Liver transplantation immune therapy

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

Liver trasnsplantation Microchapters

Home

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

Drugs used to overcome rejection reaction

Glucocorticoids

Dosing equivalents for common steroid compounds

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

Side effects:[2]

  • Maintain low-dose steroids
  •  Avoid steroids
  • A possible alternative to traditional glucocorticoids is budesonide[4]

Cyclosporine 

Tacrolimus

Sirolimus 

Side effects[11]

Everolimus 

Side effects[14]

Mycophenolate

Azathioprine 

Monoclonal antibodies

Muromonab-CD3

Basiliximab and daclizumab 

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

 

References

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  2. Henry SD, Metselaar HJ, Van Dijck J, Tilanus HW, Van Der Laan LJ (2007). "Impact of steroids on hepatitis C virus replication in vivo and in vitro". Ann N Y Acad Sci. 1110: 439–47. doi:10.1196/annals.1423.046. PMID 17911459.
  3. Kim SS, Peng LF, Lin W, Choe WH, Sakamoto N, Kato N; et al. (2007). "A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication". Gastroenterology. 132 (1): 311–20. doi:10.1053/j.gastro.2006.10.032. PMID 17241881.
  4. Bhat M, Ghali P, Wong P, Marcus V, Michel R, Cantarovich M; et al. (2012). "Immunosuppression with budesonide for liver transplant recipients with severe infections". Liver Transpl. 18 (2): 262–3. doi:10.1002/lt.22453. PMID 22006869.
  5. Stracciari A, Guarino M (2001). "Neuropsychiatric complications of liver transplantation". Metab Brain Dis. 16 (1–2): 3–11. PMID 11726086.
  6. Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL (2006). "Cyclosporin versus tacrolimus for liver transplanted patients". Cochrane Database Syst Rev (4): CD005161. doi:10.1002/14651858.CD005161.pub2. PMID 17054241.
  7. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW; et al. (2003). "Chronic renal failure after transplantation of a nonrenal organ". N Engl J Med. 349 (10): 931–40. doi:10.1056/NEJMoa021744. PMID 12954741.
  8. Hirose R, Vincenti F (1999). "Review of transplantation--1999". Clin Transpl: 295–315. PMID 11038649.
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  10. Beckebaum S, Cicinnati V, Brokalaki E, Frilling A, Gerken G, Broelsch CE (2004). "CNI-sparing regimens within the liver transplant setting: experiences of a single center". Clin Transpl: 215–20. PMID 16704152.
  11. DuBay D, Smith RJ, Qiu KG, Levy GA, Lilly L, Therapondos G (2008). "Sirolimus in liver transplant recipients with renal dysfunction offers no advantage over low-dose calcineurin inhibitor regimens". Liver Transpl. 14 (5): 651–9. doi:10.1002/lt.21429. PMID 18433069.
  12. Levy G, Schmidli H, Punch J, Tuttle-Newhall E, Mayer D, Neuhaus P; et al. (2006). "Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12- and 36-month results". Liver Transpl. 12 (11): 1640–8. doi:10.1002/lt.20707. PMID 16598777.
  13. Gurk-Turner C, Manitpisitkul W, Cooper M (2012). "A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor". Transplantation. 94 (7): 659–68. doi:10.1097/TP.0b013e31825b411c. PMID 22986894.
  14. Shipkova M, Hesselink DA, Holt DW, Billaud EM, van Gelder T, Kunicki PK; et al. (2016). "Therapeutic Drug Monitoring of Everolimus: A Consensus Report". Ther Drug Monit. 38 (2): 143–69. doi:10.1097/FTD.0000000000000260. PMID 26982492.
  15. Everson GT (2006). "Everolimus and mTOR inhibitors in liver transplantation: opening the "box"". Liver Transpl. 12 (11): 1571–3. doi:10.1002/lt.20845. PMID 17058246.
  16. Perry I, Neuberger J (2005). "Immunosuppression: towards a logical approach in liver transplantation". Clin Exp Immunol. 139 (1): 2–10. doi:10.1111/j.1365-2249.2005.02662.x. PMC 1809260. PMID 15606606.
  17. Cosimi AB (1987). "Clinical development of Orthoclone OKT3". Transplant Proc. 19 (2 Suppl 1): 7–16. PMID 3105142.
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  19. Emre S, Gondolesi G, Polat K, Ben-Haim M, Artis T, Fishbein TM; et al. (2001). "Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function". Liver Transpl. 7 (3): 220–5. doi:10.1053/jlts.2001.22455. PMID 11244163.
  20. Liu CL, Fan ST, Lo CM, Chan SC, Ng IO, Lai CL; et al. (2004). "Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: a protocol with early elimination of steroids and reduction of tacrolimus dosage". Liver Transpl. 10 (6): 728–33. doi:10.1002/lt.20144. PMID 15162466.