This clinical trial is being conducted to help liver transplant recipients safely discontinue toxic immunosuppressive drugs years after surgery. Lifelong use of these drugs is the current standard, but they come with life-threatening side effects. UCLA has pioneered this "Delayed Tolerance" approach, achieving success in numerous kidney recipients now living drug-free. The process uses a conditioning regimen followed by donor stem cell infusion to retrain the immune system to accept the liver as "self."

This study seeks to determine if patients with a pre-existing, well-functioning liver transplant from an HLA-matched living donor can be withdrawn from maintenance immunosuppressive medications without compromising allograft function through hematopoietic stem and progenitor cell (HSPC) infusion from the same donor. HSPC infusion will be preceded by a conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (rATG) that takes course over two weeks, with HSPC infusion being on the final day. This entire protocol will take place in the outpatient setting.

At serial time points, (1) graft function will be monitored, (2) chimerism will be measured in recipient whole blood and white blood cell subsets, and (3) protocol biopsies of the graft will be obtained. An attempt will be made to discontinue tacrolimus. Weaning of tacrolimus will begin at 6 months with a goal of discontinuation by 10-12 months as long as the following conditions are met: (1) donor chimerism is detectable for at least 180 days after HSPC infusion, (2) stable graft function (defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and total bilirubin (TBil) levels each ≤ 2.0 × the upper limit of normal) is maintained without clinical or biopsy-determined rejection episodes, and (3) there is no evidence of graft-versus-host disease . HSPC infusion will consist of a target dose of 10 x106 CD34+ cells/kg and 5 x106 CD3+ cells/kg with the goal of achieving durable mixed chimerism.

Immunological tolerance through combined solid organ and HSPC transplant has been demonstrated at a few centers of excellence within the United States, including UCLA. The aim of these protocols is to liberate patients from lifelong immunosuppression. Thus far, protocols have been largely limited to HLA-matched donor recipient pairs undergoing simultaneous kidney and HSPC transplant from the same donor. In all protocols, the recipient undergoes a conditioning regimen to facilitate HSPC engraftment. At UCLA, our protocol employs a conditioning regimen of TLI and ATG. We are the first center to demonstrate the feasibility of retroactive immune tolerance, where a patient with a pre-existing fully HLA-matched kidney transplant underwent HSPC infusion following a conditioning regimen of TLI and ATG over one year after the kidney transplant surgery and successfully achieved durable mixed chimerism and tolerance, allowing permanent discontinuation of immunosuppressants - a process called "delayed tolerance."

Though the liver has intrinsic tolerogenic properties, tolerance protocols for liver are largely limited by the medical and logistical demands of recovering from liver transplant. As we have demonstrated in our single center experience, delayed tolerance has potential to be a reproducible strategy to permanently discontinue immunosuppressants in recipients who receive HSPC transplant months to years after transplant surgery. As such, recipients of HLA-matched living-donor liver transplants who have recovered from their surgery may benefit from protocols to establish tolerance and liberate them from lifelong immunosuppression.

Recipient Inclusion Criteria:

1. Males and females ages 18 years and older with a pre-existing liver transplant from a living donor with a donor-recipient match at 6 or more out of 12 alleles across the HLA-A, -B, -C, -DR, -DQ, and -DP loci, as determined by high-resolution HLA typing.
2. Pre-existing living-donor liver transplant must be 12 months to 20 years from date of scheduled HSPC infusion.
3. Agreement to participate in the study and ability to give informed consent.
4. Liver biopsy within 4 weeks of enrollment without signs of rejection.
5. Meets institutional criteria for HSPC infusion.
6. Resides or is willing to stay within 3 hours distance from UCLA Medical Center by ground transportation for the first three months of the trial at the physician's discretion.
7. No known contraindication to administration of rATG or radiation therapy.
8. If subject is a female of reproductive potential (i.e., no documented absence of ovaries or uterus, history of tubal ligation, or post-menopausal status), subject must be confirmed not pregnant by a serum or urine pregnancy test and must agree to practice a reliable form of contraception including hormonal treatments, barrier methods or intrauterine device for at least 12 months following initiation of the tolerance protocol.

Recipient Exclusion Criteria:

1. Major ABO incompatibility with donor.

2. Any of the following labs > 2.0 times the upper limit of normal on screening: AST, ALT, ALP, GGT or TBil.

3. History of rejection with current HLA-matched liver transplant within the last year.

4. History of GVHD following liver transplant.

5. Positive Class II HLA Donor-Specific Antibody (DSA) or class I DSA specificity above 5,000 MFI at the time of the stem cell infusion.

6. History of multi-organ transplantation, either simultaneous or as separate events.

7. History of more than one liver transplant.

8. Known allergy to rabbit proteins.

9. History of a major post-transplant complication at investigator discretion.

10. History of active malignancy within the past 5 years except for:

    1. Malignancy that has not required treatment in the past on active surveillance.
    2. Malignancy treated with curative intent with no known active disease >2 years before the first dose of study treatment and of low potential risk for recurrence.
    3. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
    4. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ, DCIS).

11. Active bacterial, fungal or mycobacterial infection.

12. Clinically significant viremia from EBV, CMV, HCV or HBV PCR test within the past 3 months.

    1. Significant CMV viremia is defined as greater than or equal to 137 IU/mL.
    2. If CMV low-level viremia is detected, defined as 137 - 1,000 IU/mL, patients may undergo subsequent testing up to twice per week and two consecutive negative results will allow for inclusion.

13. Seropositivity for HIV 1 or 2 by 4th generation serum antibody/antigen testing, or HTLV I or II by serum antibody testing.

14. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.

15. Active extra-hepatic autoimmune disease requiring immunosuppression.

16. Autoimmune disease was the indication for liver transplantation.

17. Any condition that precludes the ability to give informed consent and/or places the subject at high risk for non-compliance with the safety monitoring requirements of the study.

18. Received immunotherapy drugs, such as immune checkpoint inhibitors (e.g. pembrolizumab, nivolumab, and ipilimumab), tumor necrosis factor inhibitors, rituximab, or interleukin-2 within six months of the study treatment.

19. Use of medications with known hepatotoxicity or potential to confound interpretation of liver function tests (e.g., methotrexate, isoniazid, amiodarone), unless reviewed and approved by the Principal Investigator and hepatology, and the subject has demonstrated stable liver function tests for ≥6 months while on the medication.

20. Active hepatobiliary and pancreatic diseases:

    1. History of chronic hepatobiliary or pancreatic disorders that may interfere with safety assessments or interpretation of protocol endpoints, including but not limited to primary sclerosing cholangitis (PSC), autoimmune hepatitis, primary biliary cholangitis (PBC), chronic pancreatitis, recurrent cholangitis, biliary strictures, biliary obstruction, untreated bile duct injury, hepatobiliary malignancy, or metabolic/genetic liver disease (e.g., Wilson's disease, alpha-1 antitrypsin deficiency).
    2. Active chronic liver diseases such as metabolic dysfunction-associated steatohepatitis (MASH) and alcohol-associated liver disease.
    3. Gallbladder diseases such as cholecystitis or symptomatic cholelithiasis.

Donor Inclusion Criteria:

1. Males and females ages 18 years and older meeting the HLA-matching requirements specified in the "Recipient Inclusion Criteria" above.

2. Must meet the following criteria for HSPC donation:

   1. Hgb: > 11 g/dl
   2. Plt: > 80,000/µL
   3. WBC: > 3,000/µL

Donor exclusion criteria:

1. Major ABO incompatibility with recipient.

2. Medically unfit to tolerate peripheral blood apheresis (e.g., small body size, poor vascular access, not a suitable candidate for placement of a central catheter).

3. Pregnant (confirmed by urine or serum pregnancy test) or lactating.

4. Seropositivity for HIV 1 or 2 by 4th generation serum antibody/antigen testing, HTLV I or II by serum antibody testing.

5. Active West Nile Virus infection.

6. Active bacterial, fungal, mycobacterial or viral infection (including active hepatitis B and/or C).

7. Psychiatric, addictive, neurological, or other disorder that compromises ability to give true informed consent for participation in this study

8. Use of oral anticoagulants within two days of apheresis.

9. History of active malignancy within the past 5 years except for:

   1. Malignancy that has not required treatment in the past on active surveillance.
   2. Malignancy treated with curative intent with no known active disease >2 years before the first dose of study treatment and of low potential risk for recurrence.
   3. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
   4. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ, DCIS).

IPD will not be shared because this is a Phase I, single-site study involving transplant recipients and their living donors, where data elements such as HLA high-resolution typing, chimerism profiles, and longitudinal graft function measurements are inherently identifiable. Sharing raw IPD would pose a significant re-identification risk and is not permitted under the study's IND, IRB approval, or institutional policies for early-phase cellular therapy trials. Aggregate, de-identified results will be disseminated through scientific publications and presentations, but participant-level datasets will not be made publicly available.