Liver transplant

1. IMMUNOSUPRESSION IN LIVER TRANSPLANT
PATHOPHYSIOLOGICAL ASPECT
Dr. WAJEED YOUSUF
DNB SS SCHOLAR
1ST YEAR
BLK-NEW DELHI 5

2.  1st transplant – Welch – In dogs- 1955
 Ist in Humans – Thomas Starlz – 1963
 1st succesful liver transplant in 1967
 Survival for :
 One year – 90-95%
 5 years – 70%

3. Graft Types
I- Based on foreignness
1- Autograft: NO IR
2- Syngraft (Isograft): NO IR, Histocompatible
3- Allograft: Histoincompatible & rejection
4- Xenograft: Histoincompatible & rejection
III- According to immunogenicity
• Bone marrow is the most immunogenic
• Liver is the least immunogenic
– 1- Lack of suitable APCs
– 2- Different expression of HLA molecules
• Privileged sites: e.g. cornea ---No significant IR
Lack of lymphatic drainage
II- According to origin
• Living graft
• Cadaveric graft

4. How liver transplant is different than others?
Largest Organ
Least amount of Immunosuppression required
Lowest incidence of hyperacute and chronic immune mediated rejection
In dual organ transplants-the LT reduces the chance of rejection of the second organ
Highly Immune Tolerogenic
Due to-
1. Continuous exposure to gut derived pathogens
2. Antigenic metabolic products

6. Why liver is more tolerogenic than other organs?

9. Rejection
Hyperacute
1 Preformed Ab. 2. Complement activation,
3 Neutrophil margination. 4 inflammation,
5.Thrombosis formation
Acute
1. T-cell, macrophage and Ab mediated,
2. myocyte and endothelial damage,
3. Inflammation
Late
1. Macrophage – T cell mediated
2. Concentric medial hyperplasia
3. Chronic DTH reaction

10. IMMUNOBIOLOGY OF ACUTE REJECTION

11. Signal I: (Alloantigen recognition)
- Alloantigen recognition requires presentation of a foreign
alloantigen along with a host major histocompatibility complex
(MHC) molecule.
- Presentation is done by an APC. The antigen, bound to an MHC
molecule, binds to the T-cell receptor.
-This is the first of three signals that are required for T-cell
-maturation.

12. Signal II : Lymphocyte activation (co-stimulation)
 T-cell activation requires co-stimulation, a process in which
a number of ligands on the APC bind to a variety of T-cell
receptors, including CD28, CD154, CD2, CD11a, and CD54.
 The T-cell receptor complex is internalized and binds to
immunophilin.
 Immunophilin stimulates calcineurin, which activates
(NFAT)
 The activated NFAT then translocates to the nucleus where
it drives interleukin (IL)-2 transcription.

13. Signal III: (Clonal expansion)
 Newly synthesized IL-2 is secreted by T cells and binds to IL-2 receptors (IL-2R)
on the cell surface in an autocrine fashion, stimulating a burst of cell
proliferation.
 Inflammation — T-cell proliferation is associated with cell-mediated
cytotoxicity and secretion of cytokines, chemokines, and adhesion molecules.
The secreted mediators recruit additional inflammatory cells to the graft. The
result is an inflammatory milieu with additional toxic and vasoactive mediators.

14. Signal I: Antigen presentation by APC to the T cell receptor.
Signal II: Costimulation - binding of additional APC ligands to specific T cell receptors.
Signal III: Newly synthesized IL-2 and growth factors feed back on T cell membrane receptors, causing clonal expansion of newly
activated T cells.

17.  Induction of immunosuppression in the early phase, intensive perioperative
prophylactic immunosuppression used to prevent acute cellular rejection in the
first months following transplantation.
Steroids
Antibodies
 Maintenance of immunosuppression in the late phase or for the treatment of
organ rejection.
CNI
Antimetabolites
mTOR

21.  There is no agreement on an ideal protocol.
 Another common regimen is a 1 gram bolus of methylprednisolone during the
an-
 Hepatic phase, followed by 20 mg/day intravenously.
 Once the patient is able to take oral medications, switched to prednisolone
20 mg/day.
 Tapering to zero is usually achieved over three to six months, although some
centres leave patients on 5 mg/day indefinitely.

23. Glucocorticoids and HCV
 If steroids are used, a flare of HCV infection with an increased viral load and
increased aminotransferases should be anticipated during tapering.
 Three options exist with regard to glucocorticoid use in patients with HCV:
 Maintain low-dose steroids indefinitely (approximately 5 mg per day)
 Taper steroids slowly
 Avoid steroids

25.  Inhibits T-cell activation by binding
intracellular cyclophilin.
 Reduces calcineurin activation.
 Nuclear factor of activated T cells (NFAT)
does not translocate to the nucleus.
 Interleukin (IL)-2 production is shut down.
CALCINEURIN INHIBITORS:

26.  Cyclosporine
 First CNI developed.
 The goal therapeutic level of cyclosporine is usually 200 to 250 ng/mL in the first three
months after transplantation.
 Tapered to 80 to 120 ng/mL by 12 months.
 Cyclosporine is cleared in the bile after extensive metabolism in the liver.
 Any change in bile flow (e g, with rejection episodes or biliary complications) caused a
change in cyclosporine absorption.

27.  Renal toxicity.
 Hypertension.
 Neurotoxicity.
 Hyperlipidaemia.
 Gingival hyperplasia.
 Hirsutism.
 Hyperkalemia.
 Side effects:

28.  Macrolide compound originally isolated
from Streptomyces tsukubaensis.
 It inhibits IL-2 and interferon-gamma
production.
 Approved for liver transplantation in
1994
Tacrolimus: (FK506)

29. Tacrolimus dosing
 Tacrolimus dosing should be individualized.
 It is 100 times more potent than cyclosporine
 Better bioavailability of 22%
 Half life 11.7 hours
 Start with a low dose (0.5 to 1 mg every 12 hours / 0.02 to 0.03 mg /kg) on
postoperative day
 Aim for a level of 7 to 10 ng/mL by the end of the first week.
 A level of 6 ng/mL is usually satisfactory after six months.
 Maintenance at a level of 4 to 6 ng/mL is common beyond one year.

31. The incidence of lymphoproliferative disease was similar with both the drugs.

32. Side Effects
 The mostly commonly concerning adverse side effect of tacrolimus is their
nephrotoxic effect at high levels (24-45%).
Produce afferent renal arteriolar vasoconstriction that could induce renal
dysfunction (dose dependent and reversible).
Tubular injury
Chronic renal injury
Rodríguez-Perálvarez M, Am J Transplant 2012; 12: 2797-2814

33.  MANAGEMENT:
 Reduction or withdrawal of CNI
therapy as soon as possible.
 CNI withdrawal and replacement
with MMF.
 TAC reduction with addition of
EVR were associated with
increased estimated GFR,
demonstrating a significant
benefit to renal function.

34.  Neurotoxicity
 Diabetes Mellitus
 HUS
 Hypertension : More common as compared to Cyclosporine
 Dyslipidemia
 OTHERS

35. INHIBITORS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR):

36. Sirolimus
 Macrolide antibiotic produced by Streptomyces hygroscopicus, structurally similar
to tacrolimus.
 Binds the same target (FK-binding protein) but does not inhibit calcineurin.
 Instead, it blocks the transduction signal from the IL-2 receptor, thus inhibiting T-
and B-cell proliferation and prevents progression of G1 to S phase.
 Its advantage over the CNIs is less likely to cause nephrotoxicity and neurotoxicity.
 Sirolimus is inadequate as monotherapy and routinely add a second agent when
switching from a CNI for any reason.

37. In LT for HCC, sirolimus was reported to be associated with
 Lower tumor recurrence rate,
 Longer recurrence-free survival and overall survival, and
 Lower recurrence-related mortality compared with CNIs.
Finn RS. Liver Cancer 2012; 1: 247-256

38.  Dose: Start with 2 mg daily without a loading dose, titrated to obtain a
level between 4 and 10 ng/mL
Side effects:
 In the postoperative period:
o Hepatic artery thrombosis
o Delayed wound healing
o Incisional hernias,
Chronic use has been associated with
o Hyperlipidemia
o Bone marrow suppression
o Mouth ulcers
o Skin rashes,
o Albuminuria
o Pneumonia.

39.  The FDA recommends that both mTORs, Everolimus and Sirolimus, not be used
earlier than 30 days after liver transplantation because of an increased risk of
hepatic artery thrombosis in the early post-transplantation period.

41.  The mechanism of action of EVR is via inhibition of mammalian target of rapamycin
(mTOR), similar to sirolimus.
 Rapidly absorbed and reaches a peak concentration within one to two hours if
given on an empty stomach.
 Higher oral availability and lower plasma binding than sirolimus.
 A starting dose of 0.75 mg – 1mg twice daily.
 Target trough level of 3 to 8 ng/dL is standard.
 Everolimus

43. Antimetabolites
 MMF (Cellcept) and an enteric coated formulation mycophenolate sodium
Myfortic®)
 Both esters are hydrolysed to the active form mycophenolic acid (MPA)
 INHIBITORS OF PURINE AND PYRIMIDINE SYNTHESIS:

44.  Mycophenolic acid :
 MPA selectively inhibits the proliferation of both B and T lymphocytes.
 Inhibits IMPDH, preventing the formation of GMP.
 Cells depleted of GMP cannot synthesize GTP and therefore cannot replicate.

45. Bioavailability = 94%
Half-life of 17 hours
Converted to an inactive form, mycophenolate glucuronide, in the liver
MMF is 1 g every 12 h
EC-MPS 720 mg every 12 h
Monitoring usually not recommended
It is used to reduce or discontinue CNI dosing in order to treat side effects.
The added immunosuppression of MMF may also allow for the early
discontinuation or avoidance of steroids.

46. Side effects:
- bone marrow suppression
- gastrointestinal complaints: abdominal pain, ileus, nausea, vomiting, and oral
ulceration.
S/E are usually dose-related and improve with temporary or permanent dose
reduction.
Food may interfere with absorption of the drugs, so they should be taken one hour
before or two hours after meals.

48.  Prodrug of 6-mercaptopurine.
 Antimetabolite that inhibits purine synthesis.
 Azathioprine inhibits the replication of T and B cells.
 One of the first immunosuppressive agents used in the field of solid organ
transplantation.
 1.5 to 2.0 mg/kg/day.
 Major side effects are related tobone marrow suppression its hepatotoxicity.
 Azathioprine

49.  Anti-thymocyte globulins:
 ATGs are polyclonal animal antibodies against multiple T-cells receptors that
are used to achieve circulating lymphocyte depletion.
Equine ATG - obtained from equines.
Rabbit ATG - generated in rabbits.
 Used for induction of immunosuppression or treatment of steroid-
resistant rejection
The protocol for ATG induction therapy differs between centers
Dose: 2 mg/kg IV infusion per day for 3 days.
 Antibodies:

50. • Adverse reactions
• Serum sickness may develop following rATG administration.
• Cytokine storm syndrome
• A more severe recurrence of hepatitis C virus (HCV) infection.
• Increased risk of post transplantation lymphoproliferative disorders
(PTLD) following rATG induction in LT patients.
Lundquist AL, Chari RS, Liver Transpl 2007; 13:v647-650

52. • Muromonab-CD3 (OKT3)
• It is directed against the CD3-antigen complex on mature T cells. Binding this
receptor causes opsonization and removal of T cells from the circulation.
• Used in managing steroid-resistant rejection
• The standard dose of OKT3 is 5 mg intravenous (IV) daily for 10 to 14 days.
• The initial two to three doses typically cause a cytokine release syndrome
characterized by fever, chills, headache, chest pain, tachycardia, dyspnea,
wheezing, nausea, and vomiting.
 Monoclonal antibodies

53. • Pulmonary edema – life threatening complication
• Close monitoring of the absolute neutrophil count (ANC). It is recommended
that patients whose ANC did not decline below 500 cells/mL be treated with a
double dose of OKT3 to overwhelm the developing antibodies.
• Post-transplant lymphoproliferative disorder (PTLD)( 3% patients)

54. • Humanized monoclonal antibodies against the IL-2 receptor.
• Blockade of the IL-2 receptor prevents T-cell proliferation.
 Used to reduce CNI in patients with pre-transplant renal disease.
 To minimize steroid use.
- Steroid-resistant rejection after transplantation.
• Daclizumab dosed at 2 mg/kg on post-orthotopic liver transplant (OLT) days 1 and 3, and 1 mg/kg on day 8,
OR 2 mg/kg before engraftment and 1 mg/kg on day 5 post-OLT
• Basiliximab: 20 mg on the day of transplant (day 0), followed by a second 20 mg dose on day 4 post-
transplantation.
 Basiliximab and daclizumab (IL-2 Inhibitors)

56. Complications of immunosuppression which impact liver transplants
• MELD: probability that recipients have renal dysfunction that is exacerbated by the
use of CNIs
• Immunosuppression increases the chance for hepatitis C virus re-infection
• Reduced immune surveillance promotes de novo malignancy and HCC re-emergence
• Re-development of fibrosis in the transplanted liver is enabled by immunosuppressive
agents that induce production of transforming growth factor b (CNIs)

57. THANKYOU ALL