Currently, transplantation of a solid organ incurs a lifelong burden of immunosuppression for the recipient. In spite of many advances including the development of new agents, the basic premises of immunosuppression strategies remain unchanged and, as such, substantial metabolic, infectious and neoplastic complications continue to threaten the recipient’s life and well-being.
Several reports have, however, shown that a significant proportion of liver recipients (19% - 42%) can maintain normal allograft function without immunosuppression - the definition of functional tolerance. Although drug weaning in these studies did precipitate rejection in some recipients, the vast majority of episodes were graded as mild or moderate, were easily reversed and did not result in long-term consequences.
These reports provide the impetus for this study of gradual and complete immunosuppression withdrawal in a highly selected subgroup of liver transplant recipients: those who underwent living donor liver transplantation as a child (<18 years of age) four or more years ago for diseases other than viral hepatitis and autoimmune liver disorders and who continue to have excellent graft function. Candidates will be meticulously assessed for willingness and appropriateness to participate. Consent will then be obtained from both the liver donor and the liver recipient. It is anticipated that enrollees will typically enter on a minimalistic regimen, such that gradual withdrawal according to protocol can be achieved over six to twelve months. During and immediately after the weaning, recipients will be closely monitored to ensure expeditious recognition, diagnosis and, if necessary, treatment of liver dysfunction.
The primary clinical endpoints are the efficacy and safety of immunosuppression withdrawal in this select subgroup of liver transplant recipients. Therefore, analyses will target the success rate of primary or secondary withdrawal, the duration for which recipients remain off of immunosuppression, the overall incidence of rejection, the incidence of severe and/or refractory rejection and the timing of rejection.
This study also encompassess a complementary scientific effort to identify, quantify and characterize donor-specific immune responses and immunologic interactions which may predict or correlate with functional tolerance. The clinical protocol, which segregates study recipients into tolerant and intolerant groups, is designed to provide serial cell and tissue specimens before, during and after withdrawal for immediate as well as future mechanistic testing through Immune Tolerance Network core facilities.