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Background: Although long-term steroid treatment is discouraged in ulcerative colitis, alternatives are lacking when therapy with immunosuppressant drugs fails. An insufficient level of phosphatidylcholine in colonic mucus is a possible pathogenetic factor for ulcerative colitis.Objective: To see whether steroid withdrawal is easier with retarded-release phosphatidylcholine or placebo in adults with chronic steroid-refractory ulcerative colitis.Design: Randomized, double-blind, placebo-controlled trial conducted from March 2003 to January 2006.Setting: University Hospital Heidelberg, a referral center for inflammatory bowel disease.Patients: 60 patients with chronic steroid-refractory ulcerative colitis and high clinical and endoscopic disease activity indexes (score > or =5).Intervention: Phosphatidylcholine or cellulose placebo was ingested 4 times daily for 12 weeks for a total dosage of 2 g/d. The follow-up rate was 97%.Measurements: The number of patients achieving complete steroid withdrawal and either a low clinical activity index (< or =3) or improvement in the clinical activity index of 50% or more.Results: The primary end point was achieved in 15 of 30 (50%) phosphatidylcholine recipients and in 3 of 30 (10%) placebo recipients (difference, 40% [95% CI, 19% to 61%]; P = 0.002). Twenty-four phosphatidylcholine recipients (80%) and 3 (10%) placebo recipients discontinued steroid therapy without disease exacerbation (difference, 70% [CI, 52% to 88%]; P <0.001). Mild bloating was a common adverse event.Limitations: The sample size was small, and the study was of short duration.Conclusion: Phosphatidylcholine reduced corticosteroid dependence more than placebo in patients with chronic steroid-refractory ulcerative colitis. The next step is long-term trials to evaluate the sustainability of steroid withdrawal in these patients. ClinicalTrials.gov registration number: NCT00259545. [ABSTRACT FROM AUTHOR]

The antiapoptotic Livin/ML-IAP gene has recently gained much attention as a potential new target for cancer therapy. Reports indicating that livin is expressed almost exclusively in tumours, but not in the corresponding normal tissue, suggested that the targeted inhibition of livin may present a novel tumour-specific therapeutic strategy. Here, we compared the expression of livin in renal cell carcinoma and in non-tumorous adult kidney tissue by quantitative real-time reverse transcription-PCR, immunoblotting, and immunohistochemistry. We found that livin expression was significantly increased in tumours (P=0.0077), but was also clearly detectable in non-tumorous adult kidney. Transcripts encoding Livin isoforms alpha and beta were found in both renal cell carcinoma and normal tissue, without obvious qualitative differences. Livin protein in renal cell carcinoma samples exhibited cytoplasmic and/or nuclear staining. In non-tumorous kidney tissue, Livin protein expression was only detectable in specific cell types and restricted to the cytoplasm. Thus, whereas the relative overexpression of livin in renal cell carcinoma indicates that it may still represent a therapeutic target to increase the apoptotic sensitivity of kidney cancer cells, this strategy is likely to be not tumour-specific. [ABSTRACT FROM AUTHOR]

Background and aims: We examined the hypothesis of an anti-inflammatory effect of phosphatidylcholine in ulcerative colitis. Methods: A phase IIA, double blind, randomised, placebo controlled study was performed in 60 patients with chronic active, non steroid dependent, ulcerative colitis, with a clinical activity index (CAl) of ⩾4. Retarded release phosphatidyicholine rich phospholipids and placebo were administered at a dose of 6 g daily over three months. The primary end point was a change in CAl towards clinical remission (CAl ⩽ 3) or CAl improvement by ⩾50%. Secondary end points included ⩾50% changes in endoscopic activity index (EAl), histology, and quality of life scores. Results: Induction of clinical remission (CAl ⩽ 3) as the primary outcome variable was attained by 16 (53%) patients in the phosphatidylcholine treated group compared with three (10%) in the placebo group (p<0.00001). The rate of clinical remission and CAl improvement was 90% in the phosphatidylcholine group and only 10% in the placebo group. A median drop of seven points in the CAl score (70% improvement) was recorded in the phosphatidylchohine group compared with no change in the placebo group. Secondary end point analysis revealed concomitant drops in EAI and histology scores (p = 0.00016 and p = 0.0067 compared with placebo, respectively). Improvement in quality of life was reported by 16 of 29 evaluated patients in the phosphatidylcholine group compared with two of 30 in the placebo group (p=0.00005). Conclusion: Retarded release oral phosphatidylcholine is effective in alleviating inflammatory activity caused by ulcerative colitis. [ABSTRACT FROM AUTHOR]

Background and aims: Erroneous thymic selection of developing T lymphocytes may be responsible for the expansion of self reactive T cells or may contribute to the absence of regulatory T cells important in controlling peripheral inflammatory processes. Colitis in bone marrow (BM) transplanted Tg∊26 mice is induced by abnormally activated T cells developing in an aberrant thymic microenvironment. We investigated the protective role of regulatory CD4+CD25+ T cells in this model. Methods: BM from (C57B1/6 × CBA/J) F1 mice was transplanted into specific pathogen free Tg∊26 mice (BM→Tg∊26). Transplanted mice received no cells (control), sorted CD4+CD25+, or CD4+CD25+ cells from mesenteric lymph nodes (MLN) of normal mice. MLN cell subsets were analysed using membrane markers. Cytokine secretion of MIN cells was measured using intracellular cytokine staining and cytokine secretion in anti-CD3 stimulated cell cultures. Colitis was measured by histological scores. Results: CD4+CD25- cells were reduced in the MINs of BM=→Tg∊26 mice. Transfer of regulatory CD4+CD25+ but not of CD4+CD25+ cells reduced the number of MIN CD4+ T cells in BM=→Tg∊26 recipients and increased the number of MLN CD8+ cells, thereby normalising the CDt/CD8+ ratio. CD4+CD25+ but not CD4+CD25+ cell transfer into BM=→Tg∊26 mice reduced the number of tumour necrosis factor α+ CD+ cells and increased the secretion of transforming growth factor β by MIN cells. Transfer of 3 × 105 CD4+CD25+ cells after BM transplantation into Tg∊26 mice prevented colitis whereas CD4+CD25+ cells had no protective effect. Conclusions: These results suggest that defective selection or induction of regulatory I cells in the abnormal thymus is responsible for the development of colitis in BM=→Tg∊26 mice. Transfer of CD4+CD25+ cells can control intestinal inflammation in BM=→Tg∊26 mice by normalising the number and function of the MIN T cell pool. [ABSTRACT FROM AUTHOR]

Background: The causes of Crohn disease (CD) are still regarded as unknown, but impaired mucosal immunoregulation with activation of T-helper-1 (Th-1) cytokine responses is probably involved and may contribute to the morphological changes. We investigated a possible role of osteopontin (Opn) in the pathogenesis of CD. This glycoprotein has been suggested to be involved in the generation of Th-1-type immune responses; moreover, it carries anti-inflammatory activities. Methods: Ileal samples from CD patients—both actively inflamed and inactive areas as well as unaffected intestinal specimens from controls (normal ileum)—were investigated by Western blot analysis, immunohistochemistry and in situ hybridization. Results: In normal gut, Opn was found to be regularly expressed by plasma cells (CD 38) and a subset of lamina propria mononuclear cells (MNC) as well as by intestinal epithelial cells (IEC). In active CD, immunohistochemistry and in situ hybridization analysis revealed a loss of Opn expression by IEC adjacent to ulcerative lesions, whereas especially plasma cells (CD 38) in the vicinity of such lesions were found to express the molecule. In addition, a slight overexpression of Opn protein was found in metaplastic crypts. However, quantitative analysis of total Opn protein in the ileal mucosa of CD patients did not reveal any difference vis-à-vis control tissues. Conclusions: The constitutive expression of Opn in normal gut indicates that it is involved in intestinal immune homeostasis. Downregulation of Opn expression in IEC might favour the disintegration of the epithelial barrier. The expression of Opn in lamina propria plasma cells could contribute to disease chronification, probably by affecting cell survival. [ABSTRACT FROM AUTHOR]

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (slL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type I T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of slL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that slL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-slL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-slL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD. [ABSTRACT FROM AUTHOR]

The article details the development, monitoring and first immunological results of a vaccination trial using genetically modified allogeneic breast cancer cells. It correlates vaccine-induced immune responses with clinical responses. The article evaluates KS24.22-associated and tumor associated antigens (TAA)-specific T cells with a combination of molecular and cellular immunodiagnostic tests.