The primary aim is to characterize mucosal immune responses in concomitant PSC and IBD. Secondary objectives are (1) to identify phenotype and function of the mucosal immune responses in peripheral blood, liver and intestinal biopsies of patients…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary aim is to characterize mucosal immune responses in concomitant PSC
and IBD
Secondary outcome
-Number and phenotype of immune cells (neutrophils, monocytes, mucosal T-cells)
in peripheral blood, intestinal tissue and liver tissue;
-Base-line levels of cytokines of mucosal T-cells from peripheral blood and
intestinal biopsies;
-The immunological response of mucosal T-cells from peripheral blood and
intestinal tissue upon re-stimulation with superantigens or microbial peptides;
-Extent of microbial translocation in peripheral blood (measured with 16S rDNA
translocation assay);
-Serological parameters (i.e. anti-flagellin antibodies);
Background summary
Patients suffering from primary sclerosing cholangitis (PSC) with concomitant
inflammatory bowel disease (IBD) may develop progressive liver disease while
also having chronic intestinal inflammatory lesions of variable severity and
extent. The prognosis is grave, with reported median survival times from
diagnosis until liver transplantation or PSC-related death varying from 13 to
21 years within 12 years after diagnosis. In addition, patients carry a high
risk for developing malignancies, in particular colon and bile duct cancer.
The disease etiopathogenesis and in particular the immunological mechanisms
that underlie PSC-IBD are ill defined. Previously, it has been shown that
livers of PSC-IBD patients contain T-cells with a typical *intestinal*
phenotype. Moreover, PSC liver cells aberrantly express chemo-attractants that
are normally expressed in the intestine. In a clinical study treatment of
patients with the antibiotic vancomycin appeared effective in reducing liver
damage. On the basis of these data PSC-IBD may be driven by the microbiota
specific mucosal immune system. We hypothesize that in PSC intestinal
microbiota specific mucosal T-cells are aberrantly present and activated in the
liver.
Recently, we found that the surface markers CD62L and CD38 allow identification
of intestinal mucosal T-cells within the pool of CD4+ circulating T-cells.
Staining of peripheral blood from celiac disease patients who underwent a
gluten challenge revealed that virtually all gluten-specific T-cells had a
CD62LnegCD38+ phenotype. Thus, by selecting for CD62LnegCD38+ expression that
comprises 5-10 % of the cells within the total CD4+ T-cell pool we are able to
highly enrich for effector T-cells with specificity for mucosal antigens
Study objective
The primary aim is to characterize mucosal immune responses in concomitant PSC
and IBD. Secondary objectives are (1) to identify phenotype and function of the
mucosal immune responses in peripheral blood, liver and intestinal biopsies of
patients with PSC-IBD in comparison with patients with a number of other liver
disorders, IBD patients without PSC and normal controls; (2) to assess
bacterial translocation in PSC-IBD and its correlation to phenotype, severity
and disease course; (3) to dissect differences in mucosal immune responses
between children and adults with concomitant PSC and IBD. By combining the
above data in a longitudinal study we will be able to dissect the phenotype and
function of circulating anti-microbial T cells in peripheral blood of PSC-IBD
patients and assess correlation with severity of disease and microbial
translocation.
Study design
The presented study is a single-center observational study with a four year
inclusion period. Patients will be asked to participate by their treating
physician during a regular visit to the out-patient clinic. If patients are
eligible and give informed consent, patients will be seen every 6 months by
their treating physician. After inclusion, patients will participate in the
study until the end of the 4-year study period.
Study burden and risks
Our study population will partly consist of pediatric patients, as pediatric
PSC-lBD seems to represent a specific group of PSC-lBD patients with a distinct
disease phenotype and clinical presentation compared with adults.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
-Diagnosis of PSC according to generally accepted criteria (EASL diagnostic guidelines): presence of elevated serum markers of cholestasis (ALP, GGT) not otherwise explained, when MRCP or ERCP show characteristic bile duct changes with multifocal strictures and segmental dilatations, and causes of secondary sclerosing cholangitis and other cholestatic disorders are excluded;
-IBD (CD, UC or indeterminate colitis) confirmed by clinical evaluation in combination with endoscopic and histological investigations;
-Informed consent by patients or, when applicable, parents.
Exclusion criteria
-Diagnosis of immunodeficiency syndromes;
-Secondary causes of sclerosing cholangitis;
-Evidence of decompensated liver disease such as previous variceal bleeding, ascites, or hepatic encephalopathy;
-Anticipated need for liver transplantation within one year; after liver transplantation these patients will be eligible again.
-Findings highly suggestive of liver disease of an alternative or concomitant etiology, such as alcoholic liver disease, hepatitis B or C, haemochromatosis, Wilson*s disease, a1-antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis;
-Pregnant or lactating patients;
-Active illicit drug or alcohol abuse;
-Suspicion of ascending cholangitis or acute (septic) cholangitis or one of these events in the previous 6 months;
-Any infection necessitating antibiotics use >14 days in the previous 6 months.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL51104.078.15 |