma of the colon and cryptogenetic inflammatory bowel diseases (Crohn's disease and ulcerative colitis) ~ are a priority for gastroenterologists in more-developed nations. A French citizen has, during his or her lifetime, a one in 25 chance of getting colon cancer and a one in 1000 chance of developing cryptogenetic inflammatory bowel disease. New treatment options--eg, chemotherapy and monoclonal antibodies to cytokines and adhesion molecules--are being developed. These treatments are increas ingly effective but, a t the same time, increasingly costly. Much attention is also being given to preventive measures. For several reasons, there has been a renewed interest in the role of the bowel flora as cause for these disorders. First, epidemiological and experimental studies consistently show that the bowel flora has a major role in colon cancer. Some colonising organisms are more favourable than others. For example, increased fermentation acidifies the contents of the colon thereby inhibiting the transformation of primary bile acids into carcinogenic secondary bile acids. Butyrate, a by-product of fermentation, aroused researchers' interest because it modulates cellular proliferation and differentiation of colonic cells. Other basic-research studies show that some still poorly identified elements of the intestinal flora might exacerbate inflammatory bowel diseases, in particular Crohn's disease, in both laboratory animals and humans. Second, there have been methodological advances in the study of the intestinal flora. Previous problems of identification because of the difficulties in growing certain micro-organisms on culture media--many intestinal micro-organisms cannot yet be cultivated--have been overcome by detecting molecular markers of their presence or activity. In particular, 16S DNA sequences specific for groups or species of bacteria, sometimes even specific for a given strain, can be identified. Such methods, along with DNA electrophoresis in a temperature gradient, have recently been applied to the human digestive tract, thus allowing previously impossible descriptions of complex ecosystems. A better understanding of the flora helps us to understand the interactions between enteric bacterial flora and mucosal immunity. Experimental models suggest that the inflammatory response in inflammatory bowel diseases is the result of abnormal immunological reactivity to normal flora in genetically-susceptible hosts. The mucosal immune system senses and interprets the local microenvironment, and under normal circumstances it exhibits a restrained response to commensal flora (tolerance), coupled with the capacity to react effectively to pathogenic bacteria (immunity). In susceptible individuals, inflammatory bowel diseases can result from a breakdown of the immunological tolerance to the normal flora. Third, the bowel ecosystem may be modulated by something other than antibiotics. There is industrial Role of the intestinal flora in gastrointestinal diseases

Immunological and genetic links in Crohn's disease

See article on page 58 Current consensus holds that the pathogenesis of Crohn's disease involves the interacting elements of multigenic host susceptibility factors and environmental priming from the enteric microflora.1...

Inflammatory mediators in inflammatory bowel disease

Considerable efforts have been made over the past 20 years to identify the chemical signals that coordinate the inflammatory response in inflammatory bowel disease. In addition to gaining a better understanding of the pathogenesis of this disorder through such studies, it is hoped that these mediators might be targets for novel therapeutics. In the past year, significant progress has been made in understanding the contributions of a number of inflammatory mediators in human inflammatory bowel disease and in animal models of intestinal inflammation. These mediators include nitric oxide, eicosanoids, and histamine as well as the cytokines (both pro and anti-inflammatory). Clinical trials have assessed the contribution of certain inflammatory mediators (eg, tumor necrosis factor) in inflammatory bowel disease

470 Venous occlusion response in inflammatory bowel disease (IBD)

470 Venous occlusion response in inflammatory bowel disease (IBD)

4. Immunopathology in trichuriasis: lessons from the mouse model

The severity and consequences of human Trichuris infection vary widely. This may reflect differences in immune response. T. muris is a natural parasite of mice which provides a close, well defined, easily manipulated model for otherwise uninvestigatable aspects of this response. Normal mice reject the parasite in 3 weeks, but mice subjected to transient immunosuppression around the time of infection develop a persistent caecal infection. Sequential histopathological studies have shown that infected, normal mice develop a marked intraepithelial, mucosal, ‘globule leucocyte’ response, accompanied by low-level lymphocytic and histiocytic responses in the lamina propria. The reaction is maximal at 3 weeks and declines towards normal after rejection. Infected, immunosuppresed mice show a slower response with, by weeks 4 and 5, fewer ‘globule leucocytes’, but a chronic colitis comprising heavy, mixed, mucosal and submucosal inflammation and crypt damage accompanied by persistent parasite infection. The ‘globule leucocyte’ has been characterized by cytochemistry and electron microscopy as having a mast cell origin. This study, with other evidence, suggests that the replacement of a Th2 (allergic) T helper cell response by a Th1 (cell-mediated) response may result in increased severity and persistence of colitis in response to Trichuris infection.

The mode of action of the aminosalicylates in inflammatory bowel disease

Sulphasalazine and other 5-aminosalicylic acid (5-ASA)-containing drugs are used in the treatment of acute inflammatory bowel disease and in the maintenance of clinical remission. Despite their use for over 50 years, the mechanism of action of this class of drugs remains uncertain, although a number of possibilities are discussed in this review. It seems likely that the aminosalicylates are important free radical scavengers, can reduce leukotriene production and can inhibit the cellular release of interleukin-1, all of which are likely to be important in reducing the acute inflammatory response in inflammatory bowel disease. The effects of these drugs on prostaglandin production are more contentious, but it appears that 10(-5) to 10(-4) M concentrations stimulate production of prostaglandins which may be cytoprotective, while higher doses of these drugs inhibit prostaglandin production. The aminosalicylates may maintain remission in inflammatory bowel disease by preventing leucocyte recruitment into the bowel wall. The drugs inhibit the chemotactic response to leukotriene B4, reduce the synthesis of platelet activating factor and also inhibit leucocyte adhesion molecule upregulation.

Why Distinguish between Ulcerative Colitis and Crohn’s Disease?

IT IS IMPORTANT TO DISTINGUISH BETWEEN ULCERATIVE COiitis and Crohn's disease because they differ in their clinical course, in their complications and, thus, in their medical and surgical management. C rohn's disease may affect any part of the gastrointestinal tract from the mouth to the anus while ulcerative colitis affects only the colon. Therefore, there is a point in distinguishing between these two diseases, mainly in patients with colonic involvement. The etiology of both ulcerative colitis and Crohn 's disease is not yet known. Infectious, immunologic, genetic, environmental, allergic and psychogenicetiologic factors have been suggested but none has been proven, so far. Most probably, the re is no one common etiology to account for both diseases, but elucidation of the etiologic factor may pave the road to more satisfactory treatment. In the last decade much effort has been devoted to research on the pathogenesis of che inflammatory response in inflammatory bowel disease. The possible role of several soluble mediators was suggested. It is not surprising that in all instances, when tested, the same mediators were found to be involved in the pathogenesis of ulcerative colitis and Crohn's disease. The colonic generation of eicosanoids proscaglandins and leukotrienes was shown to be enhanced in the active phase of both diseases ( l). Colonic interleukinI generation is stimulated to the same extent in both diseases (2). Platelet activating factor production tested, so far only in

Polyclonal nature of the intestinal mucosal lymphocyte populations in inflammatory bowel disease: A molecular genetic evaluation of the immunoglobulin and T-cell antigen receptors

To define the clonality of the intestinal lymphocytes involved in the immune response of inflammatory bowel disease, we performed a molecular genetic analysis of the arrangement of the immunoglobulin and antigen-specific T-cell receptor genes of isolated lamina propria lymphocytes derived from resected intestinal specimens of 12 patients with Crohn's disease, 5 patients with chronic ulcerative colitis, and 7 patients with other gastrointestinal diseases. The sensitivity of this technique is sufficient to detect a monoclonal population when there is as little as 1% clonal expansion in a mixed cell population. In all these groups of patients, deoxyribonucleic acid from the non-T cells demonstrated only a germ-line gene pattern, and no non-germ-line rearrangements of immunoglobulin genes as assessed by an immunoglobulin-joining heavy-chain gene probe. Deoxyribonucleic acid from the lamina propria T cells showed a rearrangement pattern of the antigen-specific T-cell receptor β- and γ-chain genes that is characteristic of polyclonal T cells as assessed by T-constant β- and T-joining γ-gene probes. These results indicate that the lamina propria non-T- and T-lymphocyte populations in inflammatory bowel disease and controls are polyclonal.

Thymosin-dependent T-lymphocyte response in inflammatory bowel disease

Peripheral blood “total” and “avid” thymus-dependent (T) lymphocytes were enumerated in 45 patients with Crohn's disease (CD) and in 23 patients with ulcerative colitis (UC) by using the spontaneous rosette technique (ER). The in vitro effect of thymosin fraction 5, a polypeptide extract of the thymus gland, on avid ER formation was also determined in these patients. The proportion and number of “total” ER were lower in patients with CD (P < 0.02), but not with UC, when compared with controls. More impressive differences were observed when “avid” ER were determined in patients with CD (P < 0.001) and UC (P < 0.05). Incubation with thymosin resulted in a significant increase in “avid” ER in patients with CD and UC, with no such effect observed in the controls. These results indicate that the determination of “avid” rather than “total” ER provides a more sensitive method for detecting alterations in T-cell immune competence. In addition, it is suggested that there is an increased number of circulating T-lymphocytes in CD and UC capable of responding to exogenous thymic factors. This may indicate the presence of a thymosin-responsive immunodeficiency state in these diseases.

ACTH and adrenalcorticosteroids in the treatment of ulcerative colitis.

The clinical course of 52 patients with ulcerative colitis in response to treatment with ACTH and adrenalcorticosteroids has been reviewed. Seventeen of these patients were maintained on continuous therapy for from 3 to 62 months, with an average follow-up period of 19 months. These preparations are potent agents capable of inducing dramatic remissions in a majority of instances when employed in adequate dosage. In this regard ACTH is more effective than cortisone or its synthetic analogue prednisone. Favorable responses, though unpredictable and subject to frequent relapse, may be obtained even in long-standing chronic and recurrent disease in all clinical aspects except in regard to the abnormal appearance of the bowel. The indications for steroid therapy, its limitations and potential risks, are reviewed in relation to established forms and results of treatment in the presteroid era. The suppressive, rather than the curative, value of these drugs is emphasized. The value of treatment prolonged beyond the initial period of an acute remission is more impressive clinically than statistically. The futility of prolonging ineffective therapy beyond a trial of 3 weeks is confirmed; the implications of such persistence in adding to the hazard of bowel disintegration and perforation are noted.