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PubMed2004

IBD: a family affair.

The recent molecular advances in the understanding of the genetics of inflammatory bowel disease (IBD) have their grounding in studies examining IBD within different family groups and populations. The risk of IBD is highest in first-degree relatives of an IBD proband but more distant relatives are also at increased risk. The risk is higher for relatives of a CD proband. The risks of developing IBD for 'high-risk' relatives might be as great as 1 in 3 but in general first-degree relatives have a 1 in 10-20 risk. Three recent systematic studies have identified a total of 326 European twin pairs to examine disease concordance rates. The derived heritability in Crohn's disease is greater than for many complex diseases and is currently under detailed examination. Strong concordance has been shown, in particular for disease type and disease location, in multiplex families and twin studies. More than 75% children are diagnosed with IBD at a younger age than their parents but true genetic anticipation appears unlikely.

Anticipation, Genetic↗
PubMed2002

Monoassociation of SCID mice with Helicobacter muridarum, but not four other enterics, provokes IBD upon receipt of T cells.

BACKGROUND & AIMS: Recently, a number of animal models for different aspects of inflammatory bowel disease (IBD) have been developed. The aim of this study was to use one of these to determine whether particular, ostensibly innocuous, intestinal bacteria could provoke or exacerbate IBD. METHODS: Conventionally reared C.B17 SCID mice were compared with germ-free and gnotobiotic mice, monoassociated with 1 of 5 intestinal bacteria, after transfer of CD45RB(high) CD4(+) T cells from conventionally reared congenic BALB/c mice. Recipient mice were monitored over 7-12 weeks for clinical signs of IBD, and tissues were analyzed by histology/flow cytometry for abnormal inflammation and CD4(+) T cell outgrowth. RESULTS: Neither germ-free mice nor mice monoassociated with segmented filamentous bacteria, Ochrobactrum anthropi, a nonpathogenic mutant of Listeria monocytogenes, or Morganella morganii developed any signs of IBD. In contrast, mice monoassociated with Helicobacter muridarum displayed an accelerated development of IBD in 5-6 weeks compared with 8-12 weeks observed in conventionally reared mice. The outgrowth of CD4(+) T cells in spleen and large intestine of H. muridarum monoassociated mice, as well as in conventionally reared mice was significantly higher than that in the other monoassociated mice. CONCLUSIONS: Among the intestinal bacteria tested, H. muridarum can serve as a provocateur of IBD in this model.

Animals↗
PubMed2005

Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD.

BACKGROUND & AIMS: Three years after the identification of NOD2/CARD15, 2 more genes for inflammatory bowel diseases (IBDs) were reported. The carnitine/organic cation transporter (OCTN) on 5q31 (IBD5) is associated with Crohn's disease (CD) and DLG5 (10q23), a member of membrane-associated guanylate kinase (MAGUK) family, with IBD. We studied mutation prevalence, assessed phenotypic expression, and performed conditional analysis to examine evidence for gene-gene interactions. METHODS: A cohort of 2032 individuals was genotyped for disease-associated OCTN and DLG5 variants, including 981 patients with IBD (CD, n = 769; ulcerative colitis, n = 186; indeterminate colitis, n = 26) followed up at a tertiary IBD center. For 373 patients, DNA from both parents was available (cohort 1) for transmission disequilibrium testing analysis; case-control analysis was performed in 608 patients and 305 controls (cohort 2). RESULTS: There was no distortion of transmission toward affected offspring for any of the variant alleles. Case-control analysis also failed to shown an association. A higher frequency of DLG5 113A was observed in CARD15-positive patients (12.2%) compared with CARD15-negative patients (8.7%; P = .033). The OCTN-TC risk haplotype was associated with penetrating disease (odds ratio, 1.474; 95% confidence interval, 1.028-2.114; P = .035). For DLG5, there were no associations with a particular phenotype. CONCLUSIONS: DLG5 and OCTN do not play a role in the susceptibility to IBD, CD, or ulcerative colitis in the Flemish population but play a role in the phenotypic expression of the disease. OCTN variants were associated with perianal and penetrating CD. More studies in independent populations are urgently needed to assess the validity of DLG5 and OCTN in the pathogenesis of IBD.

Adolescent↗
PubMed2000

Disease outcome in inflammatory bowel disease: mortality, morbidity and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).

BACKGROUND: The course of inflammatory bowel diseases (IBD) has mainly been studied using different methods in single patient cohorts. The aim of the present study was to assess clinical aspects of disease outcome in a population-based cohort of IBD patients over a 4-year period in multiple centres across Europe. METHODS: A total of 796 patients with IBD diagnosed in 10 centres between October 1991 and October 1993, registered at the EC IBD study centre (98% of the original cohort), participated in the study. Investigators filled out a standard follow-up form containing questions on the method of follow-up, vital status of the patient, change in diagnosis, extraintestinal manifestations, medical and surgical treatment, and physician's global assessment of disease activity. RESULTS: Complete relief of the complaints was reported in 255 (48%) patients with ulcerative colitis (UC), 9 (50%) with indeterminate colitis (IC), but only in 87 (35%) of patients with Crohn disease (CD). Improvement was reported in 195 (37%) patients with UC, 113 (45%) with CD and 6 (33%) with IC. During the 4-year follow-up period, 23 patients died (14 UC, 8 CD. and 1 IC). The mean age at death was 69.3 years (s, 14.9 years). The deaths of three patients were recorded as directly due to IBD. CONCLUSIONS: With the present approach to therapeutic management the short-term outcome of patients with IBD seems to be favourable in 10 medical centres in the north and south of Europe. However, more detailed studies including both objective and subjective measures are necessary.

Adult↗
PubMed2006

Incidence and clinical presentation of IBD in children: comparison between prospective and retrospective data in a selected Norwegian population.

OBJECTIVE: The results of recent research suggest that there is an increasing incidence of inflammatory bowel disease (IBD) among children. Newly diagnosed IBD was compared between two consecutive 6-year periods in the same catchment area of southeastern Norway. MATERIAL AND METHODS: Children subjected to endoscopy from 1993 to 2004 were recorded retrospectively in the first 6-year period and prospectively for the subsequent period. The mean size of the child population under 16 years in the area was 70,500. The study reports on incidence numbers, age at diagnosis, disease distribution and clinical presentation at diagnosis. RESULTS: There were 23 incident cases of IBD in the first period and 25 in the subsequent period. The rates of Crohn's disease (CD) for the two periods were, respectively, 1.95 and 3.64, and for ulcerative colitis (UC) 3.67 and 2.05/100,000 children/year. Total incidence rates of IBD for the two periods were 5.6 and 5.7, respectively, similar to the findings of the IBSEN study of 1990-94. The change in CD and UC rates from the first to the second period can be explained by better methods of diagnosis. CONCLUSIONS: The total incidence of IBD was not changed between time periods, whereas a trend towards an increase in CD and a reduction in UC was recorded. The incidence rates are in accordance with previously reported national and international data from the past decade. The extent of disease in CD and UC may indicate a serious prognosis of IBD among children.

Child↗
PubMed2006

Revisiting the immunomodulators tacrolimus, methotrexate, and mycophenolate mofetil: their mechanisms of action and role in the treatment of IBD.

Inflammatory bowel diseases (IBDs) are thought to result from unopposed immune responses to normal gut flora in a genetically susceptible host. A variety of immunomodulating therapies are applied for the treatment of patients with IBDs. The first-line treatment for IBDs consists of 5-aminosalicylate and/or budesonide. However, these first-line therapies are often not suitable for continuous treatment or do not suffice for the treatment of severe IBD. Recently, efforts have been made to generate novel selective drugs that are more effective and have fewer side effects. Despite promising results, most of these novel drugs are still in a developmental stage and unavailable for clinical application. Yet, another class of established immunomodulators exists that is successful in the treatment of inflammatory bowel diseases. While waiting for emerging novel therapies, the use of these more established drugs should be considered. Furthermore, one of the advantages of using established immunomodulators is the well-documented knowledge on the long-term side effects and on the mechanisms of action. In this review, the authors discuss 3 well-known immunomodulators that are being applied with increased frequency for the treatment of IBD: tacrolimus, methotrexate, and mycophenolate mofetil. These agents have been used for many years as treatment modalities for immunosuppression after organ transplantation, for the treatment of cancer, and for immunomodulation in several other immune-mediated diseases. First, this review discusses the potential targets for immunomodulating therapies in IBDs. Second, the immunomodulating mechanisms and effects of the 3 immunomodulators are discussed in relationship to these treatment targets.

Humans↗
PubMed2003

The association between corticosteroid use and development of fractures among IBD patients in a population-based database.

OBJECTIVES: Because the rate of fracture among patients with inflammatory bowel disease (IBD) is only slightly higher than that in the general population, it is important to define high-risk groups worthy of diagnostic evaluation or prophylactic interventions. Corticosteroid use has been considered in other diseases to be a risk for fracture, although not all studies in IBD are concordant on this point. We aimed to determine whether patients with IBD drawn from a population-based database who sustain fractures are more likely to have been using corticosteroids than a matched group of IBD patients who did not fracture. METHODS: We extracted from our population-based University of Manitoba Inflammatory Bowel Disease Epidemiology Database the number of patients with a new diagnosis of fracture between the years 1997-2000. From within our Inflammatory Bowel Disease Epidemiology Database, we extracted a control group of IBD patients who did not develop fractures matched to the case group who did by age, gender, diagnosis, year of diagnosis, and geographic area of residence. We linked our cohorts with Manitoba Health's Drug Program Information Network to study corticosteroid use within 2 yr before fracture diagnosis. The Drug Program Information Network is a population-based database, established in 1995, which records all prescription drugs. RESULTS: Fractures were identified in 13 patients with Crohn's disease and in 28 patients with ulcerative colitis. The control group included 103 Crohn's disease and 173 ulcerative colitis patients who did not fracture. In Crohn's disease, for the group who fractured compared with the controls who did not fracture, corticosteroid use before fracture was evident in seven (54%) compared with 21 (22%) who did not fracture (chi(2) = 4.45, df = 1, p = 0.035). In ulcerative colitis, for the group who fractured compared with the controls who did not fracture, corticosteroid use before fracture was evident in five (18%) compared with 37 (21%) who did not fracture (chi(2) = 0.031, df = 1, p = 0.861). Fracture cases were more likely to be exposed to oral corticosteroids (OR = 1.75; 95% CI = 0.82-3.75), but this result is not significant. Regarding corticosteroid dosing among the 12 patients with IBD who fractured and used corticosteroids, the mean total days supply was 314 days +/- 236 days compared with 258 days +/- 278 days in those who did not fracture (p = 0.16). The prescribed daily dose among corticosteroid users was comparable for those who fractured versus those who did not fracture (18 mg/day vs 21 mg/day, p = 0.90). CONCLUSIONS: Patients who require corticosteroids in Crohn's disease should be considered at risk for fracture. Further research is required to delineate after how much corticosteroid use are subjects at risk and/or after what duration of active disease.

Adult↗
PubMed2002

What are we going to do with you? Gastroenterology service providers' perceptions of "difficult to manage" IBD patients.

BACKGROUND: This paper reports the results of a systematic survey of members of a clinical gastroenterology service to determine their perceptions of patients with inflammatory bowel disease (IBD) who were deemed to function poorly and were difficult to manage clinically. OBJECTIVES: To assess objectively the defining characteristics of this perceived subgroup of patients who are encountered in virtually all gastroenterology services. METHODS: A sample of gastroenterologists and gastrointestinal surgeons (n=10), as well as gastrointestinal nurses (n=19), was surveyed regarding their beliefs about the characteristics of patients with IBD who they judged to be extremely "difficult to manage". A survey was developed to assess patient characteristics (eg, symptom presentation, narcotic over-reliance, interpersonal behaviour and illness behaviour) and the emotional impact that this perceived patient group has on individual staff members as well as on the functioning of the gastrointestinal team. RESULTS: The data indicated that patients with IBD who were perceived to be poorly functioning were viewed to have high levels of dysfunctional behaviour. In particular, negative behaviours (eg, manipulative interpersonal behaviours and excessive illness behaviours) were noted. Not only were these categories of behaviours high in frequency, but survey participants also rated these categories of behaviour to be highly distinct from those of typical patients with IBD. Moreover, this perceived patient group was reported to have a negative impact on individual staff and on the gastrointestinal team, and participants confirmed that they experience significant frustration and hostility when they work with these patients. CONCLUSIONS: These data, if replicated, confirm the general clinical opinion that a small subgroup of "difficult to manage" and poorly functioning patients with IBD exists. These patients appear to differ from typical patients with IBD in interpersonal characteristics more than in medical characteristics. If follow-up research, which is currently underway by the authors' group, shows that groups of poorly functioning gastrointestinal patients and typical gastrointestinal patients actually differ in measures of illness behaviour, then novel treatment approaches to improve the clinical services that are provided to these patients can be developed.

Behavior↗
PubMed2003

Validation of a reliable instrument (QUOTE-IBD) for assessing the quality of health care in Greek patients with inflammatory bowel disease.

Given the early onset, the chronic and recurrent nature of their disease and their normal life expectancy, patients with inflammatory bowel disease (IBD) may need considerable health care. The purpose of this study is to validate the Greek translation of the QUOTE-IBD questionnaire (GR-QUOTE-IBD). For that purpose we assessed its construct validity, and reliability. Fifty patients (33 ulcerative colitis, 17 Crohn's disease) completed the GR-QUOTE-IBD and visual-analogue scales (VAS) for the patients' evaluation of the quality of separate care dimensions, and of the total care. A subgroup of 33 patients (64%) completed the GR-QUOTE-IBD for a second time. Quality of life was assessed by the short version of the IBDQ. Clinical activity was assessed by Harvey-Bradshaw index and Colitis Activity Index. Correlations among all care dimensions and VAS were positive and highly significant (p<0.001). The total care and all eight dimensional care scores (quality impact and importance) had no significant differences between the baseline and the follow-up visit. Similarly, the correlation coefficients between the scores of the two occasions were all positive (close to one) and highly significant (p<0.001). The GR-QUOTE-IBD proved to be a valid and reliable instrument, applicable in international clinical studies.

Adolescent↗
PubMedDate not supplied

NOD2/CARD15 in healthy relatives of IBD patients.

BACKGROUND: Crohn's disease (CD) and Ulcerative Colitis (UC) are related chronic inflammatory disorders of the intestine (IBD) caused by a combination of genetic and environmental factors. Three polymorphisms within the NOD2/CARD15 gene are highly associated with CD, increasing the risk from 2 up to 44-fold, depending on the presence of one or two risk alleles. Aim of this study was to investigate the presence of two risk alleles on healthy relatives of IBD patients and prospectively follow them for possible development of IBD. MATERIALS AND METHODS: Healthy relatives of familial IBD patients were recruited in our Institution and across Italy in a multicenter study of the IG-IBD. One hundred and twenty one IBD families were identified and blood samples were obtained from 415 first-degree healthy relatives. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated by multiplex pyrosequencing technique. Data obtained in 205 healthy controls (HC) were compared by chi-square or Fisher's test. RESULTS: Ninety eight (28.7%) healthy relatives had one risk allele (HC 14.6%; p = 0.002, OR 2, C.I. 1-4), while 8 had two risk alleles (vs 0.5% of healthy controls; p = 0.01). All subjects were asymptomatic at the time of blood sample and record collections (between 1996 and 1999) and were further investigated with abdominal ultrasonography, blood chemistry and haemoccult test, after 5-8 years of follow-up. All were still asymptomatic with negative findings. CONCLUSIONS: Our study once again supports the importance of gene-gene and gene-environment interactions for the final development of the disease.

Abdomen↗
PubMed1993

Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum.

We report the results of a survey of the membership of the North American Society for Pediatric Gastroenterology and Nutrition designed to determine pediatric gastroenterologists' attitudes toward the use of immunosuppressive therapy for inflammatory bowel disease (IBD), and to assess how these medications are actually being used in the treatment of children with IBD. One hundred five physicians (27% of surveys) responded. Eighty-eight (84%) had prescribed 6-mercaptopurine and/or azathioprine for IBD, and 66 believed that they were effective. Only 12 had used cyclosporine and four methotrexate. All physicians who had used immunosuppressives in IBD had prescribed them for patients with Crohn's disease, but only 50% had prescribed them for ulcerative colitis. The predominant indications for use included intractable symptoms despite traditional medical therapy (92%) and for corticosteroid-sparing effects (86%). Potential toxicities of greatest concern included marrow and immune suppression and malignancy. The vast majority of responders were not certain what to recommend with respect to the use of immunosuppressive agents prior to and during pregnancy. A clinical database was compiled from 165 retrospective case reports submitted by 45 physicians (33 medical facilities). At the start of immunosuppressive therapy, patients were 15.3 +/- 4.0 yr of age, and 52% were Tanner IV-V. Eighty-one percent had Crohn's disease, 8% ulcerative colitis, and 11% indeterminant colitis. One hundred twenty-two were treated with 6-mercaptopurine, and 43 with azathioprine. Five also received cyclosporine concomitantly. Overall, 68% of patients treated with an immunosuppressive improved. Complications requiring discontinuation of immunosuppressive therapy occurred in 6% of patients. It appears that immunosuppressives are commonly used to treat children with IBD despite a paucity of data regarding their safety and efficacy in this age group. Controlled, prospective trials are warranted to better define the role of immunosuppressive therapy in pediatric IBD.

Adolescent↗
PubMed1999

Introduction of the IBD information into the weighted pairwise correlation method for linkage analysis.

The Weighted Pairwise Correlation (WPC) approach is a non-parametric method of linkage analysis that allows analysis of any kind of phenotypes (quantitative, binary, binary with age of onset) and to consider all pairs of relatives in a pedigree. The principle of this method is to test whether two relatives having close phenotypes also resemble at the marker locus more than expected under the null hypothesis of no linkage. So far, this marker resemblance was estimated by the proportion of alleles shared Identical By State (IBS) by the two relatives. Here, we propose a method to incorporate the Identical By Descent (IBD) information into the WPC approach. For any kind of relative pairs, the computation of the proportion of alleles shared IBD is based on the identification of the closest couple of ancestors, denoted as the reference couple. The IBD information is obtained for pairs of relatives having the same reference couple using individual genotypic vectors derived from this couple. This reconstruction of the IBD information is performed rapidly even in large pedigrees. Simulation studies conducted under various genetic models demonstrate that the use of IBD instead of IBS information leads to a large increase of power, especially in the situation of poorly informative markers.

Genetic Linkage↗
PubMed2006

CLA and n-3 PUFA differentially modulate clinical activity and colonic PPAR-responsive gene expression in a pig model of experimental IBD.

BACKGROUND AND AIMS: Conjugated linoleic acid (CLA) and n-3 polyunsaturated fatty acids (PUFA) have been proposed as important pharmaco-nutrients for modulating mucosal immunity and therapeutic responses in patients with inflammatory bowel disease (IBD). We evaluated the ability of CLA and n-3 PUFA alone or in combination to modulate IBD in a pig model of dextran sodium sulfate (DSS)-induced colitis. METHODS: Sixty-four, 15-day-old pigs were used to evaluate the effect of CLA, n-3 PUFA and a 50:50 mixture of CLA and n-3 PUFA on growth, clinical activity and colonic PPAR-responsive gene expression. Diets were formulated to contain: 1.33% soybean oil (control); 1.33% CLA; 1.33% fish oil; or 1.33% of a 50:50 mixture of CLA and fish oil. Intestinal inflammation was induced by an intragastric challenge with DSS on day 42 of dietary supplementation. The colonic expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), PPAR gamma- and delta-responsive genes, keratinocyte growth factor (KGF) and tumor necrosis factor (TNF-alpha) were assayed by quantitative RT-PCR. RESULTS: The onset of IBD was delayed, colitis less severe and growth suppression attenuated in pigs fed CLA, which correlated with induction of colonic PPAR gamma and its responsive gene PPAR gamma-coactivator-1alpha (PGC1-alpha) and downregulation of TNF-alpha. However, dietary supplementation with n-3 PUFA alone or in combination with CLA resulted in an early onset of disease (i.e., day 2) and faster recovery on days 6 and 7, which correlated with a marked induction of the PPAR delta-responsive gene uncoupling protein 3 (UCP3). CLA and n-3 PUFA acted synergistically to upregulate colonic KGF expression in DSS-challenged pigs but n-3 PUFA blocked CLA-induced PPAR gamma activation. CONCLUSION: Dietary CLA-supplementation upregulated colonic PPAR gamma expression and contributed to delaying the onset of experimental IBD, whereas n-3 PUFA failed to protect from IBD, although it accelerated colonic regeneration and clinical remission by activating PPAR delta.

Animals↗
PubMed1997

Quantitative PCR analysis of TNF-alpha and IL-1 beta mRNA levels in pediatric IBD mucosal biopsies.

Inflammatory bowel disease (IBD) is associated with increased activation of intestinal immune cells, whose overproduction of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) is implicated in mediating the sustained inflammatory response. Studies to date have largely reported qualitative differences in cytokine gene expression between IBD and controls. Our aim was to perform quantitative analysis of intestinal mucosal mRNA expression in colonic biopsies from pediatric IBD patients using a competitive polymerase chain reaction. IL-1 beta and TNF-alpha were expressed in all IBD and control biopsies. Compared to controls, IL-1 beta mRNA levels were increased in involved tissue from Crohn's disease (CD) patients, but not in histologically uninvolved CD or in ulcerative colitis (UC) mucosa. IL-1 beta expression in the latter groups were equivalent to those found in tissue from patients with eosinophilic colitis (EOC). Significantly higher levels of IL-1 beta mRNA were found in uninvolved mucosa from CD patients who presented with a relapse of disease activity, as compared to newly diagnosed cases with histological features of CD at an early stage. TNF-alpha mRNA transcripts were also significantly elevated in involved CD mucosa, but not in the other groups. TNF-alpha gene expression in CD-involved tissue decreased with disease duration. Follow-up of the patients revealed that high cytokine expression in uninvolved CD tissue correlated with an early clinical relapse. In conclusion, quantitative determination of proinflammatory cytokine gene expression reveals differences between the type, severity, and clinical course in patients with IBD.

Adolescent↗
PubMed1998

Splenic T helper cell type 1 cytokine profile and extramedullary haematopoiesis in severe combined immunodeficient (scid) mice with inflammatory bowel disease (IBD).

Scid mice develop a severe, chronic, and lethal IBD 3-6 months after engraftment of gut wall from immunocompetent congenic donors, induced by donor-derived CD4+ T cells migrating from the graft. We have investigated intracellular T-helper type 1 (Th1) cytokines in the spleens of gut wall-transplanted scid mice with IBD. Increased fractions of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-2-positive CD4+ T cells were found in the spleens of diseased mice compared with control mice. Moreover, a small but significant population of CD4+ T cells which stained positive for granulocyte-macrophage colony-stimulating factor (GM-CSF) was found in scid mice with IBD but was virtually absent in congenic non-scid control mice. Cloning of granulocyte/ macrophage colony-forming cells (G/M-CFC) revealed that both non-transplanted scid mice and scid mice with IBD had an 8-14-fold increase in splenic G/M-CFC compared with control mice. No significant difference in the number of G/M-CFC per total spleen was found between non-transplanted and disease scid mice, although both groups of mice showed a nearly two-fold increase compared with control mice. G/M-CFC were never found in the thymus, liver or lymph nodes of diseased mice. Immunohistochemistry revealed that the multinucleated giant cells observed in the gut wall of diseased mice did not represent haematopoietic foci, but were derived from macrophages. These observations point towards a dominant role for Th1-type CD4+ T cells in the immunopathogenesis of IBD, whereas haematopoiesis does not seem to be affected by the development of the disease.

Animals↗
PubMed1999

Circulating soluble factor-inhibiting natural killer (NK) activity of fresh peripheral blood mononuclear cells (PBMC) from inflammatory bowel disease (IBD) patients.

This study was performed in order to assess the cytotoxic activity, both natural (NK) and antibody-dependent (ADCC), of PBMC from 38 IBD patients and correlate it with their clinical features. Cytotoxicity assays were performed using sensitive target cells for NK and ADCC activities. In some experiments, highly purified NK cells, obtained both by Percoll density gradient and by co-culturing non-adherent PBMC with RPMI 8866 feeder cells, were used as effector cells. Furthermore, we evaluated NK cell parameters such as number, surface expression of adhesion molecules (CD11a/CD18, CD49d and CD54) and response to different stimuli. We observed a decreased NK cytotoxicity of PBMC from IBD patients, both in ulcerative colitis (UC) and Crohn's disease (CD), independently of the clinical activity of disease. In contrast, the ADCC lytic activity was within normal range. The lower NK cytotoxic activity observed in our IBD patients cannot be related to a decreased number of NK cells, surface expression of adhesion molecules, defective response to IL-2 and maturative defect. Decreased NK activity was induced in PBMC of controls when serum of patients was added and this was unrelated to monocyte-derived modulating factor(s). Our data show a decreased natural killing by fresh PBMC from IBD patients. This lower activity seems to be unrelated to a primary NK cell defect, since purified NK cells exhibited normal levels of killing. It might be hypothesized that serum factors, possibly derived from lymphocytes, with inhibitory properties on NK activity, might be functionally active in the blood of IBD patients, thus modulating NK activity.

Adolescent↗
PubMed2001

Patients with inflammatory bowel disease (IBD) reveal increased induction capacity of intracellular interferon-gamma (IFN-gamma) in peripheral CD8+ lymphocytes co-cultured with intestinal epithelial cells.

Intestinal epithelial cells seem to play a key role during IBD. The network of cellular interactions between epithelial cells and lamina propria mononuclear cells is still incompletely understood. In the following co-culture model we investigated the influence of intestinal epithelial cells on cytokine expression of T cytotoxic and T helper cells from patients with IBD and healthy controls. Peripheral blood mononuclear cells (PBMC) were purified by a Ficoll-Hypaque gradient followed by co-incubation with epithelial cells in multiwell cell culture insert plates in direct contact as well as separated by transwell filters. We used Caco-2 cells as well as freshly isolated colonic epithelia obtained from surgical specimens. Three-colour immunofluorescence flow cytometry was performed after collection, stimulation and staining of PBMC with anti-CD4, anti-CD8, anti-IFN-gamma and anti-IL-4. Patients with IBD (Crohn's disease (CD), n = 12; ulcerative colitis (UC), n = 16) and healthy controls (n = 10) were included in the study. After 24 h of co-incubation with Caco-2 cells we found a significant increase of IFN-gamma-producing CD8+ lymphocytes in patients with IBD. In contrast, healthy controls did not respond to the epithelial stimulus. No significant differences could be found between CD and UC or active and inactive disease. A significant increase of IFN-gamma+/CD8+ lymphocytes in patients with UC was also seen after direct co-incubation with primary cultures of colonic crypt cells. The observed epithelial-lymphocyte interaction seems to be MHC I-restricted. No significant epithelial cell-mediated effects on cytokine expression were detected in the PBMC CD4+ subsets. Patients with IBD-even in an inactive state of disease-exert an increased capacity for IFN-gamma induction in CD8+ lymphocytes mediated by intestinal epithelial cells. This mechanism may be important during chronic intestinal inflammation, as in the case of altered mucosal barrier function epithelial cells may become targets for IFN-gamma-producing CD8+ lymphocytes.

Antibodies, Blocking↗
PubMedDate not supplied

The rating form of IBD patient concerns: a new measure of health status.

Health status assessment for persons with chronic illness includes not only symptoms, but also an appraisal of the psychosocial concomitants of illness. In this national study of persons with inflammatory bowel disease (IBD), we standardized a disease-specific 25-item measure of perceived health status: the Rating Form of IBD Patient Concerns (RFIPC). Factor analysis yielded four indices: a) impact of disease (e.g., being a burden, loss of energy, loss of bowel control); b) sexual intimacy; c) complications of disease (e.g., developing cancer, having surgery, dying early); and d) body stigma (e.g., feeling dirty or smelly). A higher level of IBD concerns was associated with greater disease severity, female gender, and lower educational status. When controlling for these factors, as well as disease type and age, we found that concerns about: a) impact of disease was positively associated with poorer perception of health and well-being, greater psychological distress (SCL-90), and poorer daily function (Sickness Impact Profile) (p less than 0.0001); b) sexual intimacy was related to poorer psychologic function (p less than 0.01); and c) complications of disease was related to several measures of poorer daily function (p less than 0.0001 to 0.01). This standardized measure of the worries and concerns of persons with IBD may be used in clinical care and research to evaluate the effects of interventions on IBD patient outcomes.

Activities of Daily Living↗