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."
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.
Pre-existing living-donor liver transplant must be 12 months to 20 years from date of scheduled HSPC infusion.
Agreement to participate in the study and ability to give informed consent.
Liver biopsy within 4 weeks of enrollment without signs of rejection.
Major ABO incompatibility with donor.
Any of the following labs > 2.0 times the upper limit of normal on screening: AST, ALT, ALP, GGT or TBil.
History of rejection with current HLA-matched liver transplant within the last year.
History of GVHD following liver transplant.
Single group
Donor Hematopoietic Stem and Progenitor Cell Infusion
Biological/VaccineParticipants with a pre-existing, well-functioning HLA-matched living-donor liver transplant from the same donor will receive a delayed infusion of donor-derived hematopoietic stem and progenitor cells (HSPCs). Donors undergo mobilization and apheresis to collect peripheral blood stem cells, which are processed to generate a CD34+ cell product with an accompanying defined CD3+ T-cell dose. Recipients receive outpatient conditioning with total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (rATG) prior to infusion. The goal of the intervention is to induce tolerance by achieving durable mixed chimerism and enable structured withdrawal of maintenance immunosuppression.
Percentage of subjects weaned off liver transplant immunosuppressants at 12 months after HSPC infusion
The percentage of subjects who successfully discontinue all liver transplant immunosuppressant medications at 12 months after HSPC infusion.
Liver graft rejection within 48 months post-HSPC infusion
Percentage of subjects with liver graft rejection within 48 months after HSPC infusion, defined as: 1. meeting Banff criteria for rejection on biopsy obtained to confirm clinical suspicion, or 2. clinical suspicion of rejection with response to corticosteroids when biopsy is contraindicated or declined.
Graft failure
Percentage of subjects with graft failure as determined by re-listing for liver transplantation and/or re-transplantation.
Incidence of GVHD
Incidence of graft-versus-host disease (GVHD) defined as grade ≥2 acute GVHD or score ≥2 chronic GVHD.
Chimerism persistence
Percentage of subjects with detectable donor-recipient chimerism for at least 180 days within the first 12 months after HSPC infusion, and at 12, 24, 36, and 48 months.
Incidence of acute or chronic GVHD (detailed)
Percentage of subjects that experienced acute or chronic GVHD, diagnosed clinically and/or by biopsy of the affected organ.
Liver function
Percentage of subjects with normal liver function tests (AST, ALT, ALP, TBil, and GGT each ≤ 2× upper limit of normal) at 12, 24, 36, and 48 months.
Infection burden
Mean number of bacterial, fungal, and viral infections per subject at 12, 24, 36, and 48 months.
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