Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Tolerance Post Liver Transplantation
Condition: Liver Transplant; Liver Transplantation
Intervention: Immunosuppression withdrawal
Intervention description: Participants will initiate calcineurin inhibitor (CNI) withdrawal after at least 3 weeks of stable liver function, as documented by liver function tests (direct bilirubin, alanine aminotransferase and gamma-glutamyl transferase) separated by at least 1 week in the 3 week period prior to withdrawal.
CNI withdrawal will occur in eight 3 week intervals with each subsequent reduction based on liver function tests over the prior 3 week interval.
Participants on CNI and prednisone will undergo withdrawal from the two therapies concurrently.
If participants are weaned off the CNI successfully, they will initiate non-CNI withdrawal. The non-CNI withdrawal includes two dose reductions of approximately 50% over a 6 week period each, after which the drug will be discontinued.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 100.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Liver allograft recipient; Immunosuppression withdrawal; Calcineurin inhibitor (CNI) based immunosuppression; Living Donor (of the Respective Liver Transplant Recipient)

Summary:

      The primary aim of this study is to determine whether a peripheral blood or graft lymphocyte
      phenotype of immune senescence or exhaustion is different between operationally tolerant and
      non-tolerant liver allograft recipients.
    

Eligibility criteria:

        Inclusion Criteria:

        Recipient participants must meet all of the following criteria to be eligible for this
        study:

          1. At the time of screening:

               -  18 to 50 years old and more than 6 years post-transplant OR

               -  Greater than 50 years old and more than 3 years post-transplant

          2. Recipient of either deceased or living donor liver transplant. Recipients of living
             donor transplants must have a donor who is also willing to enroll

          3. Recipient of single organ transplant only

          4. Must have a screening liver biopsy that fulfills the following criteria based on the
             central pathology reading:

               -  Portal inflammation and interface activity is preferably absent, but minimal to
                  focal mild portal mononuclear inflammation may be present. Interface
                  necro-inflammatory activity is absent or equivocal/minimal and, if present,
                  involves a minority of portal tracts and not generally associated with fibrosis

               -  Negative for perivenular inflammation

               -  Lymphocytic bile duct damage, ductopenia, and biliary epithelial senescence
                  changes are absent unless there is an alternative, non-immunological explanation
                  (e.g. biliary strictures)

               -  Fibrosis (if present) should be mild overall, and portal-to-portal bridging
                  should not be more than rare. Perivenular and peri-sinusoidal fibrosis should not
                  be more than mild according to the Banff criteria

               -  Findings for obliterative or foam cell arteriopathy are negative

          5. Liver function tests (Direct bilirubin, alanine aminotransferase (ALT)), less than
             twice the upper limit of normal (ULN). ULN values for liver function tests will be
             defined by ranges from Harrison's Principles of Internal Medicine, 18th edition

          6. Receiving calcineurin inhibitor (CNI) based maintenance immunosuppression.
             Participants may also concurrently receive:

               -  Low dose mycophenolate mofetil (MMF ≤ 1500 mg daily) or mycophenolic acid (≤ 1080
                  mg daily), OR

               -  Prednisone ≤ 7.5 mg daily, or equivalent corticosteroid

          7. Ability to sign informed consent

        Living donor participants must meet all of the following criteria to be eligible for this
        study:

          1. At the time of screening: ≥18 years old

          2. Living donor of the liver allograft of an enrolled recipient participant

          3. Ability to sign informed consent

          4. Willingness to donate appropriate biologic samples

        Exclusion Criteria:

        Recipient participants who meet any of the following criteria will not be eligible for this
        study:

          1. History of hepatitis C virus (HCV) infection (defined as a positive HCV antibody test)

          2. Positive antigen-antibody immunoassay for human immunodeficiency virus, HIV-1/2

          3. Serum positivity for HBV surface antigen or HBV-DNA

          4. History of immune-mediated liver disease in which immunosuppression discontinuation is
             inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary
             cirrhosis)

          5. Any medical condition associated with a likely need for systemic corticosteroid
             administration, e.g., reactive airways disease

          6. Prospective baseline liver biopsy showing any of the following: (see recipient
             inclusion criteria #4)

               -  acute rejection according to the Banff global assessment criteria

               -  early or late chronic rejection according to the Banff global assessment criteria

               -  inflammatory activity and/or fibrosis in excess of permissive criteria according
                  to Banff 2012 criteria

               -  any other histological findings that might make participation in the trial
                  unsafe. Eligibility will be determined by the findings on the central biopsy
                  reading

          7. Rejection within the 52 weeks prior to screening

          8. Estimated glomerular filtration rate (GFR) <40 ml/min as calculated by CKD-EPI method
             (to mitigate the risk of worsening renal failure should rejection occur and high level
             of CNI be required)

          9. The need for chronic anti-coagulation that cannot be safely discontinued for a minimum
             of 1 week to safely perform a liver biopsy

         10. Pregnant females and females of childbearing age who are not using an effective method
             of birth control

         11. Current drug or alcohol dependency

         12. Inability to comply with the study visit schedule and required assessments, including
             frequent liver function monitoring and protocol biopsies

         13. Inability to comply with study directed treatment

         14. Any medical condition that in the opinion of the principal investigator would
             interfere with safe completion of the trial

         15. Participation in another interventional clinical trial within the 4 weeks prior to
             screening

        Living donor participants who meet any of the following criteria will not be eligible for
        this study:

        1. Any medical condition, such as anemia, coagulopathy, etc., that in the opinion of the
        principal investigator would interfere with safe participation in the trial