Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant (A-WISH)
San Francisco, CA
Ann Arbor, MI
It is possible that tolerance induction may be occurring in a significant number of liver transplant recipients already as a result of variables intrinsic to the organ. In these individuals, tolerance was achieved either after abrupt discontinuation of immunosuppression, or following gradual weaning of immunosuppression long after transplantation. Importantly, the occurrence of rejection during weaning was reversed by reinstitution of immunosuppression, and did not result in a significant long-term damage to the graft.
This trial examines the relationship between clinical outcomes and immune responses in liver transplant recipients with hepatitis C infection or non-immune non-viral causes of liver failure who have been maintained on, or withdrawn from, immunosuppression. The trial will examine the clinical and mechanistic outcomes of attempting to withdraw immunosuppression in a broad group of transplant recipients and relate those to a conventionally treated group in whom immunosuppression is maintained.
Among hepatitis C-infected recipients in particular, the interrelationship of coexistent anti-hepatitis C virus (HCV) and alloimmune responses during and after immunosuppression withdrawal likely significantly affects the development of tolerance and progression of HCV-related injury to the graft. In this complex system involving an organ allograft, potent immunosuppressive agents, and a chronic immunogenic infection, the study is designed to focus on the key immunoregulatory elements that are differentially regulated in chronic HCV infection and that may be modulated by immunosuppression but potentially recover once immunosuppression is withdrawn. Contrasting anti-HCV with alloimmune responses before transplantation, under immunosuppression and during withdrawal may help determine the best strategy for the management of immunosuppression in this patient population. In parallel, the pattern of anti-HCV responses can be correlated with the progression of HCV-related liver injury. Recovery of HCV responses may help identify patients in whom immunosuppressive withdrawal is safe.
Among transplant recipients with non-immune non-viral (NINV) causes of liver failure, the study is designed to determine the relationship between immunosuppression, allograft reactivity and clinical outcomes. In such individuals immunomodulatory variables related to chronic infection or underlying autoimmune disease are not present. This may allow a more direct comparison of allograft responses and other immune parameters between those who undergo withdrawal and those on maintenance immunosuppression. Similarly among those undergoing withdrawal, critical distinctions can be made between those who successfully maintain their allograft without immunosuppression - and who thus fit an operational definition of tolerance - and those who require continued immunosuppression.
The state of the alloimmune response and the presence of phenotypic profile of tolerance will be determined using cell-based and genomic assays.
Shaked A, Feng S, Punch J, Reyes J, Zimmerman M, Kopetskie H, DesMarais M, Sayre P, Levitsky J, Klintmalm G, DePaulis M, Bridges N. Lessons learned from the ITN030ST immunosuppression withdrawal (ISW) trial in liver transplant recipients. (Abstract #O-18) The 2011 Joint International Congress of ILTS, ELITA, & LICAGE, Valencia, Spain, June 22-25, 2011.
Shaked A, Asare S, Phippard D, DesMarais M, Change B, Guettouche T, Keating B. Potential Application of Serum miRNA Signature for Minimization of Immunosuppression and Diagnosis of Rejection Following Liver Transplantation. (Abstract #2930) World Transplant Congress (WTC), San Francisco, CA, July 26-31, 2014.
Shaked A, Feng S, Punch J, Reyes J, Levitsky J, Klintmalm G, Zimmerman M, DesMarais M, Kopetskie H, Bridges N, Sayre P, Priore A. Initial outcomes of early post-liver transplant immunosuppression withdrawal in ITN030ST. (Abstract #251150) American Transplant Congress, Boston, MA, June 2-6, 2012.
Feng S, Philogene M, Phippard D, Punch J, Reyes J, Levitsky J Klintmalm G, Zimmerman M, Sayre P, DesMarais M, Kopetskie H, Shaked A. Evolution of donor specific antibodies (DSA) with immunosuppression (IS) withdrawal among adult liver transplant recipients . (Abstract #0-20) The 2011 Joint International Congress of ILTS, ELITA, & LICAGE, Valencia, Spain, June 22-25, 2011.
Shaked A, Feng S, Punch J, Reyes J, Levitsky J, Klintmalm G, Kopetskie H, DesMarais M, Priore A, Bridges N, Sayre P. Early Post-Transplant Immunosuppression (IS) Withdrawal – Final Outcomes of the ITN030ST AWISH Study.. (Abstract #185) 2016 American Transplant Congress, Boston, MA, June 11-15, 2016.
Shaked A, Feng S, Punch J, Reyes J, Klintmalm G, Zimmerman M, DesMarais M, Kopetskie H, Priore A, Bridges N, Sayre P. Feasibility and Benefit of Minimization and Withdrawal of Immunosuppression (IS) Early After Liver Transplantation in HCV Positive Recipients. (Abstract #2959) World Transplant Congress (WTC), San Francisco, CA, July 26-31, 2014.