Liver transplantation immune therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Liver trasnsplantation Microchapters
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Liver transplantation immune therapy

Rejection immunology pathway

• Alloantigen recognition requires presentation of a foreign alloantigen along with a host major histocompatibility complex (MHC) molecule.
• An antigen-presenting cell presents The antigen to the T-cell receptors including CD28, CD154, CD2, CD11a, and CD54. This causes maturation of T-cells.
• T-lymphocyte activation causes stimulation of  calcineurin, which activates nuclear factor of T-cell activation (NFAT) which increases interleukin-2 transcription.
• IL-2 binds to IL-2 receptors increasing T-cell proliferation.
• T-cell proliferation causes cell-mediated cytotoxicity and secretion of cytokines, chemokines, and adhesion molecules causing inflammatory reaction against the graft organ cells.

Drugs used to overcome rejection reaction

Glucocorticoids

• Glucocorticoids upregulate interleukin -10 (inhibitory) expression, and downregulate IL-2, IL-6, and interferon-gamma ( stimulatory) synthesis by T cells [2-4].
• Glucocorticoids are the first line of initial therapy and treatment of acute allograft rejection in many centers.

Dosing equivalents for common steroid compounds

Steroid compound	Dose, mg
Hydrocortisone	20
Prednisolone	5
Prednisone	5
Methylprednisolone	4

Side effects:

• Diabetes Mellitus
• Fluid retention
• Hypertension
• Emotional lability
• Hyperlipidemia
• Cosmetic changes
• Poor wound healing
• Susceptibility to infection
• Visual changes
• Cataract
• Osteopenia
• Steroid therapy increases hepatitis C virus (HCV) replication [6,7]. There are three options exist regard to glucocorticoid use in those patients. 10] [11].

• Maintain low-dose steroids indefinitely (approximately 5 mg per day)
•  Avoid steroids A possible alternative to traditional glucocorticoids is budesonide. effects because of high first-pass hepatic metabolism. [9.

Cyclosporine 

• Cyclosporine  inhibits T-cell activation by binding intracellular cyclophilin, thus reducing calcineurin activation.
• the nuclear factor of activated T cells (NFAT) does not translocate to the nucleus, and interleukin (IL)-2 production   markedly diminished T-cell response
• cyclosporine is variably absorbed in the jejunum and enters the lymphatic system. Peak blood levels are achieved in two to four hours, The average half-life is 15 hours but ranges widely (10 to 40 hours). Cyclosporine is cleared in the bile after extensive metabolism in the liver by CYP3A4.
• The goal therapeutic level of cyclosporine is usually 200 to 250 ng/mL in the first three months after transplantation, but is typically tapered to 80 to 120 ng/mL by 12 months.
• Neurological toxicity may include altered mental status, polyneuropathy, dysarthria, myoclonus, seizures, hallucinations, and cortical blindness
• include hyperlipidemia, gingival hyperplasia, and hirsutism.
• Potassium-sparing diuretics and potentially nephrotoxic drugs should be avoided if possible. [29]. patients should be monitored for renal toxicity, hypertension, hyperkalemia, and hypomagnesemia.

Tacrolimus

• It inhibits IL-2 and interferon-gamma production and is 100 times more potent than cyclosporine.
• We usually start with a low dose (0.5 to 1 mg every 12 hours) on postoperative day 1,
• and 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, and maintenance at a level of 4 to 6 ng/mL is common beyond one year. We aim for higher levels in patients who are transplanted for autoimmune liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis.
• Both treatment regimens were effective, but tacrolimus was superior with regard to the composite endpoint and for patient and graft survival (figure 3). [34,35].Tacrolimus was superior when analyzed for survival, graft loss, acute rejection, and steroid-resistant rejection in the first year (table 5).
• CNI-induced renal failure is a serious problem after orthotopic liver transplant (OLT) [37]. The problem has been exacerbated by the switch to a MELD-based organ allocation system, which is weighted towards higher serum creatinine. (See "Model for End-stage Liver Disease (MELD)".)
• Cyclosporine and tacrolimus are potent immunosuppressive agents. Their availability has allowed us to shift our focus from acute cellular rejection and short-term post-transplant survival to long-term management of complications. They
• have similar adverse effects including nephrotoxicity, neurotoxicity, and electrolyte abnormalities, and both can be monitored with drug levels.
• Tacrolimus is superior in terms of preventing acute rejection, steroid-resistant rejection, graft loss, and postoperative death. These findings have made tacrolimus first line therapy in most liver transplant centers despite its higher association with post-transplant diabetes mellitus. Diabetes is a significant concern since it will probably contribute to the progressive renal failure that may be seen in long-term survivors.

Sirolimus 

• Sirolimus is a potent immunosuppressive agent approved by the US Food and Drug Administration (FDA) for renal transplantation in 1999 [48].
• It 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.
• Its advantage over the calcineurin inhibitors (CNIs) is its freedom from nephrotoxicity and neurotoxicity.
• Rejection was seen more commonly with monotherapy, rarely with dual therapy, and not at all with triple therapy.
• Sirolimus may be especially useful as a substitute in cases of CNI-intolerance (primarily renal failure and neurotoxicity) [51-53].
• A retrospective analysis showed no benefit for renal function when patients with chronic renal insufficiency were switched from CNIs to sirolimus [56].  [57].

Side effects 

• Hepatic artery thrombosis
•  Delayed wound healing
• Incisional hernias
• Hyperlipidemia
• Bone marrow suppression
• Mouth ulcers
• Skin rashes
• Albuminuria and pneumonia [62].

Everolimus 

• Everolimus is the hydroxyethyl derivative of sirolimus.
• The mechanism of action of EVR is via inhibition of mammalian target of rapamycin (mTOR), similar to sirolimus [73].
• Everolimus is rapidly absorbed and reaches a peak concentration within one to two hours if given on an empty stomach [74].
• It has higher oral availability and lower plasma binding than sirolimus
• A starting dose of 0.75 mg twice daily with a target trough level of 3 to 8 ng/dL is standard [75].
• Metabolism is via CYP3A4, 3A5, and 2C8

Side effects [74] 69

•  Anemia
• Peripheral edema
• Elevations in serum creatinine when used with full dose CNIs
• Diarrhea, nausea
• Urinary tract infections
• Hyperlipidemia

Mycophenolate

• MPA inhibits inosine monophosphate dehydrogenase (IMPDH), preventing the formation of guanosine monophosphate (GMP). Cells depleted of GMP cannot synthesize guanine triphosphate (GTP) or deoxy guanine triphosphate (d-GTP) and therefore cannot replicate. Most mammalian cells are able to maintain GMP levels through the purine salvage pathway. However, lymphocytes lack a key enzyme of the guanine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase), and cannot overcome the MPA-induced block. As a result, MPA selectively inhibits the proliferation of both B and T lymphocytes [77].

Azathioprine 

• Azathioprine is a prodrug of 6-mercaptopurine, which is an antimetabolite that inhibits purine synthesis. By preventing the de novo synthesis of purines, and thus interfering with RNA and DNA synthesis, azathioprine inhibits the replication of T and B cells. It is typically given at a dose of 1.5 to 2.0 mg/kg/day [84].
• Side effects include bone marrow suppression, nausea, vomiting, pancreatitis, hepatotoxicity, and neoplasia.

Polyclonal antibodies 

The resulting preparations have antibodies to multiple T-cell antigens including CD2, CD3, CD4, and CD8. They are administered via a central line and result in profound lymphopenia by complement-mediated cell lysis and uptake of opsonized cells. Repopulation occurs within 3 to 10 days. [86].

Polyclonal antibodies have been used for induction of immunosuppression or treatment of steroid-resistant rejection [15,8789].

patient and graft survival rates were 93 and 90 percent, respectively. Rejection occurred in 114 patients (23 percent) and 33 patients required glucocorticoids (7 percent).

Complications with these agents include fever, chills, rash, anemia, thrombocytopenia, serum sickness, and nephritis. Although our personal preference is to use monoclonal antibodies when necessary, some reports suggest that polyclonal antibodies are still in use in pediatric and adult patients undergoing liver transplantation [91,92].

Monoclonal antibodies

Muromonab-CD3

• It is directed against the CD3-antigen complex on mature T cells [93]
• Binding this receptor causes internalization of the receptor followed by opsonization and removal of T cells from the circulation. [93]
• 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. Onset is usually within an hour of the infusion, and symptoms usually resolve in four to six hours.
• Successful OKT treatment is associated with a rapid decline in CD3-positive T cells from approximately 60 to less than 5 percent.
• Failure of this decline or a fall followed by a rapid rise indicates the appearance of blocking antibodies. [97].
• recurrent hepatitis C and post-transplant lymphoproliferative disorder (PTLD).  [98].

Basiliximab and daclizumab 

• Basiliximab and daclizumab are humanized monoclonal antibodies against the IL-2 receptor. Blockade of the IL-2 receptor prevents T-cell proliferation.
• Antibodies can be used to reduce CNI use in patients with pre-OLT renal disease [105] or to minimize steroid use [22,106].

Drug	Frequency	Formulations	Monitoring
Prednisone	Daily	Tablets, suspension, parenteral by substitution	Blood pressure, glucose, lipids
Azathioprine	Daily	Tablets, suspension, parenteral	CBC, liver tests, pancreas toxicity
Mycophenolate mofetil	Twice daily	Tablets, suspension	CBC, abdominal symptoms
Myocphenolate sodium	Twice daily	Tablets	CBC, abdominal symptoms
Cyclosporine	Twice daily	Capsules, suspension, parenteral	Drug level, creatinine, lipids, K(+), Mg(2+), CNS toxicity
Tacrolimus	Twice daily	Capsules, suspension, parenteral	Drug level, creatinine, glucose, lipids, K(+), Mg(2+), CNS toxicity
Sirolimus	Daily	Tablets, suspension	CBC, drug level, lipids
Everolimus	Daily	Tablets	CBC, drug level, lipids