Liver transplantation immune therapy: Difference between revisions

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__NOTOC__
__NOTOC__
{{CMG}}; {{AE}} {{MAD}}
{{CMG}}; {{AE}} {{MAD}}
{{Liver transplantation}}
{{Liver transplantation}}


==Overview==
==Overview==
Acute rejection after liver transplantation depends on [[antigen]] recognition by [[antigen-presenting cell]]. This stimulates [[T cell|T-cell]] receptors [[CD28]], [[CD154]], [[CD2]], [[CD11a]], and [[CD54]]. This causes maturation of [[T cell|T-cells]]. Blockage of this pathway by drugs can stop rejection reaction. [[Glucocorticoids]] upregulate [[Interleukin 10|interleukin-10]] expression (inhibitory), and downregulate [[IL-2]], [[Interleukin 6|IL-6,]] and [[interferon-gamma]] (stimulatory) synthesis by [[T cell|T cells]]. [[Glucocorticoids]] are the first line of initial therapy and treatment of acute rejection. [[Cyclosporine]] inhibits [[T cell|T-cell]] activation by binding intracellular [[cyclophilin]] and reducing [[calcineurin]] activation. That leads to diminish [[Interleukin 2|interleukin-2]] production markedly and decreased [[T cell|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 [[Interleukin 2|IL-2]] receptor, thus inhibiting [[T cell|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]] ([[Mammalian target of rapamycin|mTOR]]). '''[[Muromonab-CD3|Muromonab]]''' is a [[Monoclonal antibodies|monoclonal antibody]] directed against the [[CD3|CD3-antigen]] complex on mature [[T cells]]. [[Basiliximab]] and [[daclizumab]] are [[monoclonal antibodies]] against the [[Interleukin 2|IL-2]] receptor. Blockade of the [[Interleukin 2|IL-2]] receptor prevents [[T cell|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 cell|B cells]].


==Liver transplantation immune therapy==
==Liver transplantation immune therapy==
=== Rejection immunology pathway ===
=== Organ rejection immunology pathway ===
* Alloantigen recognition requires presentation of a foreign alloantigen along with a host major histocompatibility complex (MHC) molecule.  
* [[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.  
* An [[antigen-presenting cell]] presents the antigen to the [[T cell|T-cell]] receptors including [[CD28]], [[CD154]], [[CD2]], [[CD11a]], and [[CD54]]. This causes maturation of [[T cell|T-cells]].  
* '''T-lymphocyte activation''' causes stimulation of  calcineurin, which activates nuclear factor of T-cell activation (NFAT) which increases interleukin-2 transcription.  
* '''[[T-lymphocytes|T-lymphocyte]] activation''' causes stimulation of [[calcineurin]], which activates nuclear factor of T-cell activation ([[NFAT]]) which increases [[Interleukin 2|interleukin-2]] transcription.  
* IL-2 binds to IL-2 receptors increasing T-cell proliferation.
* [[Interleukin 2|IL-2]] binds to [[Interleukin 2|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.
* [[T-cell proliferation]] causes [[Cell-mediated immune response|cell-mediated]] [[cytotoxicity]] and secretion of [[cytokines]], [[chemokines]], and [[Cell adhesion molecule|adhesion molecules]] causing [[Inflammatory response|inflammatory reaction]] against the graft organ cells.


== Drugs used to overcome rejection reaction ==
== Drugs used to overcome rejection reaction ==


=== Glucocorticoids ===
=== Glucocorticoids ===
* Glucocorticoids upregulate interleukin -10 (inhibitory) expression, and downregulate IL-2, IL-6, and interferon-gamma ( stimulatory) synthesis by T cells.<ref name="pmid2233715">{{cite journal| author=Ray A, LaForge KS, Sehgal PB| title=On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. | journal=Mol Cell Biol | year= 1990 | volume= 10 | issue= 11 | pages= 5736-46 | pmid=2233715 | doi= | pmc=361346 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2233715  }}</ref>  
* [[Glucocorticoids]] upregulate [[Interleukin 10|interleukin-10]] expression (inhibitory), and downregulate [[IL-2]], [[Interleukin 6|IL-6,]] and [[interferon-gamma]] (stimulatory) synthesis by [[T cell|T cells]].<ref name="pmid2233715">{{cite journal| author=Ray A, LaForge KS, Sehgal PB| title=On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. | journal=Mol Cell Biol | year= 1990 | volume= 10 | issue= 11 | pages= 5736-46 | pmid=2233715 | doi= | pmc=361346 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2233715  }}</ref>  
* Glucocorticoids are the first line of initial therapy and treatment of acute allograft rejection in many centers.  
* [[Glucocorticoids]] are the first line of initial therapy and treatment of acute rejection.  
'''Dosing equivalents for common steroid compounds'''
'''Dosing equivalents for common steroid compounds'''
{| class="wikitable"
{| class="wikitable"
Line 23: Line 25:
|'''Dose, mg'''
|'''Dose, mg'''
|-
|-
|Hydrocortisone
|[[Hydrocortisone]]
|20
|20
|-
|-
|Prednisolone
|[[Prednisolone]]
|5
|5
|-
|-
|Prednisone
|[[Prednisone]]
|5
|5
|-
|-
|Methylprednisolone
|[[Methylprednisolone]]
|4
|4
|}
|}


==== Side effects:<ref name="pmid17911459">{{cite journal| author=Henry SD, Metselaar HJ, Van Dijck J, Tilanus HW, Van Der Laan LJ| title=Impact of steroids on hepatitis C virus replication in vivo and in vitro. | journal=Ann N Y Acad Sci | year= 2007 | volume= 1110 | issue=  | pages= 439-47 | pmid=17911459 | doi=10.1196/annals.1423.046 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17911459  }}</ref> ====
==== Side effects:<ref name="pmid17911459">{{cite journal| author=Henry SD, Metselaar HJ, Van Dijck J, Tilanus HW, Van Der Laan LJ| title=Impact of steroids on hepatitis C virus replication in vivo and in vitro. | journal=Ann N Y Acad Sci | year= 2007 | volume= 1110 | issue=  | pages= 439-47 | pmid=17911459 | doi=10.1196/annals.1423.046 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17911459  }}</ref> ====
* Diabetes Mellitus
* [[Diabetes mellitus]]
* Fluid retention
* Fluid retention
* Hypertension
* [[Hypertension]]
* Emotional lability
* [[Emotional lability]]
* Hyperlipidemia
* [[Hyperlipoproteinemia|Hyperlipidemia]]
* Cosmetic changes
* Poor wound healing
* Poor wound healing
* Susceptibility to infection
* [[Cataract]]
* Visual changes
* [[Osteopenia]]
* Cataract
* There are three options exist regard to glucocorticoid use:<ref name="pmid17241881">{{cite journal| author=Kim SS, Peng LF, Lin W, Choe WH, Sakamoto N, Kato N et al.| title=A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. | journal=Gastroenterology | year= 2007 | volume= 132 | issue= 1 | pages= 311-20 | pmid=17241881 | doi=10.1053/j.gastro.2006.10.032 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17241881  }}</ref>
* Osteopenia
* Steroid therapy increases hepatitis C virus (HCV) replication.
* There are three options exist regard to glucocorticoid use in those patients.<ref name="pmid17241881">{{cite journal| author=Kim SS, Peng LF, Lin W, Choe WH, Sakamoto N, Kato N et al.| title=A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. | journal=Gastroenterology | year= 2007 | volume= 132 | issue= 1 | pages= 311-20 | pmid=17241881 | doi=10.1053/j.gastro.2006.10.032 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17241881  }}</ref>


* Maintain low-dose steroids indefinitely.
* Maintain low-dose [[steroids]]
*  Avoid steroids A possible alternative to traditional glucocorticoids is budesonide. effects because of high first-pass hepatic metabolism.<ref name="pmid22006869">{{cite journal| author=Bhat M, Ghali P, Wong P, Marcus V, Michel R, Cantarovich M et al.| title=Immunosuppression with budesonide for liver transplant recipients with severe infections. | journal=Liver Transpl | year= 2012 | volume= 18 | issue= 2 | pages= 262-3 | pmid=22006869 | doi=10.1002/lt.22453 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22006869  }}</ref>
*  Avoid steroids  
* A possible alternative to traditional glucocorticoids is [[budesonide]]<ref name="pmid22006869">{{cite journal| author=Bhat M, Ghali P, Wong P, Marcus V, Michel R, Cantarovich M et al.| title=Immunosuppression with budesonide for liver transplant recipients with severe infections. | journal=Liver Transpl | year= 2012 | volume= 18 | issue= 2 | pages= 262-3 | pmid=22006869 | doi=10.1002/lt.22453 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22006869  }}</ref>


=== '''Cyclosporine''' ===
=== '''Cyclosporine''' ===
* Cyclosporine  inhibits T-cell activation by binding intracellular cyclophilin, thus reducing calcineurin activation.
* [[Cyclosporine]] inhibits [[T cell|T-cell]] activation by binding intracellular [[cyclophilin]] and 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.<ref name="pmid11726086">{{cite journal| author=Stracciari A, Guarino M| title=Neuropsychiatric complications of liver transplantation. | journal=Metab Brain Dis | year= 2001 | volume= 16 | issue= 1-2 | pages= 3-11 | pmid=11726086 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11726086  }}</ref>  
* That leads to diminish [[Interleukin 2|interleukin-2]] production markedly and decreased [[T cell|T-cell]] response.<ref name="pmid11726086">{{cite journal| author=Stracciari A, Guarino M| title=Neuropsychiatric complications of liver transplantation. | journal=Metab Brain Dis | year= 2001 | volume= 16 | issue= 1-2 | pages= 3-11 | pmid=11726086 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11726086  }}</ref>  
* 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.
* [[Cyclosporine]] is variably absorbed in the [[jejunum]] and enters the [[lymphatic system]]. The average half-life is 15 hours.  
* Cyclosporine is cleared in the bile after extensive metabolism in the liver by CYP3A4.  
* Cyclosporine attaches to CYP3A4 in the liver and cleared in the [[bile]].  
* 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.
* 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 cortical blindness
* [[Neurological illness|Neurological toxicity]] may include altered [[mental status]], [[polyneuropathy]], [[dysarthria]], [[myoclonus]], [[Seizure|seizures]], [[Hallucination|hallucinations]], and [[blindness]].
* include hyperlipidemia, gingival hyperplasia, and hirsutism.  
* Other side effects include [[Hyperlipoproteinemia|hyperlipidemia]], [[gingival hyperplasia]], and [[hirsutism]].  
* Potassium-sparing diuretics and potentially nephrotoxic drugs should be avoided if possible.  
* [[Potassium-sparing diuretic|Potassium-sparing diuretics]] and potentially [[nephrotoxic drugs]] should be avoided.  
* Patients should be monitored for renal toxicity, hypertension, hyperkalemia, and hypomagnesemia.  
* Patients should be monitored for [[Renal insufficiency|renal toxicity]], [[hypertension]], [[hyperkalemia]], and [[hypomagnesemia]].  


=== '''Tacrolimus''' ===
=== '''Tacrolimus''' ===
* It inhibits IL-2 and interferon-gamma production and is 100 times more potent than cyclosporine.<ref name="pmid17054241">{{cite journal| author=Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL| title=Cyclosporin versus tacrolimus for liver transplanted patients. | journal=Cochrane Database Syst Rev | year= 2006 | volume=  | issue= 4 | pages= CD005161 | pmid=17054241 | doi=10.1002/14651858.CD005161.pub2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17054241  }}</ref>  
* [[Tacrolimus]] inhibits [[IL-2]] and [[interferon-gamma]] production.<ref name="pmid17054241">{{cite journal| author=Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL| title=Cyclosporin versus tacrolimus for liver transplanted patients. | journal=Cochrane Database Syst Rev | year= 2006 | volume=  | issue= 4 | pages= CD005161 | pmid=17054241 | doi=10.1002/14651858.CD005161.pub2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17054241  }}</ref>  
* We usually start with a low dose (0.5 to 1 mg every 12 hours) on postoperative day.
* [[Tacrolimus]] is 100 times more potent than [[cyclosporine]].
* and aim for a level of 7 to 10 ng/mL by the end of the first week.<ref name="pmid12954741">{{cite journal| author=Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW et al.| title=Chronic renal failure after transplantation of a nonrenal organ. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 10 | pages= 931-40 | pmid=12954741 | doi=10.1056/NEJMoa021744 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12954741  }}</ref>
* 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.<ref name="pmid12954741">{{cite journal| author=Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW et al.| title=Chronic renal failure after transplantation of a nonrenal organ. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 10 | pages= 931-40 | pmid=12954741 | doi=10.1056/NEJMoa021744 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12954741  }}</ref>  
* 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.  
* Autoimmune liver diseases such as [[primary sclerosing cholangitis]] usually need higher blood level than usual.  
* Both treatment regimens were effective, but tacrolimus was superior with regard to the composite endpoint and for patient and graft survival.
* [[Tacrolimus]] has better survival, graft loss, acute rejection, and steroid-resistant rejection in the first year.  
* Tacrolimus was superior when analyzed for survival, graft loss, acute rejection, and steroid-resistant rejection in the first year.  
* Renal failure is a serious [[Side effects|side effect]].
* CNI-induced renal failure is a serious problem after orthotopic liver transplant.
* [[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.  
* The problem has been exacerbated by the switch to a MELD-based organ allocation system, which is weighted towards higher serum creatinine.
* Other adverse effects include [[nephrotoxicity]], [[neurotoxicity]], and [[electrolyte abnormalities]].
* 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
* [[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.
* 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''' ===
* Sirolimus is a potent immunosuppressive agent approved by the US Food and Drug Administration (FDA) for renal transplantation.<ref name="pmid110386492">{{cite journal| author=Hirose R, Vincenti F| title=Review of transplantation--1999. | journal=Clin Transpl | year= 1999 | volume=  | issue=  | pages= 295-315 | pmid=11038649 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11038649  }}</ref>  
* [[Sirolimus]] binds to FK-binding [[protein]] but does not inhibit [[calcineurin]].<ref name="pmid110386492">{{cite journal| author=Hirose R, Vincenti F| title=Review of transplantation--1999. | journal=Clin Transpl | year= 1999 | volume=  | issue=  | pages= 295-315 | pmid=11038649 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11038649  }}</ref>  
* It binds the same target (FK-binding protein) but does not inhibit calcineurin.
* [[Sirolimus]] blocks the transduction signal from the [[Interleukin 2|IL-2]] receptor, thus inhibiting [[T cell|T-cell]] and [[B-cell]] proliferation.
* Instead, it blocks the transduction signal from the IL-2 receptor, thus inhibiting T- and B-cell proliferation.
* [[Sirolimus]] doesn't cause [[nephrotoxicity]] and [[neurotoxicity]].<ref name="pmid12742498">{{cite journal| author=Neff GW, Montalbano M, Tzakis AG| title=Ten years of sirolimus therapy in orthotopic liver transplant recipients. | journal=Transplant Proc | year= 2003 | volume= 35 | issue= 3 Suppl | pages= 209S-216S | pmid=12742498 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12742498  }}</ref>  
* Its advantage over the calcineurin inhibitors (CNIs) is its freedom from nephrotoxicity and neurotoxicity.<ref name="pmid12742498">{{cite journal| author=Neff GW, Montalbano M, Tzakis AG| title=Ten years of sirolimus therapy in orthotopic liver transplant recipients. | journal=Transplant Proc | year= 2003 | volume= 35 | issue= 3 Suppl | pages= 209S-216S | pmid=12742498 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12742498  }}</ref>  
* Rejection was seen more commonly with [[monotherapy]], not with dual or triple therapy.  
* 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 nephrotoxicity caused by [[Calcineurin inhibitor|calcineurin inhibitors]] intolerance.<ref name="pmid16704152">{{cite journal| author=Beckebaum S, Cicinnati V, Brokalaki E, Frilling A, Gerken G, Broelsch CE| title=CNI-sparing regimens within the liver transplant setting: experiences of a single center. | journal=Clin Transpl | year= 2004 | volume=  | issue=  | pages= 215-20 | pmid=16704152 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16704152  }}</ref>  
* Sirolimus may be especially useful as a substitute in cases of CNI-intolerance (primarily renal failure and neurotoxicity).
* A retrospective analysis showed no benefit for renal function when patients with chronic renal insufficiency were switched from CNIs to sirolimus.<ref name="pmid16704152">{{cite journal| author=Beckebaum S, Cicinnati V, Brokalaki E, Frilling A, Gerken G, Broelsch CE| title=CNI-sparing regimens within the liver transplant setting: experiences of a single center. | journal=Clin Transpl | year= 2004 | volume=  | issue=  | pages= 215-20 | pmid=16704152 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16704152  }}</ref>


==== '''Side effects'''<ref name="pmid18433069">{{cite journal| author=DuBay D, Smith RJ, Qiu KG, Levy GA, Lilly L, Therapondos G| title=Sirolimus in liver transplant recipients with renal dysfunction offers no advantage over low-dose calcineurin inhibitor regimens. | journal=Liver Transpl | year= 2008 | volume= 14 | issue= 5 | pages= 651-9 | pmid=18433069 | doi=10.1002/lt.21429 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18433069  }}</ref>====
==== '''Side effects'''<ref name="pmid18433069">{{cite journal| author=DuBay D, Smith RJ, Qiu KG, Levy GA, Lilly L, Therapondos G| title=Sirolimus in liver transplant recipients with renal dysfunction offers no advantage over low-dose calcineurin inhibitor regimens. | journal=Liver Transpl | year= 2008 | volume= 14 | issue= 5 | pages= 651-9 | pmid=18433069 | doi=10.1002/lt.21429 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18433069  }}</ref>====
* Hepatic artery thrombosis
* [[Hepatic artery]] [[thrombosis]]
*  Delayed wound healing
*  [[Wound healing|Delayed wound healing]]
* Incisional hernias
* [[Incisional hernia]]
* Hyperlipidemia
* [[Hyperlipoproteinemia|Hyperlipidemia]]
* Bone marrow suppression
* [[Bone marrow suppression]]
* Mouth ulcers
* [[Mouth ulcers|Mouth ulcer]]
* Skin rashes
* [[Skin rashes]]
* Albuminuria and pneumonia
* [[Albuminuria]] and [[pneumonia]]


=== '''Everolimus''' ===
=== '''Everolimus''' ===
* Everolimus is the hydroxyethyl derivative of sirolimus.<ref name="pmid16598777">{{cite journal| author=Levy G, Schmidli H, Punch J, Tuttle-Newhall E, Mayer D, Neuhaus P et al.| title=Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12- and 36-month results. | journal=Liver Transpl | year= 2006 | volume= 12 | issue= 11 | pages= 1640-8 | pmid=16598777 | doi=10.1002/lt.20707 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16598777  }}</ref>  
* [[Everolimus]] is the hydroxyethyl derivative of [[sirolimus]].<ref name="pmid16598777">{{cite journal| author=Levy G, Schmidli H, Punch J, Tuttle-Newhall E, Mayer D, Neuhaus P et al.| title=Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12- and 36-month results. | journal=Liver Transpl | year= 2006 | volume= 12 | issue= 11 | pages= 1640-8 | pmid=16598777 | doi=10.1002/lt.20707 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16598777  }}</ref>  
* The mechanism of action of EVR is via inhibition of mammalian target of rapamycin (mTOR), similar to sirolimus.
* The mechanism of action of [[everolimus]] is similar to [[sirolimus]] by inhibition of [[mammalian target of rapamycin]] ([[Mammalian target of rapamycin|mTOR]]).<ref name="pmid22986894">{{cite journal| author=Gurk-Turner C, Manitpisitkul W, Cooper M| title=A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor. | journal=Transplantation | year= 2012 | volume= 94 | issue= 7 | pages= 659-68 | pmid=22986894 | doi=10.1097/TP.0b013e31825b411c | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22986894  }}</ref>  
* Everolimus is rapidly absorbed and reaches a peak concentration within one to two hours if given on an empty stomach.<ref name="pmid22986894">{{cite journal| author=Gurk-Turner C, Manitpisitkul W, Cooper M| title=A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor. | journal=Transplantation | year= 2012 | volume= 94 | issue= 7 | pages= 659-68 | pmid=22986894 | doi=10.1097/TP.0b013e31825b411c | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22986894  }}</ref>  
* The [[loading dose]] is 0.75 mg twice daily and target blood level is 3 to 8 ng/dL.  
* It has higher oral availability and lower plasma binding than sirolimus
* [[Everolimus]] is metabolised via [[CYP3A4]], [[CYP3A5|3A5]], and [[CYP2C8|2C8]] in the [[liver]].
* A starting dose of 0.75 mg twice daily with a target trough level of 3 to 8 ng/dL is standard.  
* Metabolism is via CYP3A4, 3A5, and 2C8


==== '''Side effects'''<ref name="pmid26982492">{{cite journal| author=Shipkova M, Hesselink DA, Holt DW, Billaud EM, van Gelder T, Kunicki PK et al.| title=Therapeutic Drug Monitoring of Everolimus: A Consensus Report. | journal=Ther Drug Monit | year= 2016 | volume= 38 | issue= 2 | pages= 143-69 | pmid=26982492 | doi=10.1097/FTD.0000000000000260 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26982492  }}</ref> ====
==== '''Side effects'''<ref name="pmid26982492">{{cite journal| author=Shipkova M, Hesselink DA, Holt DW, Billaud EM, van Gelder T, Kunicki PK et al.| title=Therapeutic Drug Monitoring of Everolimus: A Consensus Report. | journal=Ther Drug Monit | year= 2016 | volume= 38 | issue= 2 | pages= 143-69 | pmid=26982492 | doi=10.1097/FTD.0000000000000260 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26982492  }}</ref> ====
*  Anemia
*  [[Anemia]]
* Peripheral edema
* [[Peripheral edema]]
* Elevations in serum creatinine when used with full dose CNIs
* Elevations in [[serum creatinine]]
* Diarrhea, nausea
* [[Diarrhea]], [[nausea]]
* Urinary tract infections
* [[Urinary tract infections]]
* Hyperlipidemia
* [[Hyperlipoproteinemia|Hyperlipidemia]]


=== '''Mycophenolate''' ===
=== '''Mycophenolate''' ===
* MPA inhibits inosine monophosphate dehydrogenase (IMPDH), preventing the formation of guanosine monophosphate (GMP).<ref name="pmid17058246">{{cite journal| author=Everson GT| title=Everolimus and mTOR inhibitors in liver transplantation: opening the "box". | journal=Liver Transpl | year= 2006 | volume= 12 | issue= 11 | pages= 1571-3 | pmid=17058246 | doi=10.1002/lt.20845 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17058246  }}</ref>
* [[Mycophenolate]] inhibits inosine monophosphate dehydrogenase ([[IMPDH1|IMPDH]]), preventing the formation of [[guanosine monophosphate]] ([[Guanosine monophosphate|GMP]]).<ref name="pmid17058246">{{cite journal| author=Everson GT| title=Everolimus and mTOR inhibitors in liver transplantation: opening the "box". | journal=Liver Transpl | year= 2006 | volume= 12 | issue= 11 | pages= 1571-3 | pmid=17058246 | doi=10.1002/lt.20845 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17058246  }}</ref>  
* 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.
* Most mammalian cells are able to maintain [[Guanosine monophosphate|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.
* [[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''' ===
* 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.<ref name="pmid15606606">{{cite journal| author=Perry I, Neuberger J| title=Immunosuppression: towards a logical approach in liver transplantation. | journal=Clin Exp Immunol | year= 2005 | volume= 139 | issue= 1 | pages= 2-10 | pmid=15606606 | doi=10.1111/j.1365-2249.2005.02662.x | pmc=1809260 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15606606  }}</ref>  
* [[Azathioprine]] is a prodrug of [[6-mercaptopurine]].
* Side effects include bone marrow suppression, nausea, vomiting, pancreatitis, hepatotoxicity, and neoplasia.
* [[Azathioprine]]  inhibits the de novo synthesis of [[purines]] and interferes with [[RNA]] and [[DNA]] synthesis, [[azathioprine]] inhibits the replication of [[T cells]] and [[B cell|B cells]].  
 
* The [[loading dose]] is 1.5 to 2.0 mg/kg/day.<ref name="pmid15606606">{{cite journal| author=Perry I, Neuberger J| title=Immunosuppression: towards a logical approach in liver transplantation. | journal=Clin Exp Immunol | year= 2005 | volume= 139 | issue= 1 | pages= 2-10 | pmid=15606606 | doi=10.1111/j.1365-2249.2005.02662.x | pmc=1809260 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15606606  }}</ref>  
=== '''Polyclonal antibodies''' ===
* [[Side effects]] include [[bone marrow suppression]], [[Nausea and vomiting|nausea]], [[Nausea and vomiting|vomiting]], [[pancreatitis]], [[hepatotoxicity]], and [[neoplasia]]
* 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.
* Polyclonal antibodies have been used for induction of immunosuppression or treatment of steroid-resistant rejection.
* 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.


=== '''Monoclonal antibodies''' ===
=== '''Monoclonal antibodies''' ===


==== '''Muromonab-CD3''' ====
==== '''[[Muromonab-CD3]]''' ====
* It is directed against the CD3-antigen complex on mature T cells.<ref name="pmid3105142">{{cite journal| author=Cosimi AB| title=Clinical development of Orthoclone OKT3. | journal=Transplant Proc | year= 1987 | volume= 19 | issue= 2 Suppl 1 | pages= 7-16 | pmid=3105142 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3105142  }}</ref>
* '''[[Muromonab-CD3|Muromonab]]''' is directed against the [[CD3|CD3-antigen]] complex on mature [[T cells]].<ref name="pmid3105142">{{cite journal| author=Cosimi AB| title=Clinical development of Orthoclone OKT3. | journal=Transplant Proc | year= 1987 | volume= 19 | issue= 2 Suppl 1 | pages= 7-16 | pmid=3105142 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3105142  }}</ref>
* Binding this receptor causes internalization of the receptor followed by opsonization and removal of T cells from the circulation.
* The standard dose of [[OKT3]] is 5 mg intravenous daily for 10 to 14 days.  
* 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|nausea]], and [[vomiting]].  
* 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 treatment is associated with a rapid decline in [[CD3]]-positive [[T cells]] from approximately 60 to less than 5 percent.<ref name="pmid10980055">{{cite journal| author=McLaughlin K, Wajstaub S, Marotta P, Adams P, Grant DR, Wall WJ et al.| title=Increased risk for posttransplant lymphoproliferative disease in recipients of liver transplants with hepatitis C. | journal=Liver Transpl | year= 2000 | volume= 6 | issue= 5 | pages= 570-4 | pmid=10980055 | doi=10.1053/jlts.2000.7578 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10980055  }}</ref>
* Successful OKT treatment is associated with a rapid decline in CD3-positive T cells from approximately 60 to less than 5 percent.<ref name="pmid10980055">{{cite journal| author=McLaughlin K, Wajstaub S, Marotta P, Adams P, Grant DR, Wall WJ et al.| title=Increased risk for posttransplant lymphoproliferative disease in recipients of liver transplants with hepatitis C. | journal=Liver Transpl | year= 2000 | volume= 6 | issue= 5 | pages= 570-4 | pmid=10980055 | doi=10.1053/jlts.2000.7578 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10980055  }}</ref>
* Failure of this decline or a fall followed by a rapid rise indicates the appearance of blocking [[antibodies]].
* 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|post-transplant lymphoproliferative disorde]]<nowiki/>r is one the serious [[adverse effects]].<ref name="pmid11244163">{{cite journal| author=Emre S, Gondolesi G, Polat K, Ben-Haim M, Artis T, Fishbein TM et al.| title=Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function. | journal=Liver Transpl | year= 2001 | volume= 7 | issue= 3 | pages= 220-5 | pmid=11244163 | doi=10.1053/jlts.2001.22455 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11244163  }}</ref>  
* recurrent hepatitis C and post-transplant lymphoproliferative disorder (PTLD).<ref name="pmid11244163">{{cite journal| author=Emre S, Gondolesi G, Polat K, Ben-Haim M, Artis T, Fishbein TM et al.| title=Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function. | journal=Liver Transpl | year= 2001 | volume= 7 | issue= 3 | pages= 220-5 | pmid=11244163 | doi=10.1053/jlts.2001.22455 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11244163  }}</ref>  


==== '''Basiliximab and daclizumab''' ====
==== '''[[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.<ref name="pmid15162466">{{cite journal| author=Liu CL, Fan ST, Lo CM, Chan SC, Ng IO, Lai CL et al.| title=Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: a protocol with early elimination of steroids and reduction of tacrolimus dosage. | journal=Liver Transpl | year= 2004 | volume= 10 | issue= 6 | pages= 728-33 | pmid=15162466 | doi=10.1002/lt.20144 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15162466  }}</ref>  
* [[Basiliximab]] and [[daclizumab]] are [[monoclonal antibodies]] against the [[Interleukin 2|IL-2]] receptor.
* Antibodies can be used to reduce CNI use in patients with pre-OLT renal disease or to minimize steroid use.
* Blockade of the [[Interleukin 2|IL-2]] receptor prevents [[T cell|T-cell]] proliferation.<ref name="pmid15162466">{{cite journal| author=Liu CL, Fan ST, Lo CM, Chan SC, Ng IO, Lai CL et al.| title=Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: a protocol with early elimination of steroids and reduction of tacrolimus dosage. | journal=Liver Transpl | year= 2004 | volume= 10 | issue= 6 | pages= 728-33 | pmid=15162466 | doi=10.1002/lt.20144 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15162466  }}</ref>  


== Table for immunosuppressant drugs and monitoring methods ==
== Table for immunosuppressant drugs and monitoring methods ==
Line 152: Line 139:
|'''Monitoring'''
|'''Monitoring'''
|-
|-
|Prednisone
|[[Prednisone]]
|Daily
|Daily
|Tablets, suspension, parenteral by substitution
|Tablets, suspension, parenteral by substitution
|Blood pressure, glucose, lipids
|Blood pressure, glucose, lipids
|-
|-
|Azathioprine
|[[Azathioprine]]
|Daily
|Daily
|Tablets, suspension, parenteral
|Tablets, suspension, parenteral
|CBC, liver tests, pancreas toxicity
|CBC, liver tests, pancreas toxicity
|-
|-
|Mycophenolate mofetil
|[[Mycophenolate sodium|Mycophenolate mofetil]]
|Twice  daily
|Twice  daily
|Tablets, suspension
|Tablets, suspension
|CBC, abdominal symptoms
|CBC, abdominal symptoms
|-
|-
|Myocphenolate sodium
|[[Mycophenolate sodium|Myocphenolate sodium]]
|Twice  daily
|Twice  daily
|Tablets
|Tablets
|CBC, abdominal symptoms
|CBC, abdominal symptoms
|-
|-
|Cyclosporine
|[[Cyclosporine]]
|Twice  daily
|Twice  daily
|Capsules, suspension, parenteral
|Capsules, suspension, parenteral
|Drug level, creatinine, lipids, K(+), Mg(2+), CNS toxicity
|Drug level, creatinine, lipids, K(+), Mg(2+), CNS toxicity
|-
|-
|Tacrolimus
|[[Tacrolimus]]
|Twice  daily
|Twice  daily
|Capsules, suspension, parenteral
|Capsules, suspension, parenteral
|Drug level, creatinine, glucose, lipids, K(+), Mg(2+), CNS toxicity
|Drug level, creatinine, glucose, lipids, K(+), Mg(2+), CNS toxicity
|-
|-
|Sirolimus
|[[Sirolimus]]
|Daily
|Daily
|Tablets, suspension
|Tablets, suspension
|CBC, drug level, lipids
|CBC, drug level, lipids
|-
|-
|Everolimus
|[[Everolimus]]
|Daily
|Daily
|Tablets
|Tablets
|CBC, drug level, lipids
|CBC, drug level, lipids
|} 
|} 


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 17:25, 28 December 2017


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

  1. ↑ Ray A, LaForge KS, Sehgal PB (1990). "On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion". Mol Cell Biol. 10 (11): 5736–46. PMC 361346. PMID 2233715.
  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.
  9. ↑ Neff GW, Montalbano M, Tzakis AG (2003). "Ten years of sirolimus therapy in orthotopic liver transplant recipients". Transplant Proc. 35 (3 Suppl): 209S–216S. PMID 12742498.
  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.
  18. ↑ McLaughlin K, Wajstaub S, Marotta P, Adams P, Grant DR, Wall WJ; et al. (2000). "Increased risk for posttransplant lymphoproliferative disease in recipients of liver transplants with hepatitis C." Liver Transpl. 6 (5): 570–4. doi:10.1053/jlts.2000.7578. PMID 10980055.
  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.
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