Immunosuppression in Liver Transplantation Amany AbdelMaqsod Sholkamy Prof. of Internal Medicine&Hepatology Kasr AlAiny Liver Transplantation Team Supervisor of Liver ICU (Elfaransawy H)

No conflicts of interest Amany A Maqsod ETS 2014

Agenda: Introduction and historical points Immunological privilege in liver Tx The strategy of immunosuppression. Immunosupressive drugs. The future. Amany A Maqsod ETS 2014

Due to advances in immunosuppression and improvements in surgical techniques, liver Tx has become a highly successful treatment option for pts with end stage liver disease, with one year patient and graft survival rates exceeding 80%. Amany A Maqsod ETS 2014

In 2013, it was reported that there are 8pts worldwide who have survived more than three decades after liver transplantation. Amany A Maqsod ETS 2014

Historical points In the fifties, multiple interventions including splenectomy, thymectomy and thoracic duct drainage were employed with limited success. The first successful human liver transplant was performed by Thomas Starzl in Denver in 1967 on an 18 month old child with unresectable hepatoblastoma. The immunosuppressive regimen included anti-lymphocyte globulin (ALG), AZA and prednisolone and the child survived for greater than one year.

Immunological privilege: The liver is thought to be an immunologically privileged organ with a lower incidence of rejection (despite less immunosuppression) in comparison with other solid organ transplants. Amany A Maqsod ETS 2014

Immunological privilege: Animal models show spontaneous lifetime tolerance to liver grafts. Liver recipients require ↓ immunosupressives than other organ Tx. Liver grafts confer immunoprotection to other organ Tx. HLA matching has little impact on graft survival. The mechanism is not completely understood. Amany A Maqsod ETS 2014

Why is the liver Immunologically privileged ? Regenerative capacity of the liver. Large number of donor hematopoietic cells transferred with the graft: Chimerism. Donor leucocytes mediate tolerance by acting as surrogate targets of rejection. Hence, the talk about complete withdrawal. Amany A Maqsod ETS 2014

Immunological privilege Both micro and macrochimerism models have been used to explain this phenomenon as well as, to some degree, hepatic dissolution of donor specific antibodies.

Administration Of Immunosupressives Is An Art Few markers of rejection, tolerance, and alloimmunity. Administration Of Immunosupressives Is An Art

Strategy: Ideally, the long term objective is to achieve immune tolerance or the ability to alter the recipient’s immune system to promote long-term graft function without immunsuppressive therapy. Unfortunately, except for a small % of patients (≈20%) who were successfully weaned off immunosuppressive medications, most experienced rejection with the discontinuation of these drugs and had to be kept on maintenance doses. Amany A Maqsod ETS 2014

Effective immunosuppression in Tx relies on preventing the immune system from rejecting the allograft while preserving immunologic control of infection and neoplasia. Amany A Maqsod ETS 2014

Immunotherapy in transplantation must balance Downregulation of the allogeneic response -- the prophylaxis of acute and chronic rejection Maintenance of nominal immune responses Avoidance of drug-induced adverse events. Amany A Maqsod ETS 2014

Individualize when possible: HCC, HCV, autoimmune liver diseases… Drug cost Use evidence based data when choosing regimes. Amany A Maqsod ETS 2014

Immunosuppressives Double edged weapon Beneficial Adverse Accept the graft Avoid acute and chronic rejection Infection Malignancy Effect on the original disease Amany A Maqsod ETS 2014

Immunosupressives

Immunosuppressive drugs: Corticosteroids Tacrolimus = (FK 506)= Prograph Cyclosporine (Neoral, Sandimmune) Mycophenolate mofetil (CellCept or Myfortic) Sirolimus(Certicane/rapamune) Basiliximab (Simulect ) Amany A Maqsod ETS 2014

Immunosuppressive drugs CNI: Cyclosporin Tacrolimus (FK506) Antiproliferative: Mycophenolate mofetil Mammalian target of rapamycin inhibitors mTOR: Sirolimus, everolimus Monoclonal antibodies (antiCD): Basiliximab, Rituximab Calcineurin inhibitors; they primarily suppress the activation of T lymphocytes by inhibiting the production of cytokines, specifically IL-2. Sirolimus is a macrocyclic antibiotic, modulates the activity of the mTOR inhibitor, which inhibits IL-2–mediated signal transduction and results in T- and B-cell cycle arrest. Antiproliferative agents inhibit DNA replication and suppress B- and T-cell proliferation. Antibodies interact with lymphocyte surface antigens, depleting circulating thymus-derived lymphocytes and interfering with cell-mediated and humoral immune responses. Amany A Maqsod ETS 2014

Mechanism of action Immunotherapy in transplantation is based on T-cell control because of the critical role of the T cell in the allogeneic response. These agents target different sites in the T cell activation cascade, usually by T cell depletion or inhibiting T cell activation or proliferation. The selection of agents is based on an individual’s medical history as well as institution experience and preference. Amany A Maqsod ETS 2014

Cornerstone Amany A Maqsod ETS 2014 inhibit antigen presentation, cytokine production, and proliferation of lymphocytes. Amany A Maqsod ETS 2014

Side Effects CNI augments TGF beta this is why they may predispose to PTLD, lymphoma and HCC recurrence. 2 successive studies on sirolimus were terminated because of HAT --- black box warning. This was not found with EVL.

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Immunosuppressives metabolized by cytochrome p450: CNI Sirolimus Amany A Maqsod ETS 2014

Drug-drug interaction:

Administration Of Immunosupressives Is An Art Few markers of rejection, tolerance, and alloimmunity. Administration Of Immunosupressives Is An Art

Why? Few markers of: Overall immunosuppression Rejection/tolerance Poor correlation between: Rejection and liver functions Drug level (if present) and effective immunosuppression Liver biopsy is the gold standard Amany A Maqsod ETS 2014

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Current concept of immunosuppression The early approach to immunosuppression was based on a heavy induction protocol followed by maintenance therapy Amany A Maqsod ETS 2014

Today’s concepts of immunosuppression Attention has focused on reducing immunosuppression and fostering tolerance. The introduction of tolerance (stable and normal graft function in the absence of immunosuppression) has long been a goal of transplant clinicians and scientists. Amany A Maqsod ETS 2014

Attention has been made to the window of immunological engagement, suggesting that, if the host immune system is allowed to see graft antigens, tolerance can be encouraged; thus, overimmunosuppression soon after transplantation can lead to a greater need for immunosuppression. WOFIE Amany A Maqsod ETS 2014

Combination therapy Most regimens combine drugs with different sites of action of T cell responses: Inhibits immune response at different sites. Allow lower doses. Reduce dose dependent toxicity Lower rejection rate Amany A Maqsod ETS 2014

Induction/Mainainence

Currently, the mainstay of maintenance are CNI, used in the vast majority of transplant patients upon discharge, although there is a known increased risk of renal impairment, metabolic derangements, neurotoxicity and de novo malignancies. Amany A Maqsod ETS 2014

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SRTR 2011 annual report (the same by UNOS)

EASL 2014 stated no Consensus regarding this observation Amany A Maqsod ETS 2014

Tolerance Immunosuppression Withdrawal النوبة فريد فاضل Tolerance Immunosuppression Withdrawal

While liver allograft recipients require less immunosuppression than other organ recipients and some do become tolerant to their graft, there is, as yet, no regime that will reliably induce tolerance in the human host. Amany A Maqsod ETS 2014

Withdrawal of Immunosuppression There are no clear markers of those who are tolerant to the graft. Withdrawal programmes will select those who have stable and normal graft function after 5 years. Those who were Tx due to an autoimmune disease are less likely to be tolerant. Amany A Maqsod ETS 2014

Withdrawal of Immunosuppression The complete withdrawal of immunosuppression has been studied in several non RCT with a success rate of approximately 20-25%. Weaning in the remaining patients typically results in rejection and the reinstatement of immunosuppression. Amany A Maqsod ETS 2014

Withdrawal of Immunosuppression Results were better in pediartic recipients of parental living donor LT. Again, no definite markers/protocols for withdrawal of immunosupressives. Monitoring for the development of donor-specific antibodies during withdrawal appears promising. Amany A Maqsod ETS 2014

Calcineurin Inhibitors Downregulate cytokine production without turning it off completely. Inhibit only 50% of the calcineurin in a T cell. This is useful, because T cells responding to infectious agents need to retain their cytokine-producing properties in order for the recipient to successfully combat infection. Amany A Maqsod ETS 2014

Antiproliferative (antimetabolite) Inhibit de novo synthesis of the purine building blocks of DNA namely, guanine and adenine. Mycophenolate mofetil(Cellcept), Amany A Maqsod ETS 2014

The future

Trends/future in immunosuppression for liver Tx: No induction New drugs tackling different T-cell pathways. (Belatacept, Efalizumab, Sotrastaurin) Steroid free protocols Combined bone marrow transplantation Organ engineering Amany A Maqsod ETS 2014

Annual Conference Amany A Maqsod ETS 2014

Art happens all the time, everywhere Art happens all the time, everywhere. All we have to do is to keep our minds open.

References: Current status of immunosuppression in liver transplantation. Posted on ILTSEducation.org 19 August 2013 Immunosuppression: Conventions and Controversies. Neil Mehta, and Ryutaro Hirose. Clinical Liver Disease, Vol 2, No 4, August 2013 Scientific Registry of Transplant Recipients (SRTR) 2006/2011 EASEL consensus 2014 Hepatology, transplantation proceedings j 2013, 2014 Amany A Maqsod ETS 2014