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

2. No conflicts of interest
Amany A Maqsod ETS 2014

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

4. 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

5. 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

6. 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.

7. 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

8. 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

9. 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

10. 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.

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

12. 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

13. 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

14. 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

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

16. 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

17. Immunosupressives

18. 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

19. 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

20. 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

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

24. 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.

25. Amany A Maqsod ETS 2014

26. Amany A.Maqsoud 2014

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

28. Drug-drug interaction:

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

32. 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

33. Amany A Maqsod ETS 2014

34. 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

35. 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

36. 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

37. 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

38. Induction/Mainainence

40. 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

41. Amany A Maqsod ETS 2014

43. SRTR 2011 annual report (the same by UNOS)

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

45. Tolerance Immunosuppression Withdrawal
النوبة فريد فاضل
Tolerance Immunosuppression Withdrawal

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. The future

53. 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

54. Annual Conference
Amany A Maqsod ETS 2014

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

56. 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