Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Tolerance Post Liver Transplantation

Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Operational Tolerance Following Liver Transplantation in Adults (ITN056ST)

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.

People who have liver transplants must take anti-rejection medication (immunosuppression) for the rest of their lives. If they stop, their immune system may reject the transplanted liver. All anti-rejection medications have side effects. Because of the side effects of anti-rejection medications, an important goal of transplant research is to allow people to accept their transplanted organ without long term use of anti-rejection medications. This is called tolerance. In this study, participants who received a liver transplant will have their anti-rejection medication(s) gradually reduced over a period of time and then stopped. The study calls this 'immunosuppression withdrawal'.

The purpose of this research study is to see how many people will develop tolerance after immunosuppression withdrawal. The researchers also want to find out if there are blood or liver biopsy tests that can help transplant doctors in the future predict whether it is safe to decrease or stop anti-rejection medications in people who received a liver transplant.

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