Immune Tolerance Induction After Liver Transplantation

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to determine if patients with a pre-existing, well-functioning liver transplant from an HLA-matched living donor can be withdrawn from maintenance immunosuppressive medications without compromising allograft function through hematopoietic stem and progenitor cell (HSPC) infusion from the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.