The unmet medical need in solid organ transplantation is to eliminate the lifelong requirement of powerful immune suppression drug combinations with their attendant side effects, and to prevent immune mediated rejection of the organ transplant. The proposed trial is designed to study if following a 'standard of care' deceased donor liver transplant host conditioning using Total Lymphoid Irradiation (TLI) and Anti-Tthymocyte Globulin (ATG) will result in operational tolerance and ultimately allow for immunosuppression drug minimization or cessation.

It has been hypothesized that the ATG and TLI conditioning regimen post liver transplant will be safe and well tolerated and will result in recipients successfully being withdrawn from immunosuppression within 2 years after liver transplantation. We will test the hypothesis that by using a conditioning regimen of ATG and TLI to induce this operational tolerance will allow immunosuppressive drug minimization and cessation while maintaining normal graft function and without the risk of graft rejection.

Importance of this knowledge:

Operational tolerance occurs spontaneously in a minority of liver transplant recipients; however, predictable and reproducible induction of tolerance remains an unmet need. Building on extensive experience with TLI-based tolerance induction in kidney transplantation at Stanford, this study aims to evaluate whether a non-myeloablative conditioning regimen using TLI and ATG can safely facilitate immunosuppression minimization and withdrawal in liver transplant recipients without the use of donor hematopoietic cell infusion.

Inclusion Criteria:

• Undergoing liver transplantation at Stanford University
• No contraindications to Total Lymphoid Irradiation or rabbit antithymocyte globulin (rATG)

Exclusion Criteria:

• Contraindications to Total Lymphoid Irradiation (e.g. pregnancy, bone marrow suppression or disease, autoimmune disease, prior radiation in the field)
• Contraindications to rATG
• Patients with history of hepatocellular carcinoma (HCC) or other malignancies with exception of non melanoma skin cancer in remission Model of End-Stage Liver Disease (MELD) score > 25 Liver transplants with severe reperfusion syndrome (hemodynamic instability requiring 3 or more pressors after reperfusion) Liver transplant with early allograft dysfunction (Orloff criteria) Diagnosis of hepatitis B Diagnosis of hepatitis C, except for patients that have been treated and eradicated of hepatitis C Virtual and/or flow crossmatch positive (MFI added up to 8000 for each DSA with MFI>1000).

Subject has previously received or is receiving another organ for transplant other than liver Subject is currently on dialysis Recipient or donor is HIV positive Subject has received an ABO incompatible donor Subject has received a donor liver greater than 65 years of age Subject has an active infection at the time of transplant Subject will require immunosuppressive agent other than those prescribed in this study Subject is pregnant or lactating Subject is unlikely to comply with the visits scheduled in the protocol, including protocol biopsies Subject has any form of current substance use, psychiatric disorder or condition that may invalidate communication with the Investigators