Pilot study to evaluate whether frequencies of donor-specific Teff and Treg in blood differ between tolerant and non-tolerant LTx recipients. Furthermore, the mechanism of tolerance will be studied by characterization of T cells within the blood of…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Frequencies of donor-specific CD4+ Teff, CD4+Foxp3+ Treg, and CD4+CD49b+LAG-3+
Treg will be expressed as percentages of CD4+ T-cells. Frequencies of
donor-specific CD8+ Teff will be expressed as percentages of CD8+ T-cells. The
same calculations will be made for frequencies of T cells responding to 3rd
party allo-antigen. A single cell RNA profile for tolerance will be
established, as well as a functional immune response and TSDR methylation of
immune cells within tolerant and control LTx recipients.
In the case-control study frequencies of donor-specific T cells and 3rd-party
specific T cells will be compared between tolerant patients and patients using
IS, using the Mann-Whitney test or, if the variables are normally distributed,
using the Wilcoxon test for unpaired samples.
In the cohort study at each time point frequencies of donor-specific T cells
and 3rd-party specific T cells will be compared between patients that do not
reject during or after IS withdrawal and patients that do reject, using the
same statistical tests.
Secondary outcome
In tolerant patients only: degree of liver fibrosis (in kPa) as detected by
fibroscan and by a combination of serum markers e.g. PINP, PIINP, TIMP, MMP
Background summary
The life long treatment with immunosuppressive drugs (IS) to prevent graft
rejection in liver transplant (LTx) recipients is accompanied by adverse effect
such as nephrotoxicity, infections, diabetes and cancer. Gradual withdrawal of
IS is possible in about 25% of LTx recipients without signs of graft rejection,
and these patients apparently tolerate their liver graft. However, since no
biomarkers that identify tolerant LTx recipients are available, deliberate
withdrawal of IS has not entered clinical practice. We hypothesize that
tolerant and non-tolerant LTx recipients may differ in numbers of circulating
donor-specific effector T-cells (Teff) and regulatory T cells (Treg), and in
concentrations of immune-regulatory cytokines, such as IL-10 and TGF-beta.
Furthermore, the mechanism of tolerance will be studied by characterization of
T cells within the blood of tolerant LTx recipients compared to a control group.
For patient safety reasons we would like to monitor whether liver fibrosis
might develop in the patients without IS. We will use a transient elastography
ultrasound technique (Fibroscan), which is a recognized alternative diagnostic
technique to asses liver fibrosis but without patient burden.
Study objective
Pilot study to evaluate whether frequencies of donor-specific Teff and Treg in
blood differ between tolerant and non-tolerant LTx recipients. Furthermore, the
mechanism of tolerance will be studied by characterization of T cells within
the blood of tolerant LTx recipients compared to a control group.
Secondary objective: To determine whether long-term absence of IS medication in
tolerant LTx recipients might promote fibrosis of the liver graft.
Study design
1). Case-control study in which we compare LTx-recipients in which IS has been
stopped for clinical reasons in the past and which are IS-free for at least 6
months (*tolerant patients*) with stable LTx-recipients that are treated with
IS and are matched for time after LTx with the tolerant patients. For each
patient, two blood samples will be collected during a venapunction performed
for diagnostic reasons during a regular visit to our out-patient clinic. IA
fibroscan will be performed by tolerant patients. Study duration: 1 year.
2). Cohort study in LTx-recipients in which IS will be gradually withdrawn for
clinical reasons. Patients will be followed until signs of acute rejection or
until 6 months after complete cessation of IS. Blood will be collected before
lowering of IS, during the first visit to the out-patient clinic after IS has
been halved, and 6 months after complete cessation of IS. An anual firbroscan
will be performed starting 6 month after stopping of IS.
Study duration: 4 years
Study burden and risks
There is no extra risk for the patient.
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Listed location countries
Age
Inclusion criteria
Case control study: The experimental group consists of 8 LTx patients in
Erasmus MC that are currently at least 6 months free of IS. 5 additional
patients are currently in the process of IS reduction, and will be included as
soon as they are 6 months free of IS. As a control group we will include 39 LTx
patients matched with the experimental group for LTx-indication and time after
LTx and have been continuously treated with IS., Cohort study: LTx-recipients
in Erasmus MC in which for clinical reasons IS will be gradually withdrawn. Our
estimation is that we can include 25 patients during the next 4 years, but this
is fully dependent on clinical need to reduce and finally stop IS.
Exclusion criteria
Severe recurrence of primary liver disease with development of cirrhosis.
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 | NL48667.078.14 |