Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents

April 14, 2015 updated by: Josh Levitsky, Northwestern University
This study is being done with the purpose of trying to understand if and why transplant recipients may develop tolerance to their transplanted organ. Tolerance means being able to lower or take away immunosuppression (anti-rejection medications) without causing organ rejection.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Life-long immunosuppressive therapy is typically required in the majority of liver allograft recipients. In the early years of liver transplantation (LT), the majority of deaths occurred secondary to graft loss from acute or chronic rejection despite immunosuppression (IS). With the advent of more powerful and specific IS agents, e.g. calcineurin-inhibitors (CNIs) cyclosporine (CyA) and tacrolimus (TAC), graft rejection rates significantly declined and short and long term graft/patient survival dramatically improved. However, along with the advance in survival rates came the adverse effects of long term immunosuppression (IS), e.g. morbidity and mortality from cardiovascular events, renal insufficiency, infectious complications, recurrent viral hepatitis and malignancy. These events are exacerbated by pre-existing conditions and an aging transplant population. Immunosuppression tapering or withdrawal could lower the incidence of these complications and improve long term graft and patient survival.

Therefore, the study proposed is a laboratory investigation (using blood samples collected from the subjects) comparing immune tolerance and alloreactivity profiles in LT recipients on monotherapy IS or converted to rapamycin monotherapy, to determine tolerogenic properties of the different IS agents. Knowledge of these properties would support the need for specific IS therapy to promote immune tolerance and consider IS withdrawal.

Monotherapy patients will be identified by the organ transplant database and medical charts at Northwestern. Patients will be invited to participate in the study and asked to undergo venipunctures for our analysis. Patient demographics, laboratories and other clinical data will be recorded. Patients on CNI monotherapy are continuously being identified for conversion to rapamycin monotherapy during clinic visits or chart reviews at Northwestern. Patients are selected for conversion due to significant CNI side effects, e.g. chronic kidney disease (creatinine clearance < 50 in the absence of significant proteinuria > 1g, poorly controlled diabetes mellitus/hypertension/hyperlipidemia, peripheral neuropathy). In general, patients are converted from CNIs to rapamycin over 2-3 weeks once therapeutic rapamycin levels are achieved.

Study procedures will be carried out by the investigators and associated personnel. Patients will be assigned a number in numerical order, to remove patient identifiers from the data analysis. A separate screening/enrollment log will be kept separate from the data. Baseline characteristics of the patients will be recorded: age, sex, liver disease, past medical history, history of acute rejection or other graft dysfunction, other post-LT complications, previous and current IS regimens. Monotherapy patients (10 from CyA, Tacrolimus, and MMF; 5 rapamycin) will be identified as above and asked to participate. Blood will be drawn at one time point for the following analysis:

  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G

Ten patients who have been pre-selected for rapamycin conversion will have the above assays performed two weeks prior to conversion and 3-6 months following conversion. They will also have liver function and drug level tests.

Study Type

Observational

Enrollment (Actual)

31

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern Memorial Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Liver transplant patients converting on stable IS monotherapy or undergoing conversion to rapamycin or MMF monotherapy.

Description

Inclusion Criteria:

  • Age ≥18 years
  • Orthotopic or Living-Related liver transplant (LT) recipient
  • Monotherapy patients: > 6 months with stable graft function on current monotherapy (CNI, MMF, or rapamycin)
  • Converting patients: CNI therapy converting to rapamycin or MMF monotherapy and > 6 months of stable graft function.
  • >1 years post-LT without an acute rejection episode or chronic rejection
  • Normal liver function tests (no recurrent HCV, chronic rejection, autoimmune hepatitis, etc.)
  • No history of induction or lymphocyte depletion therapy

Exclusion Criteria:

  • Multi-visceral organ recipients
  • Graft dysfunction of any etiology
  • Inadequate follow-up or available outcomes
  • Unable to understand, sign or ask questions regarding the informed consent process and protocol

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Control Group

Ten Healthy individuals will have blood drawn (4 green top tubes(40 ml = 8 tsp.)) at one time point at Northwestern for control purposes. Blood will be drawn to conduct the following tests:

  1. Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  2. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and
  3. HLA microchimerism & HLA G.
Procedure: Blood Draw from Control Subjects

Ten healthy individuals will have blood drawn (40 ml = 8 teaspoons (tsps.)).Blood will be drawn at one time point for the following:

  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G
Monotherapy Group

Monotherapy patients [cyclosporine (CyA) (10 patients), Tacrolimus (5 patients), mycophenolate mofetil (MMF) (10 patients), rapamycin (10 patients)]: Blood will be drawn at one time point (4 green top tubes (40 ml = 8 tsp.)) to conduct the following tests:

  1. Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  2. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and
  3. HLA microchimerism & HLA G.
Procedure: Blood Draw - Rapamycin
Ten calcineurin-inhibitors (CNI) monotherapy or dual therapy (CNI+MMF) patients will have blood taken (40 ml=8 tsp.) 2 wks. prior to conversion, 3-6 months post successful conversion. 1) Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low cells). 2) Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers shown to induce regulatory T cells (ILT3; ILT4), 3) Soluble HLA G, and 4) Liver function/drug levels. If problems develop during conversion (e.g. acute rejection, significant drug side effects) requiring discontinuation of rapamycin, MMF and/or reversion to CNI therapy, assays will not be performed. Monthly liver function/drug levels performed after successful conversion (standard of care).
Other Names:
  • Sirolimus
Procedure: Blood Draw - CyA

Blood drawn from 10 patients on cyclosporine (CyA) (40 ml = 8 tsp.)). Blood will be drawn at one time point for the following:

  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G
Other Names:
  • cyclosporine
Procedure: Blood Draw - Tacrolimus

Blood drawn from 5 patients on Tacrolimus (40 ml = 8 tsp.) at one time point for the following:

  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G
Other Names:
  • Tacrolimus
Procedure: Blood Draw - MMF

Blood will be drawn from 10 patients on mycophenolate mofetil (MMF) (40 ml or the equivalent of 8 teaspoons). Blood will be drawn at one time point for the following analysis:

  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G
Other Names:
  • mycophenolate mofetil
Procedure: Blood Draw - Rapamycin

Blood drawn from 10 patients on rapamycin (40 ml = 8 tsp.)) at one time point for the following:

  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G
Other Names:
  • Rapamycin
Conversion Group
Ten CNI monotherapy/dual therapy (CNI + MMF) patients pre-selected for conversion to rapamycin or wean to MMF monotherapy. Assays performed 2 weeks prior to conversion, 3-6 months following successful conversion. Liver function/drug levels monitored weekly during conversion until stable levels achieved. Patients converting from CNI monotherapy to rapamycin monotherapy (2-4 wks.): CNI discontinued when 2 therapeutic rapamycin levels (5-10) reached, graft function stable (clinical care protocol). MMF conversion: MMF dose slowly increased to 3 g/day (max.) while CNI therapy reduced by 1-2 mg/day (FK506) or 25-50 mg/day (CyA) monthly until CNI discontinued (1-6 months) (clinical care protocol). Monthly liver function/drug levels performed after successful conversion (standard of care).
Procedure: Blood Draw - Rapamycin
Ten calcineurin-inhibitors (CNI) monotherapy or dual therapy (CNI+MMF) patients will have blood taken (40 ml=8 tsp.) 2 wks. prior to conversion, 3-6 months post successful conversion. 1) Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low cells). 2) Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers shown to induce regulatory T cells (ILT3; ILT4), 3) Soluble HLA G, and 4) Liver function/drug levels. If problems develop during conversion (e.g. acute rejection, significant drug side effects) requiring discontinuation of rapamycin, MMF and/or reversion to CNI therapy, assays will not be performed. Monthly liver function/drug levels performed after successful conversion (standard of care).
Other Names:
  • Sirolimus
Procedure: Blood Draw - Rapamycin

Blood drawn from 10 patients on rapamycin (40 ml = 8 tsp.)) at one time point for the following:

  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G
Other Names:
  • Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Track interval outcome measures for development of higher percentages of FOXP3+ T1 regulatory cells in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy.
Time Frame: Two weeks prior to conversion, Months 3 & 6 following conversion
  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • Liver function and drug levels.
Two weeks prior to conversion, Months 3 & 6 following conversion
Track interval outcome measures for development of higher percentages of FOXP3+ T regulatory cells in liver transplant recipients after conversion from CNI to rapamycin comparing to MMF monotherapy.
Time Frame: Two weeks prior to conversion, Months 3 & 6 following conversion
  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
Two weeks prior to conversion, Months 3 & 6 following conversion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy.
Time Frame: Two weeks prior to conversion, Months 3 & 6 following conversion
  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G (dendritic cell ratios, soluble HLA G)
  • Liver function and drug levels.
Two weeks prior to conversion, Months 3 & 6 following conversion
Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in liver transplant recipients after conversion from CNI to rapamycin or MMF monotherapy.
Time Frame: Two weeks prior to conversion, Months 3 & 6 following conversion
  • Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
  • Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
  • HLA microchimerism & HLA G (dendritic cell ratios, soluble HLA G)(hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy)
Two weeks prior to conversion, Months 3 & 6 following conversion
Document improvement in adverse CNI side effects after conversion to rapamycin or MMF monotherapy, comparing designated time points.
Time Frame: Two weeks prior to conversion, Months 3 & 6 following conversion
CNI side effects - hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy. Review liver function and drug levels at designated time points.
Two weeks prior to conversion, Months 3 & 6 following conversion
Document the development of any adverse rapamycin or MMF side effects after conversion, comparing designated time points.
Time Frame: Two weeks prior to conversion, Months 3 & 6 following conversion
Document Rapamycin side effects - oral ulcers, edema, pancytopenia, gastrointestinal dysfunction; or MMF side effects - pancytopenia, gastrointestinal dysfunction. Review liver function and drug levels at designated time points.
Two weeks prior to conversion, Months 3 & 6 following conversion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northwestern University

Collaborators

Northwestern Memorial Hospital

Investigators

  • Principal Investigator: Josh Levitsky, MD, Northwestern University, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2007

Primary Completion (Actual)

May 1, 2008

Study Completion (Actual)

September 1, 2008

Study Registration Dates

First Submitted

July 8, 2011

First Submitted That Met QC Criteria

August 30, 2012

First Posted (Estimate)

September 5, 2012

Study Record Updates

Last Update Posted (Estimate)

April 15, 2015

Last Update Submitted That Met QC Criteria

April 14, 2015

Last Verified

April 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1783-011

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Immunosuppression

Clinical Trials on Blood Draw from Control Subjects

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Mauritius

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe