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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Patient Information
Overview
Historical Perspective
Indications
Pre-surgical management
Choice of donor
Epidemiology and Demographics
Techniques
Complications
Acute rejection
Immune therapy
Post-surgical infection
Prognosis

Overview

Acute rejection after liver transplantation depends on antigen recognition by antigen-presenting cell. This stimulates T-cell receptors CD28, CD154, CD2, CD11a, and CD54. This causes maturation of T-cells. Blockage of this pathway by drugs can stop rejection reaction. Glucocorticoids upregulate interleukin-10 expression (inhibitory), and downregulate IL-2, IL-6, and interferon-gamma (stimulatory) synthesis by T cells. Glucocorticoids are the first line of initial therapy and treatment of acute rejection. Cyclosporine inhibits T-cell activation by binding intracellular cyclophilin and reducing calcineurin activation. That leads to diminish interleukin-2 production markedly and decreased T-cell response. Tacrolimus inhibits IL-2 and interferon-gamma production. Tacrolimus is 100 times more potent than cyclosporine. Sirolimus binds to FK-binding protein but does not inhibit calcineurin. Sirolimus blocks the transduction signal from the IL-2 receptor, thus inhibiting T-cell and B-cell proliferation. Sirolimus doesn't cause nephrotoxicity and neurotoxicity. Everolimus is the hydroxyethyl derivative of sirolimus. The mechanism of action of everolimus is similar to sirolimus by inhibition of mammalian target of rapamycin (mTOR). Muromonab is a monoclonal antibody directed against the CD3-antigen complex on mature T cells. Basiliximab and daclizumab are monoclonal antibodies against the IL-2 receptor. Blockade of the IL-2 receptor prevents T-cell proliferation. Azathioprine is a prodrug of 6-mercaptopurine. Azathioprine inhibits the de novo synthesis of purines and interferes with RNA and DNA synthesis, azathioprine inhibits the replication of T cells and B cells.

Liver transplantation immune therapy

Organ rejection immunology pathway

• Antigen recognition by immune system requires presentation of a foreign antigen by antigen-presenting cell.
• 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 expression (inhibitory), and downregulate IL-2, IL-6, and interferon-gamma (stimulatory) synthesis by T cells.
• Glucocorticoids are the first line of initial therapy and treatment of acute rejection.

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
• Poor wound healing
• Cataract
• Osteopenia
• There are three options exist regard to glucocorticoid use:

• Maintain low-dose steroids
•  Avoid steroids
• A possible alternative to traditional glucocorticoids is budesonide

Cyclosporine 

• Cyclosporine inhibits T-cell activation by binding intracellular cyclophilin and reducing calcineurin activation.
• That leads to diminish interleukin-2 production markedly and decreased T-cell response.
• Cyclosporine is variably absorbed in the jejunum and enters the lymphatic system. The average half-life is 15 hours.
• Cyclosporine attaches to CYP3A4 in the liver and cleared in the bile.
• The goal therapeutic level is 200 to 250 ng/mL in the first three months then tapered to 80 to 120 ng/mL.
• Neurological toxicity may include altered mental status, polyneuropathy, dysarthria, myoclonus, seizures, hallucinations, and blindness.
• Other side effects include hyperlipidemia, gingival hyperplasia, and hirsutism.
• Potassium-sparing diuretics and potentially nephrotoxic drugs should be avoided.
• Patients should be monitored for renal toxicity, hypertension, hyperkalemia, and hypomagnesemia.

Tacrolimus

• Tacrolimus inhibits IL-2 and interferon-gamma production.
• Tacrolimus is 100 times more potent than cyclosporine.
• Loading dose is 0.5 to 1 mg every 12 hours and aimed level in blood is 7 to 10 ng/mL by the end of the first week.
• Autoimmune liver diseases such as primary sclerosing cholangitis usually need higher blood level than usual.
• Tacrolimus has better survival, graft loss, acute rejection, and steroid-resistant rejection in the first year.
• Renal failure is a serious side effect.
• 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.
• Other adverse effects include nephrotoxicity, neurotoxicity, and electrolyte abnormalities.
• 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 binds to FK-binding protein but does not inhibit calcineurin.
• Sirolimus blocks the transduction signal from the IL-2 receptor, thus inhibiting T-cell and B-cell proliferation.
• Sirolimus doesn't cause nephrotoxicity and neurotoxicity.
• Rejection was seen more commonly with monotherapy, not with dual or triple therapy.
• Sirolimus may be especially useful as a substitute in cases of nephrotoxicity caused by calcineurin inhibitors intolerance.

Side effects

• Hepatic artery thrombosis
•  Delayed wound healing
• Incisional hernia
• Hyperlipidemia
• Bone marrow suppression
• Mouth ulcer
• Skin rashes
• Albuminuria and pneumonia

Everolimus 

• Everolimus is the hydroxyethyl derivative of sirolimus.
• The mechanism of action of everolimus is similar to sirolimus by inhibition of mammalian target of rapamycin (mTOR).
• The loading dose is 0.75 mg twice daily and target blood level is 3 to 8 ng/dL.
• Everolimus is metabolised via CYP3A4, 3A5, and 2C8 in the liver.

Side effects

•  Anemia
• Peripheral edema
• Elevations in serum creatinine
• Diarrhea, nausea
• Urinary tract infections
• Hyperlipidemia

Mycophenolate

• Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH), preventing the formation of guanosine monophosphate (GMP).
• Most mammalian cells are able to maintain GMP levels through the purine salvage pathway.
• Lymphocytes lack a key enzyme of the guanine salvage pathway hypoxanthine-guanine phosphoribosyltransferase, and cannot overcome the MPA-induced block.
• Mycophenolate selectively inhibits the proliferation of both B lymphocytes and T lymphocytes.

Azathioprine 

• Azathioprine is a prodrug of 6-mercaptopurine.
• Azathioprine  inhibits the de novo synthesis of purines and interferes with RNA and DNA synthesis, azathioprine inhibits the replication of T cells and B cells.
• The loading dose is 1.5 to 2.0 mg/kg/day.
• Side effects include bone marrow suppression, nausea, vomiting, pancreatitis, hepatotoxicity, and neoplasia

Monoclonal antibodies

Muromonab-CD3

• Muromonab is directed against the CD3-antigen complex on mature T cells.
• The standard dose of OKT3 is 5 mg intravenous 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.
• Successful 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.
• Recurrent hepatitis C and post-transplant lymphoproliferative disorder is one the serious adverse effects.

Basiliximab and daclizumab 

• Basiliximab and daclizumab are monoclonal antibodies against the IL-2 receptor.
• Blockade of the IL-2 receptor prevents T-cell proliferation.

Table for immunosuppressant drugs and monitoring methods

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