Perspectives of the International Society for Cell & Gene Therapy Gastrointestinal Scientific Committee on the Intravenous Use of Mesenchymal Stromal Cells in Inflammatory Bowel Disease (PeMeGi).

Inflammatory bowel disease (IBD), namely, Crohn's disease and ulcerative colitis, remains a grievous and recalcitrant problem incurring significant human and health care costs, even in consideration of the growing incidence. Initial goals of care aimed to achieve the induction and maintenance of clinical remission. The advent of novel treat-to-target approaches using patient stratification, early introduction of immunosuppressants and rapid escalation to biologics or early use of combination therapy has refocused the goals of care toward the achievement of mucosal healing. This is in an attempt to preserve intestinal function, decrease hospitalization and surgery rates and improve the quality of life of affected patients. Cellular therapeutics for the treatment of IBD offers an unprecedented opportunity to change the current paradigm from single-targeted to systems-targeted therapy, trying to dampen the whole inflammatory cascade instead of a only molecule. Therefore, as we move forward, the importance of designing informative and possibly adaptive trial designs, standardizing methodologies, harmonizing goals of therapy and evaluating methods cannot be underemphasized. In this article, we review the current literature on the application of mesenchymal stromal cells for the treatment of IBD in an effort to establish a consensus on designing efficient and consistent clinical trials for the intravenous use of this cellular therapy in IBD.

Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study.

BACKGROUND: Vedolizumab, a monoclonal antibody targeting the α4ß7-integrin, is effective in inducing and maintaining clinical remission in Crohn's disease and ulcerative colitis according to randomised clinical trials. AIM: To determine the long-term effectiveness of vedolizumab in a real-world clinical setting. METHODS: This observational registry assessed the clinical outcome in patients treated with vedolizumab for clinically active Crohn's disease (n = 67) or ulcerative colitis (n = 60). Primary endpoint was clinical remission (HBI ≤ 4/pMayo ≤ 1) at week 54. Secondary endpoints included clinical response rates (HBI/pMayo score drop ≥3) and steroid-free clinical remission at weeks 30 and 54. RESULTS: Vedolizumab was stopped in 69/127 (56%) patients after a median time of 18 weeks (range 2-49) predominantly owing to lack or loss of response. Using nonresponder imputation analysis, clinical remission and steroid-free remission rates were 21% and 15% in Crohn's disease and 25% and 22% in ulcerative colitis, respectively. Lack of clinical remission was associated with prior treatment with anti-TNF or with steroids for more than 3 months in the last 6 months in ulcerative colitis. At week 14, the absence of remission in Crohn's disease or nonresponse in ulcerative colitis indicated a low likelihood of clinical remission at week 54 [2/31 (7%) in Crohn's disease, 4/41 (10%) in ulcerative colitis]. Accordingly, declining C-reactive protein in inflammatory bowel disease and/or lower faecal calprotectin in ulcerative colitis at week 14 predicted remission at week 54. CONCLUSION: Among patients who started vedolizumab for active inflammatory bowel disease, clinical remission rates are 21-25% after 54 weeks.

Autoimmunity in Crohn's Disease-A Putative Stratification Factor of the Clinical Phenotype.

Inflammation in inflammatory bowel diseases (IBD) has been linked to a loss of tolerance to self-antigens suggesting the existence of autoantibodies in specific disease phenotypes. However, the lack of clearly defined autoantigenic targets has slowed down research. Genome-wide association studies have identified an impressive number of immune-related susceptibility loci for IBD with no clearly discernible pattern among them. Growing evidence supports the hypothesis that innate immune responses to a low-diversity and impaired gut microbiota may be of key importance in initiating and perpetuating chronic inflammation in IBD. Increasing evidence suggests that reduced microbial diversity and microbial-mucosal epithelium interaction (including adhesion and clearance) are critically involved in IBD pathogenesis. Along these lines the discovery of autoantigenic targets in Crohn's disease (CD) has refocused research in IBD on the possible role of autoimmune responses. The identification of the major zymogen granule membrane glycoprotein 2 (GP2) as an autoantigen in CD patients and its proposed role in the sensing of the microbiota lends credence to this trend. Loss of tolerance to GP2 occurs in up to 40% of patients with CD. Corresponding autoantibodies appear to be associated with distinct disease courses (types or phenotypes) in CD. Here, we critically review autoantibodies in CD for their impact on clinical practice and future IBD research. The immunomodulatory role of GP2 in innate and adaptive intestinal immunity is also discussed.

Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study.

BACKGROUND: Ferric maltol was effective and well-tolerated in iron deficiency anaemia patients with inflammatory bowel disease during a 12-week placebo-controlled trial. AIM: To perform a Phase 3 extension study evaluating long-term efficacy and safety with ferric maltol in inflammatory bowel disease patients in whom oral ferrous therapies had failed to correct iron deficiency anaemia. METHODS: After 12 weeks of randomised, double-blind treatment, patients with iron deficiency anaemia and mild-to-moderate ulcerative colitis or Crohn's disease received open-label ferric maltol 30 mg b.d. for 52 weeks. RESULTS: 111 patients completed randomised treatment and 97 entered the open-label ferric maltol extension. In patients randomised to ferric maltol ('continued'; n = 50), mean ± s.d. haemoglobin increased by 3.07 ± 1.46 g/dL between baseline and Week 64. In patients randomised to placebo ('switch'; n = 47), haemoglobin increased by 2.19 ± 1.61 g/dL. Normal haemoglobin was achieved in high proportions of both continued and switch patients (89% and 83% at Week 64, respectively). Serum ferritin increased from 8.9 µg/L (baseline) to 26.0 µg/L (Week 12) in ferric maltol-treated patients, and to 57.4 µg/L amongst all patients at Week 64. In total, 80% of patients reported ≥1 adverse event by Week 64. Adverse events considered related to ferric maltol were recorded in 27/111 (24%) patients: 8/18 discontinuations due to adverse events were treatment-related. One patient was withdrawn due to increased ulcerative colitis activity. CONCLUSIONS: Normal haemoglobin was observed in ≥80% of patients from weeks 20-64 of long-term ferric maltol treatment, with concomitant increases in iron storage parameters. Ferric maltol was well-tolerated throughout this 64-week study.

Vedolizumab induction therapy for inflammatory bowel disease in clinical practice--a nationwide consecutive German cohort study.

BACKGROUND: Vedolizumab (VDZ) is a humanised monoclonal IgG1 antibody targeting α4 ß7 integrin. AIM: To investigate the real-world efficacy of vedolizumab for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A consecutive cohort of 212 adult IBD patients with active disease (HBI >7/partial Mayo >4) newly receiving VDZ was prospectively recruited from 7 academic and 17 community centres. The primary endpoint was clinical remission (CRM) (CD HBI ≤4, UC pMayo ≤1) in week 14. Secondary endpoints included steroid-free remission (SFCRM), clinical response (CRS) (HBI/pMayo score drop ≥3), vedolizumab impact on CRP, calprotectin and haemoglobin. RESULTS: Data of 97 CD (71.1% female, HBI 11) and 115 UC (42.6% female, pMayo 6) patients were analysed. Only 5.2% CD and 24.3% UC were anti-TNFα naïve. Most had extensive mucosal involvement (Montreal L3 69.1%/E3 53.9%). At week 14, 23.7% vs. 23.5% of CD vs. UC patients achieved CRM, 19.6% vs. 19.1% SFCRM and 60.8% vs. 57.4% CRS, respectively (all based on NRI). Week 14 CRM in CD was significantly associated with no history of extraintestinal manifestations (P = 0.019), no prior adalimumab use (P = 0.011), no hospitalisation in the past 12 months (P = 0.015) and low HBI score (P = 0.02) and in UC with active or previous smoking (P = 0.044/0.028) and no anti-TNFα (P = 0.023) use. Low HBI (P = 0.019) and no hospitalisation in the past 12 months (P = 0.01) predict CD CRM. The three most common AE were joint pain, acne and nasopharyngitis. CONCLUSION: Vedolizumab is effective in routine use.

Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues.

BACKGROUND AND AIMS: Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. METHODS: In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. RESULTS: We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. CONCLUSIONS: Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.

Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn's disease and ulcerative colitis.

Dendritic cell (DC) function is believed to be of critical importance for the pathogenesis of inflammatory bowel disease (IBD). To date, most research in animal models and the few human data available is restricted to myeloid DC, while plasmacytoid DC (pDC) capable of controlling both innate and adaptive immune responses have not yet been investigated systematically in human Crohn's disease (CD) or ulcerative colitis (UC). CD11c(-) , CD303(+) /CD304(+) and CD123(+) pDC from peripheral blood (n = 90), mucosal tissue (n = 28) or mesenteric lymph nodes (n = 40) (MLNs) of patients with UC and CD or controls were purified and cultured. Thereafter, pDC were enumerated, phenotyped and cytokine secretion measured by flow cytometry (FACS), immunohistochemistry and/or cytometric bead array, respectively. Interferon (IFN)-α secretion following cytosine phosphatidyl guanine (CpG) A oligodeoxynucleotide (ODN) 2216 (5'-GGGGGACGATCGTCGGGGGG-3') stimulation was assessed by enzyme-linked immunosorbent assay (ELISA). We found a significantly higher frequency of pDC in the inflamed colonic mucosa and MLN of IBD patients. Moreover, the fraction of CD40 and CD86 expressing cultured peripheral blood pDC was significantly higher in flaring UC and CD patients and their secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 were increased significantly compared with controls. In contrast, the IFN-α secretion of peripheral blood pDC isolated from flaring IBD, particularly in UC patients, was reduced significantly compared with controls. Our data suggest an aberrant distribution and function of pDC in IBD, contrary to their generally implicated role as inducers of tolerance. We speculate that the impaired IFN-α secretion may relate to the hypothesized defect in innate immunity in IBD and could also impact upon the generation of regulatory T cells (T(reg) ).

Exaggerated inflammatory response of primary human myeloid dendritic cells to lipopolysaccharide in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) results from a breakdown of tolerance towards the indigenous flora in genetically susceptible hosts. Failure of dendritic cells (DC) to interpret molecular microbial patterns appropriately when directing innate and adaptive immune responses is conceivable. Primary (conventional, non-monocyte generated) CD1c(+)CD11c(+)CD14(-)CD16(-)CD19(-) myeloid blood or mucosal dendritic cells (mDC) from 76 patients with Crohn's disease (CD) or ulcerative colitis (UC) in remission, during flare-ups (FU) and 76 healthy or non-IBD controls were analysed by fluorescence activated cell sorter (FACS) flow cytometry and real-time polymerase chain reaction. Cytokine secretion of freshly isolated, cultured and lipopolysaccharide (LPS)-stimulated highly purified mDC (purity >95%) was assessed using cytometric bead arrays (CBA). More cultured and stimulated circulating mDC express CD40 in IBD patients. Stimulated circulating mDC from IBD patients secrete significantly more tumour necrosis factor (TNF)-alpha and interleukin (IL)-8. Toll-like receptor (TLR)-4 expression by mDC was higher in remission and increased significantly in flaring UC and CD patients compared with remission (P < 0.05) and controls (P < 0.001). Fluorochrome-labelled LPS uptake by mDC was evaluated at different time-points over 24 h by measuring mean fluorescence intensity (MFI). Circulating mDC from IBD patients take up more LPS and the uptake begins earlier compared with controls (P < 0.05 in CD-FU and UC-FU at 24 h). The frequency of mucosal mDC (P < 0.05) and the number of CD40 expressing mucosal mDC is significantly greater in UC and CD compared with non-IBD controls (P < 0.001 versus P < 0.01, respectively). Our data suggest an aberrant LPS response of mDC in IBD patients, resulting in an inflammatory phenotype and possibly intestinal homing in acute flares.

Saccharomyces boulardii inhibits lipopolysaccharide-induced activation of human dendritic cells and T cell proliferation.

Saccharomyces boulardii (Sb) is a probiotic yeast preparation that has demonstrated efficacy in inflammatory and infectious disorders of the gastrointestinal tract in controlled clinical trials. Although patients clearly benefit from treatment with Sb, little is known on how Sb unfolds its anti-inflammatory properties in humans. Dendritic cells (DC) balance tolerance and immunity and are involved critically in the control of T cell activation. Thus, they are believed to have a pivotal role in the initiation and perpetuation of chronic inflammatory disorders, not only in the gut. We therefore decided to investigate if Sb modulates DC function. Culture of primary (native, non-monocyte-derived) human myeloid CD1c+CD11c+CD123(-) DC (mDC) in the presence of Sb culture supernatant (active component molecular weight < 3 kDa, as evaluated by membrane partition chromatography) reduced significantly expression of the co-stimulatory molecules CD40 and CD80 (P < 0.01) and the DC mobilization marker CC-chemokine receptor CCR7 (CD197) (P < 0.001) induced by the prototypical microbial antigen lipopolysaccharide (LPS). Moreover, secretion of key proinflammatory cytokines such as tumour necrosis factor-alpha and interleukin (IL)-6 were notably reduced, while the secretion of anti-inflammatory IL-10 increased. Finally, Sb supernatant inhibited the proliferation of naive T cells in a mixed lymphocyte reaction with mDC. In summary, our data suggest that Sb may exhibit part of its anti-inflammatory potential through modulation of DC phenotype, function and migration by inhibition of their immune response to bacterial microbial surrogate antigens such as LPS.

Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn's disease but also ulcerative colitis.

BACKGROUND: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. AIM: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. METHODS: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. RESULTS: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. CONCLUSIONS: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.

Nephrotoxicity of iso-osmolar versus low-osmolar contrast media is equal in low risk patients.

BACKGROUND: Contrast media-induced nephropathy (CIN) is an increasing cause of hospital-acquired acute kidney injury and leads to a significant increase in mortality. There is uncertainty whether the use of iso-osmolar contrast media as opposed to the use of low-osmolar contrast media would be associated with a lower incidence of CIN. Therefore, we compared the nephrotoxicity of isoosmotic contrast media iodixanol with the low-osmotic contrast media iopromid in patients receiving contrast media during coronary angiography. METHODS: In this prospective double-blind study we examined 221 patients with normal renal function who received up to 1,000 ml of contrast media during coronary angiography, and compared the effect of iodixanol and iopromid on inducing contrast media nephropathy. Patients received 800 ml fluid orally before contrast media administration and 1,000 ml saline i.v. thereafter. Creatinine clearance, serum creatinine and urine-N-acetyl-beta-D-glucosaminidase (NAG) concentration was obtained 24 h before and 48 h after contrast media administration. Decrease of 20% of the creatinine clearance, increase of 25% of serum creatinine and increase of 20% of the urine concentration of NAG was defined as CIN. RESULTS: Incidence of CIN assessed by decreased creatinine clearance was 22.2% in the iopromid group and 19.7% in the iodixanol group. CIN defined by increased serum creatinine was 6.9% in the iopromid group and 8.6% in the iodixanol group. The difference between these two groups was not significant. Subgroup analysis of the diabetic patients or the patients that received high dose of contrast media revealed no significant difference in the incidence of CIN between the two contrast media. CONCLUSION: The iso-osmolar and the low-osmolar contrast media exhibited the same incidence of CIN in our study population. If fluid administration is sufficient, the selection of either iopromid or iodixanol has no impact on the risk of developing CIN in patients with normal renal function, even when they are diabetic or receive a high dose of more than 500 ml contrast media.

Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells.

BACKGROUND: Breakdown of tolerance against the commensal microflora is believed to be a major factor in the pathogenesis of inflammatory bowel disease (IBD). Dendritic cells (DC) have been implicated in this process in various animal models, but data on human DC in IBD are very limited. AIM: To characterise plasmacytoid DC (PDC) and myeloid DC (MDC) in patients with active versus inactive IBD and healthy controls. PATIENTS AND METHODS: Peripheral blood was obtained from 106 patients (Crohn's disease (CD) n=49, ulcerative colitis (UC) n=57) and healthy controls (n=19). Disease activity was scored using the modified Truelove Witts (MTWSI) for UC and the Harvey Bradshaw severity indices (HBSI) for CD. Four colour flow cytometric analysis was used to identify, enumerate, and phenotype DC. DC from patients with acute flare ups and healthy controls were cultured and stimulated with CpG ODN 2006 or lipopolysaccharide (LPS). RESULTS: IBD patients in remission (PDC UC, 0.39%; CD, 0.35%; MDC-1 UC, 0.23%; CD, 0.22% of PBMC) have slightly lower numbers of circulating DC compared with healthy controls (PDC 0.41%, MDC-1 0.25% of PBMC). In acute flare ups IBD patients experience a significant drop of DC (PDC UC, 0.04%; CD, 0.11%; MDC-1 UC, 0.11%; CD, 0.14% of PBMC) that correlates with disease activity (correlation coefficients: PDC MTWSI, 0.93; HBSI, 0.79; MDC-1 MTWSI, 0.75; HBSI, 0.81). Moreover, both express alpha4beta7 integrin and display an immature phenotype. Freshly isolated PDC and MDC-1 from untreated flaring IBD patients express higher baseline levels of CD86 which increases further in culture and upon stimulation compared with healthy controls. CONCLUSION: IBD patients lack immature blood DC during flare ups which possibly migrate to the gut. An aberrant response to microbial surrogate stimuli suggests a disturbed interaction with commensals.

Insulin sensitivity and coronary vasoreactivity: insulin sensitivity relates to adenosine-stimulated coronary flow response in human subjects.

OBJECTIVE: Diabetes is associated with coronary microvasculature abnormalities and impaired coronary flow reserve (CFR). CFR is the ratio of coronary flow under maximal vasodilation to basal flow and is a measure for coronary vasoreactivity. Insulin resistance is the central defect in the development of type 2 diabetes, preceding its onset by 10-20 years. Thus, the relationship between insulin sensitivity and CFR in nondiabetic subjects is particularly interesting. The aim of the study was to investigate this relationship. DESIGN: Cross-sectional study. PATIENTS: The study population consisted of 18 nondiabetic subjects without coronary artery stenosis on coronary angiography. We excluded patients with structural heart disease or with conditions affecting CFR or insulin sensitivity such as low density lipoprotein (LDL)-cholesterol > or = 4.14 mmol/l, smoking, hypertension or obesity with a body mass index (BMI) > 28 kg/m(2). MEASUREMENTS AND RESULTS: CFR was 3.1 +/- 0.8 (range 1.7-4.8), as assessed by intracoronary Doppler measurements in the left anterior descending coronary arteries after adenosine stimulation. Intravascular ultrasound revealed zero to moderate coronary atherosclerotic changes. Whole-body insulin sensitivity (M-value) was 7.5 +/- 2.9 mg/kg/min (range 2.2-12.6), as assessed by the hyperinsulinaemic-euglycaemic clamp test. Subjects with low CFR (< 3.0) had a significantly lower M-value than subjects with normal CFR (> 3.0) (6.0 +/- 2.5 vs. 9.0 +/- 2.5 mg/kg/min, P = 0.021). Univariate linear regression demonstrated a strong correlation between CFR and M-value (r = 0.76, P < 0.001). In multiple regression analysis, the significant association of CFR with M-value was independent of potential confounders (sex, age, BMI, LDL-cholesterol and plaque burden on intravascular ultrasound). Bootstrap analysis corroborated this finding. CONCLUSIONS: Whole-body insulin sensitivity relates to coronary vasoreactivity. Across a wide range of both insulin sensitivity and coronary flow reserve from markedly abnormal to normal values, an increase in insulin sensitivity appears to be associated with an increase in coronary flow reserve. Insulin resistance is therefore associated with coronary microvasculature abnormalities in nondiabetics.

Prognostic value of electron-beam computed tomography-derived coronary calcium scores compared with clinical parameters in patients evaluated for coronary artery disease. Prognostic value of EBCT in symptomatic patients.

OBJECTIVE: The electron-beam computed tomography-(EBCT-)derived calcium score provides a measure of coronary atherosclerotic plaque disease which may allow for more precise risk stratification in symptomatic patients. However, it remains unclear if EBCT can add prognostic information compared with the clinical information derived from risk factor assessment, exercise stress testing, and coronary angiography. METHODS AND RESULTS: A cohort of 300 consecutive patients with recent (<3 months) onset of symptoms was retrospectively identified who were examined for possible coronary artery disease (CAD) and who all underwent EBCT. Successful follow-up after 3.5 years was obtained in 255 (85%) patients whose mean age at baseline was 58+/-11 years (n = 181 (71%), males). Four clinical categories with increasing evidence of CAD were constructed on the basis of risk factor assessment, exercise stress testing, coronary angiographic anatomy, and coronary revascularization at baseline. During follow-up, major adverse cardiac events (MACE: myocardial infarction, cardiac death, revascularization) were observed in 40 (16%) patients, including myocardial infarction and cardiac death in 5 patients. The 4 clinical categories were highly predictive of MACE, with a relative risk estimate of 28.3 (95% CI, 6.7-119.1) in the upper vs. the reference category. In univariate analysis, the relative risk estimate of MACE associated with a calcium score > or =100 was 12.0 (95% CI, 4.7-30.6). After adjustment for the clinical categories and for age, this estimate decreased in multivariate analysis, but remained predictive at 4.4 (95% CI, 1.5-12.6). CONCLUSION: In patients with first-time evaluation of possible CAD, EBCT-derived coronary calcium is suggested to provide for independent and additional information compared with the clinically available information.

Review article: the aetiopathogenesis of inflammatory bowel disease--immunology and repair mechanisms.

Although the aetiopathogenesis of Crohn's disease and ulcerative colitis, remains unsolved, current evidence indicates that defective T-cell apoptosis and impairment of intestinal epithelial barrier function play important roles in the pathogenesis of both conditions. Without appropriate control of T-cell proliferation and death during an immune response, an inappropriate accumulation of T cells and subsequent intestinal inflammation may occur. Differences in T-cell responses between Crohn's disease and ulcerative colitis have been identified, with mucosal T-cell apoptosis being defective in Crohn's disease, but not in ulcerative colitis. Furthermore, cell cycling is considerably faster, with a vigorous clonal expansion, in Crohn's disease, whereas, in ulcerative colitis, T cells cycle normally, but have a remarkably reduced capacity to divide and expand. The elimination of excessive T cells therefore seems to be a reasonable approach to restore the gut to a physiological state or, at least, a controlled state of inflammation. The tumour necrosis factor-alpha blocker, infliximab, exerts its beneficial effects, at least in part, by the induction of apoptosis in lamina propria T cells and monocytes. In addition, repeated damage and injury of the intestinal surface is a hallmark of inflammatory bowel disease and may facilitate the entry of luminal antigens into the mammalian organism and the initiation and perpetuation of both nonspecific and specific immune responses. A better understanding of and enhancement of intestinal repair mechanisms may thus provide future approaches for the treatment of inflammatory bowel disease.

Colonic epithelial cell mediated suppression of CD4 T cell activation.

BACKGROUND AND AIMS: As the first point of contact with enteric antigens, intestinal epithelial cells (IEC) may be key in regulating mucosal immune responses. We determined therefore if murine colonic epithelial cells (CEC) have tolerogenic or activating effects on CD4 T cells. METHODS: Using a novel CEC, macrophages, and CD4 T cell coculture system, mitogen and antigen specific responses of naïve and antigen primed CD4 T cells were assessed. RESULTS: Although a proportion of CEC express the costimulatory molecules B7.1, B7.2, CD40, and CD54, they were unable to promote mitogen or antigen driven activation of CD4 T cells, even in the presence of exogenous costimulatory signals. CD4 T cells cocultured with CEC were CD25lo and CD45RBlo and remained in the G1 phase of the cell cycle. CEC were also able to prevent CD4 T cell activation by professional antigen presenting cells. CEC mediated suppression of T cell activation was cell contact dependent and transforming growth factor beta independent. CONCLUSIONS: These observations suggest that CEC contribute to the maintenance of T cell tolerance in the gut by preventing inappropriate activation of CD4 T cells.

[Biologic therapy of inflammatory bowel disease]. / Biologische Therapie chronisch-entzündlicher Darmerkrankungen.

Biological therapies in inflammatory bowel disease reflect the exponential advancement in understanding the human intestinal immune system and particularly the biology of intestinal inflammation during the past decade. The better understanding of the mechanisms of inflammatory bowel disease has evolved from desriptive clinical data and genetically engineered animal models. It led to great interest in the evaluation of a variety of new therapeutic agents with novel actions. This review will discuss the mechanisms of biologicals (antibodies against pro-inflammatory cytokines, T cell antibodies, anti-inflammtory cytokines, adhesion molecule blockers, growth factors, hormones, colony stimulating factors, fusion proteins, anti-sense oligonucleotides, trefoil peptides, immunostimulatory [ISS] DNA) used in the treatment of inflammatory bowel disease and summarizes the available data on established biologic therapies as well as investigational agents and briefly touch on probiotics. Based on the data discussed, it seems that biologicals will play an important role in managing inflammatory bowel disease in the near future.

Clinical and angiographic acute and follow up results of intracoronary beta brachytherapy in saphenous vein bypass grafts: a subgroup analysis of the multicentre European registry of intraluminal coronary beta brachytherapy (RENO).

OBJECTIVE: To assess clinically and angiographically the feasibility, safety, and effectiveness of vascular brachytherapy (VBT) in saphenous vein bypass grafts (SVG). PATIENTS AND METHODS: 67 of 1098 (6.1%) consecutive patients of the European registry of intraluminal coronary beta brachytherapy underwent treatment for 68 SVG lesions by VBT using a Sr/Y(90) source train (BetaCath). Clinical follow up data were obtained for all of them after a mean (SD) of 6.3 (2.4) months and angiographic follow up was performed in 61 patients (91.0%) after 6.9 (2.0) months. RESULTS: 58 (86.6%) patients were men, their mean (SD) age was 66 (10) years, 28 (41.8%) had unstable angina, and 21 (31.3%) had diabetes. Fifty three (77.9%) lesions were in-stent restenosis, 13 (19.1%) de novo lesions, and 2 (3.0%) non-stented restenotic lesions. Mean (SD) reference diameter before the intervention was 4.19 (0.52) mm, mean (SD) lesion length was 23.56 (20.38) mm, and mean (SD) minimum lumen diameter measured 0.73 (0.62) mm. Mean (SD) acute gain was 3.02 (0.88) mm. The prescribed radiation dose was 20.1 (3.2) Gy. Pullback manoeuvres were performed in 17 (25.0%) of cases. Most patients received combined aspirin and thienopyridin treatment for 6 or 12 months after the procedure. Technical success was obtained in 62 (91.2%) treated lesions and in-hospital major adverse cardiac events occurred in 4.5%. At follow up, mean (SD) reference diameter was 4.20 (0.53) mm, minimum lumen diameter 2.94 (1.50) mm, and late loss 0.86 (1.25) mm. The overall major adverse cardiac events rate was 26.7%. CONCLUSION: VBT of SVG is feasible and safe. At follow up the reintervention rate and cardiac morbidity and mortality seem to be favourable, considering that interventions in SVG usually are associated with the highest risks.

A multicentre European registry of intraluminal coronary beta brachytherapy.

AIMS: To assess the feasibility, safety and effectiveness of intravascular brachytherapy (VBT) in routine clinical practice. METHODS AND RESULTS: Between April 1999 and September 2000, 1098 consecutive patients treated in 46 European centres by intraluminal irradiation using a Sr/Y(90)source train (BetaCath, Novoste, GA) were included in a registry, and follow-up data were obtained for 98.8% of them after 6.3+/-2.4 months. Eight hundred and forty (76.5%) patients were males, and mean age was 62.0+/-10.2 years. Two hundred and seventy-one (26.9%) had unstable angina, and 256 (23.5%) were diabetics. Nine hundred and thirteen lesions (77.7%) were the result of in-stent restenosis, 208 (17.7%) were de novo lesions and 48 (4.1%) non-stented restenotic lesions. Mean estimated reference diameter was 3.2+/-0.5mm and mean estimated lesion length was 19.0+/-11.8mm. The prescribed radiation dose was 18.8+/-3.2Gy. Multivessel irradiation was done in 6.2% of cases, and a new stent was implanted in 29.6% of cases. Most patients received 6 or 12 months of combined aspirin and thienopyridin treatment after the procedure. Technical success was obtained in 95.9% of treated lesions, and the in-hospital major adverse cardiac event (MACE) rate was 1.8%. At follow-up, the MACE rate was 18.7% (1.9% deaths from any cause, 2.6% AMI, 13.3% TVR by PCI and 3.3% TVR by CABG). CONCLUSION: The major current application of VBT is the treatment of in-stent restenosis. The good results of VBT observed in recent randomized controlled trials can be reproduced in clinical practice.

[Brachytherapy after coronary interventions: current state and future perspectives]. / Brachytherapie nach koronaren Interventionen: aktueller Stand und Zukunftsperspektiven.

Intracoronary brachytherapy is a novel, meanwhile established therapy. It is currently the only interventional procedure which has proven to effectively reduce the restenosis rates after intervention of long and diffuse in-stent restenosis. For this indication, brachytherapy can be regarded as the current treatment of choice. Randomized studies yield promising results for bypass interventions or interventions in small vessels or diabetic patients. These findings may encourage the decision to perform a percutaneous, transluminal intervention in such high-risk patients. In clinical practice, implantation of new stents in combination with brachytherapy procedures should be avoided as far as possible. In any case, the combined antiaggregatory therapy should be conducted sufficiently long to minimize the danger of late stent thrombosis. Under this treatment, the expected thrombosis rates ar within the range of placebo-treated patients. The length of the radiation source should be sufficient to cover the entire interventional injury length to avoid recurrent edge stenosis. De novo lesions are currently not a routine indication for intracoronary brachytherapy. Although intracoronary brachytherapy may effectively reduce restenosis rates in sufficiently irradiated de novo lesion segments, de novo lesions should be treated only within the set-up of controlled studies. The current available data with a follow-up period of up to 5 years show that intracoronary brachytherapy is also in the mid-term a safe and effective therapy for the reduction of restenosis after coronary interventions.