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).
