Gene therapy with interleukin 10 in Crohn's disease: too early yet

An improved understanding of the pathogenesis of inflammatory bowel disease (IBD) has led to the development of new drugs such as infliximab and insights into the modes of action of commonly used drugs such as azathioprine and methotrexate. These drugs act, at least in part, by inducing apoptosis of activated T-cells, which are an important phenomenon in the aberrant mucosal immune response in Crohn's disease. Gene therapy directed towards delivering anti-inflammatory proteins such as interleukin 10 (IL-10) to the inflamed mucosa is another new means of correcting the balance between the proinflammatory and anti-inflammatory cytokines in IBD. Gene-therapeutic manipulation of T-cells or bacteria to make them selectively deliver IL-10 to the gut mucosa has been successfully described in experimental models of IBD. Although interleukin-10-based gene therapy for Crohn's disease is an attractive option, safety aspects concerning the gene transfection method and questions about the efficacy of interleukin-10 in Crohn's disease in particular, prevent its application in the near future.     

Molecular biology background of inflammatory bowel disease

The exact pathological background of inflammatory bowel disease has not been clarified yet. Many aspects of genetical and environmental factors, as well as certain alterations of the functions of epithelial cells and immunoregulation which may attenuate chronic inflammation in the gastrointestinal tract are known. These three components have many connecting points. Among the inflammatory bowel disease genes we know only the function of the NOD2/CARD gene, and we have some idea about the OCTN and DRG genes. The function of the intestinal epithelial cells is changed in inflammatory bowel disease. The latter two genes may have a role in the increased permeability, so as the tumor necrosis factor alpha, interferon gamma may play affect it. The interleukin-10 helps the mucosal integrity. The interleukin-6 production is elevated in these diseases, and the interleukin-8 level can be elevated in case of mutation of toll like receptor 5. The tumor necrosis factor alpha, interferon gamma and lymphotoxin-3-alpha increased the chemokine secretion and adhesion molecule expression also. The amount of certain cytokines are changed in inflammatory bowel disease. There were no association between the incidence and phenotype of Crohn's disease and cytokine gene polymorphisms, except the interleukin 6 gene. It seems that these alterations are secondary, and don't play a major role in the pathogenesis of inflammatory bowel disease.     

Immunohistologic changes of the intestinal mucosa in chronic inflammatory bowel diseases

In the pathogenesis of inflammatory bowel disease abnormally increased immune reactions in the intestinal mucosa play a basic role. The revealing of these reactions was facilitated by the rapidly spreading immunohistological methods in last decades. This review discusses in detail the characteristic distribution of lymphocyte subsets and plasma cells in Crohn's disease and ulcerative colitis. Results indicating increased expression of adhesion molecules are also presented, as well as the different patterns of cytokine production in Crohn's disease and ulcerative colitis. The rapid epithelial turnover developing as a consequence of increased rate of proliferation and apoptosis in inflammatory bowel disease is also shown. The epithelial expression of MHC II antigen in colonic mucosa which is not observed in healthy subjects is also discussed. In addition, the pathogenetic role of lost oral tolerance in the development of inflammatory bowel is reviewed in detail.     

Improvement of bone metabolism after infliximab therapy in Crohn's disease

BACKGROUND: Osteoporosis has received increasing attention as a potential complication of Crohn's disease. Among cytokines tumor necrosis factor-alpha plays a pivotal role in the pathogenesis of inflammatory bowel diseases by inducing a wide variety of inflammatory responses, including bone resorption. Only few data are present about the effect of infliximab on bone metabolism. AIMS: The authors evaluated the effect of infliximab on bone metabolism in patients with Crohn's disease. PATIENTS AND METHODS: Twenty seven patients (17 females, 10 males, mean age 32.58 yrs) with refractory fistulizing Crohn's disease were treated with a series of three infusions of 5 mg infliximab per kg at weeks 0, 2, and 6. Biochemical markers of bone formation (osteocalcin) and bone resorption (beta-CrossLaps) were measured before administration of each infliximab infusion. 54 patients were studied with inactive Crohn's disease (Crohn's disease activity index < 150) as a control. RESULTS: There were significant differences in beta-CrossLaps concentrations (ng/ml) between the day 0 and 14 (0.57 +/- 0.32 vs. 0.46 +/- 0.29, p < 0.01) and the day 0 and 42 (0.57 +/- 0.32 vs. 0.45 +/- 0.26, p < 0.05). The osteocalcin levels significantly increased from day 0 to day 42 (21.31 +/- 12.14 vs. 25.64 +/- 16.97, p < 0.05). The serum beta-CrossLaps and osteocalcin levels were 0.47 +/- 0.24, 27.2 +/- 8.44 in the control group respectively. These results differed from the serum levels of active patients before the treatment, but there were no notable differences at the day 42. CONCLUSION: Infliximab therapy in Crohn's disease patients displayed a rapid influence on bone metabolism by enhancing bone formation and decreasing bone resorption. In addition to its mucosal effect affecting the bone homeostasis, indicate a further rationale usage of tumor necrosis factor-alpha blockade in the therapy of inflammatory bowel diseases.     

Nutrition in inflammatory bowel disease

Recent developments concerning nutritional complications of inflammatory bowel disease include a better understanding of disease-associated anorexia and increasing recognition of the interaction of nutrition and cytokines in the pathogenesis of growth impairment of children. Decreased bone mineral density is a multifactorial complication and an increased focus of research. Enteral nutrition continues to play an important role in the therapy of Crohn's disease. The mechanisms whereby specific nutrients, such as n-3 fatty acids, antioxidants, and butyrate, ameliorate inflammation are being elucidated in in-vitro studies, but beneficial effects have yet to be translated into the clinical sphere.     

Visceral fat and gut inflammation

The etiology of inflammatory bowel disease and, in particular, Crohn's disease involves a deregulated mucosal immune system under the influence of intestinal flora and environmental factors in genetically susceptible individuals. A new hypothesis has focused on mesenteric fat hypertrophy and the presence of ectopic fat surrounding inflamed bowel, the so-called creeping fat, which are hallmarks of Crohn's disease. Mesenteric adipose tissue is currently recognized as an active actor in immunity with a capacity for mediator secretion. These mediators include classic pro- and anti-inflammatory cytokines or chemokines and hormone-like adipokines with multiple effects. Mesenteric fat participates in the course of Crohn's disease and may play an active role in the regulation of intestinal inflammation. However, little is known about the origin and role of mesenteric fat in Crohn's disease, essentially because of a lack of experimental models that develop creeping fat. The purpose of this review is to present the recent data describing the immune properties of mesenteric fat and the recent advances in animal models, which have suggested a new hypothesis about the role of creeping fat in Crohn's disease.     

Dipeptidyl peptidase IV in inflammatory bowel diseases (DPP IV/CD26)

Inflammatory bowel diseases (Crohn's disease, ulcerative colitis, undetermined colitis) are a group of chronic autoimmune inflammatory diseases distinguished by recurrent inflammation of various parts of the gastrointestinal (GI) system and presenting a significant public health problem. Despite large basic and clinical research, the aetiology of these diseases and the pathogenesis of inflammation itself remain elusive. Previous studies have confirmed a causal relationship between mediators of inflammatory response and molecules involved in the regulation of their biological activity, especially proteases. The aim of this review is to summarise earlier findings on different aspects of inflammatory bowel diseases, paying particular attention to the involvement of dipeptidyl peptidase IV (CD26 molecule, DPP IV/CD26) in the etiopathogenesis of inflammatory processes in the GI tract. Animal studies of colitis have significantly contributed to the understanding and treatment of these diseases, investigations of ulcerative colitis (DSS-colitis) and Crohn's disease (TNBS-colitis) on the murine model in particular.     

Enteral feeding in inflammatory bowel disease

PURPOSE OF REVIEW: Treatment algorithms for inflammatory bowel disease are changing rapidly. Increased and earlier use of immunomodulatory drugs and availability of biologic agents have reduced dependence on corticosteroids and made mucosal healing a realistic goal. It is timely to debate the role of enteral nutrition in this evolving therapeutic armamentarium for Crohn's disease, and to examine the mechanisms of its anti-inflammatory effects in light of current understanding of disease pathogenesis. RECENT FINDINGS: Clinical studies have suggested that response to enteral nutrition is associated with decreased mucosal inflammation in Crohn's disease, that isolated Crohn's colitis is less responsive and that exclusive enteral nutrition is required. Basic research has demonstrated that lipids in the intestinal lumen can alter signalling of the mucosal immune system by intestinal epithelial cells. Exclusive enteral nutrition is associated with alteration of enteric microflora. SUMMARY: Enteral nutrition is an efficacious treatment of active inflammation involving the ileum; recent-onset disease may be particularly responsive. The significance of effects on enteric flora deserves further exploration in view of the importance of microbes to disease pathogenesis.     

Crohn's disease associated to chordoma: a case report

Crohn's disease is an inflammatory bowel disease characterized by remissions and exacerbations. Immunosuppressants are frequently used to induce and maintain remission in these patients. The use of the immunomodulator azathioprine has been associated to malignancies. Chordomas are rare, locally aggressive tumors arising from remnants of the notochord. A specific trigger for this tumor has not been identified and association to any medication has not been reported. The purpose of this report is to present the first case reported in the literature of Crohn's disease associated to a chordoma. The patient to be presented was on azathioprine therapy, among other medications. A review of literature revealed that Crohn's disease and chordoma have abnormalities in chromosomes 1 and 10. Inflammatory bowel disease and chordoma also have abnormalities in chromosomal regions 1p, 3p, and 7q. Despite these findings, a direct genetic relationship between these diseases is speculative.     

Cytokines and immunotherapy in infectious diseases

Cytokines are essential mediators in infection and inflammation. Almost all cytokines have not only positive but also noxious effects: the proinflammatory cytokines released during severe infections in high concentrations lead to organ damage and death. The antagonistic anti-inflammatory cytokines inhibit the defense against infections. Immunotherapy through modulation of the cytokine response may aim at inhibition of the proinflammatory and reinforcement of the anti-inflammatory cytokine response, so as to limit the damage of inflammation. In patients with sepsis this has so far been little successful, probably owing to the multiple effects of the cytokines. Inhibition of proinflammatory cytokines was successful, on the other hand, in patients with rheumatoid arthritis or Crohn's disease. Another possibility is to aim, on the contrary, at reinforcement of the proinflammatory and inhibition of the anti-inflammatory cytokine response, to strengthen the resistance of the host. This has given favourable results in a limited number of infections.     

Polymorphisms of the Toll-like receptor 4 gene and their potential role in infectious diseases and chronic inflammatory disorders

The Toll-like receptor 4 is a key mediator of the innate immune response. Besides its main ligand, the Gram-negative bacterial lipopolysaccharides, other molecules such as heat-shock protein 60, oxidized low density lipoprotein and fibronectin can also bind to the receptor. Activation of the Toll-like receptor induces the production of proinflammatory cytokines. There is increasing evidence showing that the Toll-like receptor 4 plays a role not only in the immune reaction against infectious agents but also in chronic non-infectious inflammatory diseases, such as atherosclerosis, diabetes mellitus and inflammatory bowel disease. This review briefly summarizes recent knowledge on the Toll-like receptor 4, its common co-segregation polymorphisms and the impact of these polymorphisms on various human diseases.     

Inflammatory bowel disease: nutritional implications and treatment

It is clear that the nutritional state of patients with inflammatory bowel disease is often impaired and that the provision of nutritional support results in an improvement in nutritional state of these patients. Improvement in nutritional status can be achieved as effectively with enteral as with parenteral nutrition. The nutritional support appears to have no primary therapeutic effect in patients with ulcerative colitis. With regard to nutritional support in Crohn's disease, parenteral nutrition should be restricted to use as supportive rather than primary therapy. Available information now seems to suggest that most of the benefits of parenteral nutrition in Crohn's disease are related to improvement in nutritional state rather than as primary therapy, and its use should be restricted to treatments of specific complications of Crohn's disease, such as intestinal obstruction, related to stricture formation or short bowel syndrome following repeated resection. The present available evidence indicates that defined elemental diets may have a primary therapeutic role in the management of first acute attacks of Crohn's disease when there is a need to improve the nutritional status of patients with inflammatory bowel disease as an adjunct to primary drug therapy. Enteral nutrition is as efficacious as parenteral nutrition; moreover, it is safer to administer and more cost-effective.     

Probable Crohn's colitis mimicking ischaemic colitis in a young adult

The features on barium enema of ischaemic colitis is characteristic and the radiological sign of "thumb printing" thought to be almost pathognomonic of the condition. We report a case of inflammatory bowel disease, probably Crohn's disease mimicking these radiological features. This has not to our knowledge been previously documented.     

Surgical management of inflammatory bowel diseases

The development of the medical management of the inflammatory bowel disease (IBD-ulcerative colitis, Crohn's disease) has reduced the number of the acute surgical interventions. Beyond the medical treatment the surgical management, the operative modalities, the pre and postoperative care has gone through a lot of changes. They review the different types of surgical alternatives and debating on the advantages and disadvantages, they put emphasis on the different surgical solutions of the Crohn's disease and that of the ulcerative colitis. Among the applied surgical alternatives to the ulcerative colitis they discuss the traditional proctocolectomy with end-ileostomy, the Kock-reservoir (as continent stoma), as well as the restorative proctocolectomy which is sufficient to preserve the anal continence. Principles of the surgery of the Crohn's disease are discussed according to the localisation of the inflammatory process (small bowel, colonic, rectal, anal channel). Because of the predisposition of relapses and the necessity of the successive surgical therapy, the extensive resections should be avoided.     

Is there clustering of inflammatory bowel disease at birth?

Evidence points to possible cohort effects in inflammatory bowel disease, the possible role of perinatal infection as a risk factor for inflammatory bowel disease, and the occurrence of clusters of Crohn's disease. This evidence suggests the value of searching for birth date clustering among cases of inflammatory bowel disease. The authors looked for clustering by birth date and maternal residence at birth in a population-based series of 845 Crohn's disease patients and 1,330 ulcerative colitis patients born from 1924 through 1957 and diagnosed in the Uppsala Health Care Region, Sweden, until the end of 1983. Over this period, 43% of persons with Crohn's disease had been born within 6 days of another case, compared with 36% of controls simulated to account for monthly variation in births (p = 0.0002). The number of pairs of inflammatory bowel disease cases whose births occurred in the same county (close in space) and whose birth dates were also close in time was statistically significantly greater than expected for most birth dates 23-57 days apart. Results after 1944, when ascertainment was more complete, generally corroborate these findings and suggest some seasonality in the birth dates of ulcerative colitis cases. Results from the entire study period and after 1944 thus provide evidence for clustering by birth (including seasonality) among Crohn's disease cases and also, to a lesser extent, among ulcerative colitis cases.     

Epidemiology of Crohn's disease and ulcerative colitis in a central Canadian province: a population-based study.

The aim of this study was to assess the accuracy and utility of administrative health data in identifying persons with inflammatory bowel disease on a population basis and to determine the incidence and prevalence of this disease in the Canadian province of Manitoba. The data from Manitoba Health (the province's single insurer) were used to identify residents with physician and/or hospital contacts for Crohn's disease or ulcerative colitis based on International Classification of Diseases, Ninth Revision, Clinical Modification, codes between 1984 and 1995. Of 5,182 eligible individuals, 4,514 were mailed questionnaires and 2,725 responded. Cases were defined as individuals with five or more separate medical contacts with one of these diagnoses or three or more such contacts if they were resident for less than 2 years. The accuracy of the study case definitions was high when compared with either self-report or chart review. The 1989-1994 age- and sex-adjusted annual incidence was 14.6/100,000 for Crohn's disease and 14.3/100,000 for ulcerative colitis. The prevalence of Crohn's disease in 1994 was 198.5/100,000, and that of ulcerative colitis was 169.7/100,000. In conclusion, the authors have successfully established and validated a population-based database of inflammatory bowel disease based on administrative data. The high incidence rates and dynamic epidemiology of inflammatory bowel disease in Manitoba indicate the presence of important environmental risk factors, which warrants further investigation.     

Evaluation of psychological disorders in Tunisian patients with inflammatory bowel disease. A comparative case-control study

AIM: To evaluate the psychological state in Tunisian patients with inflammatory bowel disease using the general health questionnaire in 12 items. METHODS: A prospective case-control study was performed, including 60 cases of Crohn's disease. 60 cases of ulcerative colitis and 60 healthy control subjects. The total score of the general health questionnaire was calculated on the basis of 0-0-1-1 system. RESULTS: The total score of the general health questionnaire was significantly higher in inflammatory bowel disease patients compared to control group (3.70+3,57 vs 0,16+ 0,52, p<0.0001). In inflammatory bowel disease patients, the total score of the general health questionnaire was significantly higher in Crohn's disease patients compared to ulcerative colitis patients (4,40+3,84 vs 3.01+3.18,p=0.03) and in case of active disease compared to quiescent disease (5,57+3.18 vs 1,64+2,78,p<0.0001). CONCLUSION: Psychological disorders are frequent in Tunisian patients with inflammatory bowel disease, essentially in patients with Crohn's disease or in case of active disease.     

Nutrition in inflammatory bowel disease

Clinical and basic research continues to expand our understanding of the complex pathogenesis of inflammatory bowel diseases. The potential roles played by fatty acid intake, serum leptin, and nitric oxide in the promotion of intestinal inflammation in Crohn's disease and ulcerative colitis will be reviewed. In addition, important advances in the areas of bone disease, vitamin deficiency, growth failure, and home parenteral nutrition will be discussed.     

慢性盆腔炎患者促炎因子与抗炎因子的关系

目的:探讨慢性盆腔炎患者血清促炎因子与抗炎因子的表达与相关性。方法:选择87例慢性盆腔炎患者作为病例组,选择同期健康体检妇女69例作为对照组,ELISA法检测血清TNF-α、IL-1β、IL-6和抗炎细胞因子IL-4、IL-10的表达。结果:病例组患者血清TNF-α、IL-1β和IL-6表达高于对照组(P<0.05),而血清IL-4和IL-10表达低于对照组(P<0.05);病例组患者血清促炎因子的表达与抗炎因子的表达呈负相关(P<0.05)。结论:慢性盆腔炎患者促炎因子过度激活,而抗炎因子被抑制,并且二者表达具有一定的相关性,共同促进慢性盆腔炎的发生发展。     

Chlamydia trachomatis and inflammatory bowel disease--a coincidence?

Serological tests of 35 patients suffering from inflammatory bowel disease were compared to those of 35 healthy controls. The tests were performed using the indirect immunoperoxidase assay. Ninety-three per cent of 15 patients with Crohn's disease had IgG antibodies against Chlamydia, compared to 26% in the control group. In the 20 patients with ulcerative colitis, 45% had IgG antibodies against Chlamydia, compared to 10% in the control group. High serum titres of IgG antibodies were found in most of the patients with inflammatory bowel disease, mainly with Crohn's disease, while weak reactions appeared in most of the controls in which antibodies were detected. These results suggest a high incidence of Chlamydia infection in the studied patients with inflammatory bowel disease, especially in those with Crohn's disease. The possible association between Chlamydia trachomatis and inflammatory bowel disease is discussed.