Immunology demystified: A guide for transplant hepatologists

Table 1 Types of acute rejection and clinical manifestations

	T cell-mediated rejection	Antibody-mediated rejection
Time of occurrence	Within 90 d after LT with a median onset of 8 d[47]	Within the first few weeks after LT
Incidence	10%–30%[92,93]	0.3%–2%[94]
Clinical manifestations	Elevation of serum aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase and/or bilirubin	Elevated aminotransferases; Graft injury with refractory thrombocytopenia, hyperbilirubinemia, low serum complements levels; Rapid allograft failure, hemorrhagic necrosis
Diagnostic criteria (histology needed)	Quantitative scoring - Rejection activity index (RAI): Portal inflammation - mixed (predominantly mononuclear activated lymphocytes, neutrophils, and eosinophils); Bile duct inflammation/damage; Venous endothelial inflammation; Each of these parameters is scored as 1 to 3 and thus a maximum score of 9 is possible; 0–2 is no rejection,3 borderline (consistent with), 4–5 is mild, 6–7 is moderate and 8–9 as severe ACR[49]	Histology: endothelial cell hypertrophy, portal capillary dilatation, microvasculitis with monocytes, eosinophils and neutrophils, and portal/peri-portal edema. Microvascular involvement involving the central veins can distinguish acute AMR from other types of injury early after LT; Elevated DSA; Diffuse C4d deposition of microvasculature in ABO-compatible tissues, or portal stroma in ABO-incompatible tissues; Exclusion of other liver diseases[49]

ACR: Acute cellular rejection; AMR: Antibody-mediated rejection; C4d: Complement component 4d; DSA: Donor-specific antibodies; LT: Liver transplantation; RAI: Rejection activity index.

Table 2 Types of chronic rejection after liver transplantation

	T cell-mediated chronic rejection	Antibody-mediated chronic rejection
Time of occurrence	Months to years after LT[95]
Incidence	2%-5%[96]	Unknown[65]
Clinical manifestations	Cholestatic-pattern in liver function tests – the most typical presentation; Range from mild alterations in blood tests to liver failure and death[65]	Normal liver tests despite histologic evidence of allograft injury; Abnormal liver tests during immunosuppression weaning; Graft injury and/or advanced fibrosis; Development of portal hypertension after transplantation[97]
Definition (liver histology required)	(1) Presence of bile duct atrophy/pyknosis affecting most bile ducts; OR; (2) Bile duct loss in more than 50% of the portal tracts; OR; and (3) Foam cell obliterative arteriopathy[49]	(1) Histopathological pattern of injury - both required: Otherwise unexplained and at least mild mononuclear portal and/or perivenular inflammation with interface and/or perivenular necro-inflammatory activity; At least moderate portal/periportal, sinusoidal and/or perivenular fibrosis; (2) Positive DSA within 3 months of biopsy; (3) Focal C4d positivity (> 10%) portal tracts; and (4) Exclusion of other liver insults[49]

AMR: Antibody-mediated rejection; C4d: Complement component 4d; DSA: Donor-specific antibodies; LT: Liver transplantation.

Table 3 Immunosuppressive therapy in liver transplantation: Drugs used for induction and maintenance

Drug name (Class)	Mechanism of Action	Dosing	Comments
Induction
Basiliximab (Immunosuppressant Agent, Monoclonal Antibody)	Directed against the IL-2 receptor on activated T lymphocytes; does not cause lymphocyte depletion.	IV: 20 mg on day 0 and 4 post-LT	Induction by IL-2R antibodies is linked to less renal impairment, fewer rejection episodes, and lower post-transplant diabetes rates. Is not potent enough to be used as monotherapy, usually used in CNI sparing regimens- CNIs introduced later or at reduced doses, especially in chronic kidney disease. Used in steroid-free regimes
Methylprednisolone (Systemic Corticosteroid)	Inhibition of lymphocyte activation and proliferation.	Subject to variations across different centres and disease aethiology. Up to 1000 mg used in induction, IV	Adverse effects are common with high-doses. Delirium is a common early issue. Infections and metabolic problems (e.g. hypertension, hyperlipidemia, diabetes, obesity) pose short-term health risks
Maintenance
Azathioprine (Antimetabolite)	Purine synthase antagonist inhibiting lymphocyte proliferation	Oral or IV administration. Typically, 1 to 2 mg/kg once daily as part of combination therapy. No established maximum dose; however, experts advise not exceeding 200 mg/d	Off-label use in LT
Mycophenolate (Antimetabolite)	MMF and MNa are prodrugs of MPA, a reversible inhibitor of inosine monophosphate dehidrogenase. MPA blocks the synthesis of guanosine nucleotides utilized by B- ant T-cell lymphocytes for proliferation exerting a significant cytostatic effect	MMF: Oral, IV: 500 mg to 1.5 g twice daily. MNa: Oral: 360 to 1080 mg twice daily	MMF is quickly absorbed in the stomach, while MNa is a delayed-release formulation absorbed in the small intestine. Both formulations have high bioavailability, TDM is possible but not recommended due to poor correlation between drug levels and toxicity. Common side effects include bone marrow disorders and GI upset. Both MMF and MNa have teratogenic properties
Cyclosporine (CNI)	Interacts with cyclophilin in T-cells, inhibiting calcineurin, a calcium-dependent phosphatase, which in turn blocks IL-2 transcription and T-cell activation	Oral or IV administration. Oral: Starting 10-15 mg/kg daily divided into 2 doses. IV: Initial dose: 5 to 6 mg/kg/d or one-third of the oral dose as a single dose, infused over 2-6 h	TDM and tapering according to C2 or C0 is advised. Not commonly used as initial choice in modern era. Gingival hypertrophy and hirsutism can occur
Tacrolimus (CNI)	Inhibits calcineurin by binding to FKBP12, in turn blocking IL-2 transcription and T-cell activation. More potent than cyclosporine	Oral or IV administration. Oral: Starting 0.075 mg/kg daily divided into 2 doses, increased to 0.1-0.15 mg/kg daily divided into 2 doses. IV: 0.03-0.05 mg/kg/d as a continuous infusion	Extender release formulations are in use for patients with stable graft function and IS levels, conversion is done used 1:1 ratio (mg:mg) using a previously established total daily dose. Administer once daily
Prednizone, Prednizolone (Systemic Corticosteroids)	Inhibition of lymphocyte activation and proliferation.	Prednison or prednisolon commonly used with starting maintenance dose of 20 mg daily, typically tapered and discontinued within 3-6 months. For moderate to severe rejection, common regimen is intravenous methylprednisolone (500-1000 mg daily, then tapered). In patients transplanted for AIH, low-dose prednisone (5-10 mg/day) reduces recurrence	Numerous side-effects with prolonged use, including hypertension, hyperglycemia, hyperlipidemia, weight gain, sleep disturbances, psychosis
Sirolimus (mTORi)	Inhibits the mTOR pathway which prevents IL-2 signalling to T-cells and stops T-cell proliferation	CNI minimization: Oral: 2 mg once daily in combination with CNI, adjust to a trough level of 4-10 ng/mL. CNI avodiance: Oral: 2-4 mg once daily in combination with MPA derivates, with or without corticosteroids, adjust to trough level of 5-10 ng/mL	Despite similar structure to tacrolimus, they do not compete and can be used simultaneously
Everolimus (mTORi)	Inhibits the mTOR pathway which prevents IL-2 signalling to T-cells and stops T-cell proliferation	Oral: Initial 1 mg twice daily, adjust to a trough level of 3-8 ng/mL	Half-life is shorter than sirolimus (30 vs 60 h) which might facilitate dose adjustment

AIH: Autoimmune hepatitis; CNI: Calcineurin inhibitor; GI: Gastrointestinal; IL-2: Interleukin-2; IV: Intravenous; LT: Liver transplantation; MMF: Mycophelonate mofetil; MNa: Mycophenolate sodium; MPA: Mycophenolate acid; mTORi: Mammalian target of rapamycin inhibitor; TDM: Therapeutic drug monitoring.