Clinical trial NCT01678937: Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents
Official title: Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Liver Transplant Rejection
Immunosuppression
Keywords: Immunosuppression
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: Northwestern Memorial Hospital
First posted: 2012-09-05
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Liver transplant patients converting on stable IS monotherapy or undergoing conversion to rapamycin or MMF monotherapy.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: Two weeks prior to conversion, Months 3 & 6 following conversion
measure: 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.
timeFrame: Two weeks prior to conversion, Months 3 & 6 following conversion
Secondary outcomes:
measure: 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.
timeFrame: Two weeks prior to conversion, Months 3 & 6 following conversion
measure: 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.
timeFrame: Two weeks prior to conversion, Months 3 & 6 following conversion
measure: Document improvement in adverse CNI side effects after conversion to rapamycin or MMF monotherapy, comparing designated time points.
timeFrame: Two weeks prior to conversion, Months 3 & 6 following conversion
measure: Document the development of any adverse rapamycin or MMF side effects after conversion, comparing designated time points.
timeFrame: Two weeks prior to conversion, Months 3 & 6 following conversion
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
Study officials:
affiliation: Northwestern University, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation
name: Josh Levitsky, MD
role: PRINCIPAL_INVESTIGATOR
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