Immunosuppressants pharmacology final.ppt

pharmacology

1. Immunosuppressants

2. Introduction:Thefunctionoftheimmunesystemisprotecting
thebodyagainstharmfulforeignmolecules.However,insome
instances,thisprotectioncanresultinseriousproblems.For
example,theintroductionofanallograftcanelicitadamaging
immuneresponse,causingrejectionofthetransplantedtissue.
Transplantationoforgansandtissueshasbecomeroutine
duetoimprovedsurgicaltechniquesandbettertissuetyping.
Also,drugsarenowavailablethatmoreselectivelyinhibit
rejectionoftransplantedtissueswhilepreventingthepatient
frombecomingimmunologicallycompromised(Figure.1).
Earlierdrugswerenonselective,andpatientsfrequently
succumbedtoinfectionduetosuppressionofboththe
antibody-mediated(humoral)andcell-mediatedarmsofthe
immunesystem.

3. Theprincipalapproachtoimmunosuppressivetherapyisto
alterlymphocytefunctionusingdrugsorantibodiesagainst
immuneproteins.Becauseoftheirseveretoxicitieswhenused
asmonotherapy,acombinationofimmunosuppressiveagents,
usuallyatlowerdoses,isgenerallyemployed.
Immunosuppressiveisalsousedinautoimmunediseases;
e.g.,corticosteroidscancontrolacuteglomerulonephritis.
Theimmuneactivationcascadecanbedescribedasa3-
signalmodel.Signal1constitutesT-celltriggeringattheCD3
receptorcomplexbyanantigenonthesurfaceofanantigen-
presentingcell(APC).Signal2,alsoreferredtoasco-
stimulation,occurswhenCD80andCD86onthesurfaceof
APCsengageCD28onTcells.

4. BothSignals1and2activateseveralintracellularsignal
transductionpathways,oneofwhichisthecalcium-calcineurin
pathway,whichistargetedbycyclosporineandtacrolimus.
Thesepathwaystriggertheproductionofcytokinessuchas
interleukin(IL)-2,IL-15,CD154,andCD25.IL-2thenbindsto
CD25(alsoknownastheIL-2receptor)onthesurfaceofother
Tcellstoactivatemammaliantargetofrapamycin(mTOR),
providingSignal3,thestimulusforT-cellproliferation.
Immunosuppressivedrugscanbecategorizedaccordingto
theirmechanismsofaction:1)Someagentsinterferewith
cytokineproductionoraction;2)othersdisruptcellmetabolism,
preventinglymphocyteproliferation;and3)mono-and
polyclonalantibodiesblockT-cellsurfacemolecules.

5. Figure .1 Immunosuppressant drugs.

6. I. Selective Inhibitors of Cytokine Production and Function
Cytokinesaresoluble,antigen-nonspecific,signalingproteins
thatbindtocellsurfacereceptorsonavarietyofcells.Theterm
cytokineincludesthemoleculesknownasILs,interferons
(IFNs),tumornecrosisfactors(TNFs),transforminggrowth
factors,andcolony-stimulatingfactors.
Ofparticularinterest,IL-2thatstimulatestheproliferationof
antigen-primed(helper)Tcells,whichsubsequentlyproduce
moreIL-2,IFN-ɣ,andTNF-α(Figure.2).
Thesecytokinescollectivelyactivatenaturalkillercells,
macrophages,andcytotoxicTlymphocytes.Clearly,drugsthat
interferewiththeproductionoractivityofIL-2,ascyclosporine,
willsignificantlydampentheimmuneresponse.

7. Figure .2 Summary of selected cytokines.

8. A.Cyclosporine
Cyclosporine(CsA)isalipophilliccyclicpolypeptide
composedof11aminoacids(severalaremethylatedonthe
peptidylnitrogen).Thedrugisextractedfromasoilfungus.
CsAisusedtopreventrejectionofkidney,liver,andcardiac
allogeneictransplants.CsAismosteffectiveinpreventing
acuterejectionoftransplantedorganswhencombinedina
double-drugortriple-drugregimenwithcorticosteroidsandan
antimetabolitesuchasmycophenolatemofetil.
CsAisanalternativetomethotrexateforthetreatmentof
severe,activerheumatoidarthritis.Itcanalsobeusedfor
patientswithrecalcitrantpsoriasisthatdoesnotrespondto
othertherapies.

9. Mechanismofaction
Cyclosporinepreferentiallysuppressescell-mediated
immunereactions,whereashumoralimmunityisaffectedtoa
farlesserextent.AfterdiffusingintotheTcell,CsAbindstoa
cyclophilin(moregenerallycalledanimmunophilin)toforma
complexthatbindstocalcineurin(Figure.3).
ThelatterisresponsiblefordephosphorylatingNFATc
(cytosolicNuclearFactorofActivatedTcells).TheCsA-
calcineurincomplexcannotperformthisreaction;thus,NFATc
cannotenterthenucleustopromotethereactionsthatare
requiredforthesynthesisofanumberofcytokines,including
IL-2.TheendresultisadecreaseinIL-2theprimarychemical
stimulusforincreasingthenumberofTlymphocytes.

10. Figure .3 Mechanism of action of cyclosporine and tacrolimus.

11. Pharmacokinetics:
CsAmaybegiveneitherorallyorbyIVinfusion.Oral
absorptionisvariable.Interpatientvariabilitymaybedueto
metabolismbyaCYP3A4intheGIT,wherethedrugis
metabolized.About50%ofthedrugisassociatedwiththe
bloodfraction.Halfofthisisintheerythrocytes,andlessthan
one-tenthisboundtothelymphocytes.
CsAisextensivelymetabolized,byhepaticCYP3A4.When
otherdrugsubstratesforthisenzymearegivenconcomitantly,
manydruginteractionshavebeenreported.Itisnotclear
whetheranyofthe25ormoremetaboliteshaveanyactivity.
Excretionofthemetabolitesisthroughthebiliaryroute,with
onlyasmallfractionoftheparentdrugappearingintheurine.

12. Adverseeffects:
ManyoftheadverseeffectscausedbyCsAaredose
dependent;therefore,itisimportanttomonitorbloodlevelsof
thedrug.
Nephrotoxicityisthemostcommonandimportantadverse
effectofCsA.Itisthereforecriticaltomonitorkidneyfunction.
ReductionoftheCsAdosagecanresultinreversalof
nephrotoxicityinmostcases,althoughnephrotoxicitymaybe
irreversiblein15%ofpatients.
Coadministrationofdrugsthatalsocancausekidney
dysfunction(forexample,theaminoglycosideantibiotics)and
anti-inflammatories,e.g.,diclofenac,naproxen,orsulindac,can
potentiatethenephrotoxicityofCsA.

13. Hepatotoxicitycanalsooccur;therefore,liverfunctionshould
beperiodicallyassessed.
InfectionsinpatientstakingCsAarecommonandmaybe
life-threatening.Viralinfectionsduetoherpesgroupand
cytomegalovirus(CMV)areprevalent.
Lymphomamayoccurinalltransplantedpatientsduetothe
netlevelofimmunosuppressionandhasnotbeenlinkedtoany
oneparticularagent.
Anaphylacticreactionscanoccuronparenteral
administration.Othertoxicitiesincludehypertension,
hyperlipidemia,hyperkalemia(notuseK+-sparingdiureticsin
thesepatients),tremor,hirsutism,glucoseintolerance,andgum
hyperplasia.

14. B.Tacrolimus
Tacrolimus(TAC,originallycalledFK506)isamacrolidethat
isisolatedfromasoilfungus.TACisapprovedforthe
preventionofrejectionofliverandkidneytransplantsandis
givenwithacorticosteroidsand/oranantimetabolite.
ThisdrughasfoundfavoroverCsA,notonlybecauseofits
potencyanddecreasedepisodesofrejection(Figure.4)but
alsobecauselowerdosesofcorticosteroidscanbeused,thus
reducingthelikelihoodofsteroid-associatedadverseeffects.
TACisfrom10-to100-foldmorepotentthanCsA.
Mechanismofaction:TACexertsitsimmunosuppressive
effectinthesamemannerasCsA,exceptthatitbindstoa
differentimmunophilin,FKBP-12(FK-bindingprotein;Fig.3).

15. Figure .4 Five-year renal allograft survival in patients treated
with cyclosporine or tacrolimus.

16. Pharmacokinetics:TACmaybeadministeredorallyorIV.
Theoralrouteispreferable,butaswithCsA,oralabsorptionof
TACisincompleteandvariable,requiringtailoringofdoses.
TACabsorptionisdecreasedifitistakenwithhigh-fator
high-carbohydratemeals.
Itishighlyboundtoserumproteinsandisalsoconcentrated
inerythrocytes.LikeCsA,TACmetabolizedbytheCYP3A4;
thus,thesamedruginteractionsoccur.Atleastonemetabolite
ofTAChasbeenshowntohaveimmunosuppressiveactivity.
Renalexcretionisverylow,andmostofthedrugandits
metabolitesarefoundinthefeces.
Anointmenthasapprovedformoderatetosevereatopic
dermatitisthatdoesnotrespondtoconventionaltherapies.

17. Adverseeffects:Nephrotoxicityandneurotoxicity(tremor,
seizures,andhallucinations)tendtobemoreseverein
patientswhoaretreatedwithTACthaninpatientstreatedwith
CsA,butcarefuldoseadjustmentcanminimizethisproblem.
Developmentofposttransplant,insulin-dependentdiabetes
mellitusisaproblem,especiallyinblackandHispanicpatients.
OthertoxicitiesarethesameasthoseforCsA,exceptthat
TACdoesnotcausehirsutismorgingivalhyperplasia.
ComparedwithCsA,TAChasalsobeenfoundtohavea
lowerincidenceofCVStoxicitiese.g.,hypertensionand
hyperlipidemia,bothofwhicharecommondiseasestatesfound
inkidneytransplantrecipients.Anaphylactoidreactionstothe
injectionvehiclehavebeenreported.

18. C.Sirolimus(SRL)isarecentlyapprovedmacrolideobtained
fromfermentationsofasoilmold.Theearliernameandone
thatissometimesstillusedisrapamycin.
SRLisapprovedforuseinrenaltransplantation,tobeused
togetherwithCsAandcorticosteroids,therebyallowinglower
dosesofthosemedicationstobeemployedand,thus,lowering
theirtoxicpotential.ThecombinationofSRLandCsAis
apparentlysynergisticbecauseSRLworkslaterintheimmune
activationcascade.
Tolimitthelong-termsideeffectsofthecalcineurininhibitor,
SRLisoftenutilizedincalcineurininhibitorwithdrawalprotocols
inpatientswhoremainrejectionfreeduringthefirst3months
posttransplant.

19. TheantiproliferativeactionofSRLhasfoundusein
cardiology.SRL-coatedstentsinsertedintothecardiac
vasculatureinhibitrestenosisofthebloodvesselsbyreducing
proliferationoftheendothelialcells.Inadditiontoits
immunosuppressiveeffects,SRLalsoinhibitsproliferationof
cellsinthegraftintimalareasand,thus,iseffectiveinhalting
graftvasculardisease.
Mechanismofaction:SRLandTACbindtocytoplasmicFK-
bindingprotein,butinsteadofformingacomplexwith
calcineurin,SRLbindstomTORinterferingwithSignal3.The
latterisaserine-threoninekinase.TORproteinsareessential
formanycellularfunctions,suchascell-cycleprogression,DNA
repair,andasregulatorsinvolvedinproteintranslation.

20. Figure .5 Mechanism of action of sirolimus. mTOR =
molecular target of rapamycin (sirolimus).

21. BindingofSRLtomTORblockstheprogressionofactivated
T-cellsfromtheG1totheSphaseofthecellcycleand,
consequently,theproliferationofthesecells(Figure.5).
UnlikeCsAandTAC,SRLdoesnotoweitseffecttolowering
IL-2productionbut,rather,toinhibitingthecellularresponses
toIL-2.
Pharmacokinetics:Thedrugisavailableonlyasoral
preparations.Althoughitisreadilyabsorbed,high-fatmeals
candecreasethedrugabsorption.
SRLhasalonghalf-lifecomparedtothoseofCsAandTAC,
andaloadingdoseisrequiredatthetimeofinitiationof
therapy.LikebothCsAandTAC,SRLismetabolizedbythe
CYP3A4andhasthesamedruginteracts.

22. SRLalsoincreasesthedrugconcentrationsofCsA,and
carefulbloodlevelmonitoringofbothagentsmustbeemployed
toavoidharmfuldrugtoxicities.Theparentdrugandits
metabolitesarepredominantlyeliminatedinthefeces.
Adverseeffects:Afrequentsideeffectishyperlipidemia
(cholesterol&triglycerides)canrequiretreatment.
ThecombinationofCsAandSRLismorenephrotoxicthan
CsAaloneduetothedruginteractionbetweenthetwo;
therefore,lowerdosesareinitiated.
AlthoughtheadministrationofSRLandTACappearstobe
lessnephrotoxic,SRLcanstillpotentiatethenephrotoxicityof
TAC,anddruglevelsofbothmustbemonitoredclosely.

23. Otheruntowardeffectsareheadache,nauseaanddiarrhea,
leukopenia,andthrombocytopenia.
ImpairedwoundhealinghasbeennotedwithSRLinobese
patientsandthosewithdiabetes;thiscanbeespecially
problematicimmediatelyfollowingthetransplantsurgeryandin
patientsreceivingcorticosteroids.

24. II. Immunosuppressive Antimetabolites
Theseagentsaregenerallyusedincombinationwith
corticosteroids,andthecalcineurininhibitors,CsAandTAC.
A.Azathioprine
Itwasthefirstagenttoachievewidespreaduseinorgan
transplantation.Itisaprodrugthatisconvertedfirstto6-
mercaptopurine(6-MP)andthentothecorresponding
nucleotide,thioinosinicacid.
Theimmunosuppressiveeffectsofazathioprinearedueto
thisnucleotideanalog.Becauseoftheirrapidproliferationinthe
immuneresponseandtheirdependenceonthedenovo
synthesisofpurinesrequiredforcelldivision,lymphocytesare
predominantlyaffectedbythecytotoxiceffectsofazathioprine.

25. Thedrughaslittleeffectonsuppressingachronicimmune
response.
Itsmajornonimmunetoxicityisbonemarrowsuppression.
Concomitantusewithangiotensin-convertingenzyme
inhibitorsorcotrimoxazoleinrenaltransplantpatientscanlead
toanexaggeratedleukopenicresponse.
Allopurinol,anagentusedtotreatgout,significantlyinhibits
themetabolismofazatihioprine;therefore,thedoseof
azathioprinemustbereducedby60to75%.
Nauseaandvomitingarealsoencountered.
Occurranceofhepatotoxicityintheformof
jaundicehasbeenreportedinabout1/3ofpatients.

26. B.Mycophenolatemofetil(MMF)
Azathioprinehasforthemostpartbeenreplacedby
mycophenolatemofetil(MMF)becauseofthelattersafetyand
efficacyinprolonginggraftsurvival.Ithasbeensuccessfully
usedinheart,kidney,andlivertransplants.
Asanester,itisrapidlyhydrolyzedintheGITto
mycophenolicacid(MPA),whichisapotent,reversible,
uncompetitiveinhibitorofinosinemonophosphate
dehydrogenase,blockingthedenovoformationofguanosine
phosphate.Thus,like6-MP,itdeprivestherapidlyproliferating
TandBcellsofakeycomponentofnucleicacids(Figure.6).
Lymphocyteslackthesalvagepathwayforpurinesynthesis
and,therefore,aredependentondenovopurineproduction.

27. Figure .6 Mechanism of action of mycophenolate.

28. MPAisquicklyandalmostcompletelyabsorbedafteroral
administration.BothMPAanditsglucuronidatedmetaboliteare
highlybound(>90%)toplasmaalbumin,butnodisplacement-
typeinteractionshavebeenreported.Theglucuronideis
excretedpredominantlyintheurine.
Themostcommonadverseeffectsincludediarrhea,nausea,
vomiting,abdominalpain,leukopenia,andanemia.Higher
dosesofMMF(3g/day)wereassociatedwithahigherriskof
CMVinfection.
MPAislessmutagenicorcarcinogenicthanazathioprine.
Concomitantadministrationwithantacidscontaining
magnesiumoraluminum,orwithcholestyramine,candecrease
absorptionofthedrug.

29. C.Enteric-coatedmycophenolatesodium
Inanefforttominimizethegastrointestinaleffectsassociated
withMMF,enteric-coatedmycophenolatesodium(EC-MPS)
wasdeveloped.
Theactivedrug(MPA)iscontainedwithinadelayed-release
formulationdesignedtoreleaseintheneutralpHofthesmall
intestine.
EC-MPSat720mgandMMFat1000mgcontainequivalent
amountsofMPA.InPhaseIIIstudies,thenewformulationwas
foundtobeequivalenttoMMFinthepreventionofacute
rejectionepisodesinkidneytransplantrecipients.However,the
rateofgastrointestinaladverseeventswassimilartothatwith
MMF.

30. D.Methotrexate
Mechanismofaction:Anantifolatewhichactsbyinhibitingthe
enzymedihydrofolatereductase(DHFR)whichisresponsible
fortheconversionoffolateintoitsreducedform.Thereduced
folateformactsasacofactorinpyrimidinesynthesis(required
forDNAsynthesis).
Uses:
•MTXislargelyusedasanti-cancerdrugasinleukemiasand
lymphomas.Itisalsousedasimmunosuppressantinimmune-
mediateddiseasessuchasrheumatoidarthritisandpsoriasis.
Adverseeffects:
Themaintoxicitiesarebonemarrowsuppression,GItoxicity
(nausea,vomiting),nephrotoxicityandhairloss.

31. IV. Antibodies
Theuseofantibodiesplaysacentralroleinprolonging
allograftsurvival.Theyarepreparedeitherbyimmunizationof
rabbitsorhorseswithhumanlymphoidcells(producinga
mixtureofpolyclonalantibodiesdirectedagainstanumberof
lymphocyteantigens),orbyhybridomatechnology(producing
antigen-specific,monoclonalantibodies).
Hybridomasareproducedbyfusingmouseantibody-
producingcellswithimmortal,malignantplasmacells(Figure
.7).Hybridcellsareselectedandcloned,andtheantibody
specificityoftheclonesisdetermined.Clonesofinterestcanbe
culturedinlargequantitiestoproduceclinicallyusefulamounts
ofthedesiredantibody.

32. RecombinantDNAtechnologycanalsobeusedtoreplace
partofthemousegenesequencewithhumangeneticmaterial,
thushumanizingtheantibodiesproduced,makingthemless
antigenic.
Thenamesofmonoclonalantibodiesconventionallycontain
“muro”iftheyarefromamurine(mouse)sourceandxiorzuif
theyarehumanized(Figure.7).
Thesuffixmab(monoclonalantibody)identifiesthecategory
ofdrug.
Thepolyclonalantibodies,althoughrelativelyinexpensiveto
produce,arevariableandlessspecific,whichisincontrastto
monoclonalantibodies,whicharehomogeneousandspecific.

33. Figure .7 Conventions for naming monoclonal antibodies.
Muromonab was named before the convention was adopted to
make the last three letters in their names mab.

34. A.Antithymocyteglobulins
Thymocytesarecellsthatdevelopinthethymusandserve
asT-cellprecursors.Theantibodiesdevelopedagainstthem
arepreparedbyimmunizationoflargerabbitsorhorseswith
humanlymphoidcellsand,thus,arepolyclonal.
Theyareprimarilyemployed,togetherwithother
immunosuppressiveagents,atthetimeoftransplantationto
preventearlyallograftrejection,ortheymaybeusedtotreat
severerejectionorcorticosteroid-resistantacuterejection.
Rabbitformulationsofpolyclonalantithymocyteglobulinare
morecommonlyusedoverthehorsepreparationduetogreater
potency.

35. TheantibodiesbindtothesurfaceofTlymphocytes,then
undergovariousreactions;complement-mediateddestruction,
antibody-dependentcytotoxicity,apoptosis,andopsonization.
Theantibody-boundcellsarephagocytosedintheliverand
spleen,resultinginlymphopeniaandimpairedT-cellresponses.
TheantibodiesareslowlyinfusedIV,andtheirhalf-life
extendsfrom3to9days.Becausethehumoralantibody
mechanismremainsactive,antibodiescanbeformedagainst
theseforeignproteins.Thisislessofaproblemwiththe
humanizedantibodies.
Otheradverseeffectsincludechillsandfever,leukopenia
andthrombocytopenia,infectionsduetoCMVorotherviruses,
andskinrashes.

36. B.Muromonab-CD3(OKT3)
Muromonab-CD3isamurinemonoclonalantibodythatis
synthesizedbyhybridomatechnologyanddirectedagainstthe
glycoproteinCD3antigenofhumanTcells.
Muromonab-CD3isusedfortreatmentofacuterenal
rejectionandforcorticosteroid-resistantacuterejectionin
cardiacandhepatictransplantpatients.Itisalsousedto
depleteTcellsfromdonorbonemarrowpriortotransplantation.
Mechanismofaction:BindingtotheCD3proteinresultsina
disruptionofT-lymphocytefunction,becauseaccessofantigen
totherecognitionsiteisblocked.CirculatingTcellsare
depleted;thus,theirparticipationintheimmuneresponseis
decreased.

37. Becausemuromonab-CD3recognizesonlyoneantigenic
site,theimmunosuppressionislessbroadthanthatseenwith
thepolyclonalantibodies.Tcellsusuallyreturntonormalwithin
48hoursofdiscontinuationoftherapy.
Pharmacokinetics:Theantibodyisadministered
intravenously.Initialbindingofmuromonab-CD3totheantigen
transientlyactivatestheTcellandresultsincytokinerelease
(cytokinestorm).
Itisthereforecustomarytopremedicatethepatientwith
methylprednisolone,diphenhydramine,andacetaminophento
alleviatethecytokinereleasesyndrome.

38. Adverseeffects:Anaphylactoidreactionsmayoccur.
Cytokinereleasesyndromemayfollowthefirstdose.The
symptomscanrangefromamild,flu-likeillnesstoalife-
threatening,shock-likereaction.Highfeveriscommon.
Centralnervoussystemeffects,suchasseizures,
encephalopathy,cerebraledema,asepticmeningitis,and
headache,mayoccur.Infectionscanincrease,includingsome
duetoCMV.
Muromonab-CD3iscontraindicatedinpatientswithseizures,
uncompensatedheartfailure,pregnantwomen,andinthose
whoarebreast-feeding.Becauseoftheseadverseeffectsand
theimprovedtolerabilityofthymoglobulinandtheIL-2receptor
antagonists,muromonab-CD3israrelyusedtoday.

39. C.IL-2-receptorantagonists
Theantigenicityandshortserumhalf-lifeofthemurine
monoclonalantibodyhavebeenavertedbyreplacingmostof
themurineaminoacidsequenceswithhumanonesbygenetic
engineering.
Basiliximabissaidtobechimerizedbecauseitconsistsof25
%murineand75%humanprotein.
Daclizumabis90%humanprotein,andisdesignated
humanized.
Bothagentshavebeenapprovedforprophylaxisofacute
rejectioninrenaltransplantationincombinationwithCsAand
corticosteroids.Theyarenotusedforthetreatmentofongoing
rejection.

40. Mechanismofaction:
Bothcompoundsareanti-CD25antibodiesandbindtotheα
chainoftheIL-2receptoronactivatedTcells.Theythus
interferewiththeproliferationofthesecells.Basiliximabis
about10-foldmorepotentthandaclizumabasablockerofIL-2
stimulatedT-cellreplication.
Blockadeofthisreceptorfoilstheabilityofanyantigenic
stimulustoactivatetheTcellresponsesystem.
Pharmacokinetics:BothantibodiesaregivenIV.
TheserumT1/2ofdaclizumabisabout20days,andthe
blockadeofthereceptoris120days.Fivedosesofdaclizumab
areusuallyadministeredthefirstat24hoursbefore
transplantation,andthenextfourdosesat14-dayintervals.

41. TheserumT1/2ofbasiliximabisabout7days.Usually,two
dosesofthisdrugareadministeredthefirstat2hourspriorto
transplantation,andthesecondat4daysafterthesurgery.
Adverseeffects:Bothdaclizumabandbasiliximabarewell
tolerated.Theirmajortoxicityisgastrointestinal.Noclinically
relevantantibodiestothedrugshavebeendetected,and
malignancydoesnotappeartobeaproblem.
D.Alemtuzumab
Alemtuzumab,ahumanizedmonoclonalantibodydirected
againstCD52,exertsitseffectsbycausingprofounddepletion
ofTcellsfromtheperipheralcirculation.Thiseffectmaylastfor
upto1year.Alemtuzumabiscurrentlyapprovedforthe
treatmentofrefractoryB-cellchroniclymphocyticleukemia.

42. Althoughitisnotcurrentlyapprovedforuseinorgan
transplantation,itisbeingutilizedincombinationwithSRLand
low-dosecalcineurininhibitorsincorticosteroidavoidance
protocolsatmanytransplantcenters.
Preliminaryresultsarepromising,withlowratesofrejection
withaprednisone-freeregimen.
Sideeffectsincludefirst-dosecytokinereleasesyndrome,
requiringpremedicationwithacetaminophen,diphenhydramine,
andcorticosteroids.
Adverseeffectsincludeneutropenia,anemia,andrarely,
pancytopenia.Earlyresultshavenotshownanincreasein
opportunisticinfectionsorlymphomaswithalemtuzumab
despiteitspotentimmunosuppressiveactivity.

43. Figure .8 A summary of the major immunosuppressive drugs

44. V.Corticosteroids
Thecorticosteroidswerethefirstpharmacologicagentstobe
usedasimmunosuppressivesbothintransplantationandin
variousautoimmunedisorders.
Theyarestilloneofthemainstaysforattenuatingrejection
episodes.Fortransplantation,themostcommonagentsare
prednisoneormethylprednisolone,whereasprednisoneor
prednisoloneareemployedforautoimmuneconditions.
Thesteroidsareusedtosuppressacuterejectionofsolid
organallograftsandinchronicgraft-versus-hostdisease.
Inaddition,theyareeffectiveagainstautoimmune
conditions;refractoryrheumatoidarthritis,systemiclupus
erythematosus,temporalarthritis,andasthma.

45. Mechanismofimmunosuppression:
Theexactmechanismoftheimmunosuppressiveactionof
thecorticosteroidsisunclear.Tlymphocytesarethemost
affected.Thesteroidsareabletorapidlyreducelymphocyte
populationsbylysisorredistribution.Onenteringcells,they
bindtotheglucocorticoidreceptor.Thecomplexpassesinto
thenucleusandregulatesthetranslationofDNA.Amongthe
genesaffectedarethoseinvolvedininflammatoryresponses.
InhighIVpulsedoses(methylprednisolone250-1000mg
dailyfor1-3days)theyaredirectlylymphocytotoxic.
Insmallerdoses,theyareimmunosuppressiveandanti-
inflammatorybylimitingcytokineproductionsuchasTNF-α,IL-
1andIL-4.

46. Therequireddoseanddurationoftreatmentthereforetends
tobediseasespecific.
Somediseases,forexampleasthma,respondtoashort
coursewhichcanbeabruptlystopped,butmostrheumatic
diseasesrequirethedosetobeveryslowlytaperedover
months.
Theuseoftheseagentsiscoupledwithnumerousadverse
effects.Forexample,theyarediabetogenic,andtheycan
causehypercholesterolemia,cataracts,osteoporosis,peptic
ulceration&hypertensiononprolongeduse.
Consequently,effortsarebeingdirectedtowardreducingor
eliminatingtheuseofsteroidsinthemaintenanceofallografts.