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Immunosuppressive Therapy and Protocols

Immunosuppressive Therapy and Protocols

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11
ImmunosuppressiveTherapy and Protocols
T
he 1990s have seen major steps in the dissection of basic mecha-nisms of allorecognition, and renal graft survival has achievedunprecedented clinical results. Transplantation has turned into awidespread modality of therapy for patients with chronic renal failurethat benefits thousands worldwide. Combinations of immunosuppres-sive agents have proved to be an effective strategy to inhibit diversepathways of the multifaceted immune system, allowing the reduction of both dosage and adverse effects of each individual drug. As under-standing of the molecular basis of the immune response has expandedrapidly, so have the possibilities for designing therapeutic interventionsthat are more effective, more specific, and safer than are current treat-ment options. As we reach the end of the century, several different andinnovative approaches will add to this fascinating and complex therapy.
Angelo M. de Mattos 
C H A PT ER
 
11.2
Transplantation as Treatment of End-Stage Renal Disease
CalcineurinCsa/CypDNADNARNAPCaIL-2
X
NF-AT boxNF-ATcTac/FK-BPppRapa/FKBPeIF-4FPHAS-1PHAS-1IL-2 receptorIL-2m-TORG
1
G
0
MG
2
S
FIGURE 11-1
Mechanism of action for cyclosporine (Csa) and tacrolimus (Tac).The common cytoplasmic target for cyclosporine and tacrolimus iscalcineurin. After binding to cyclophillin (Cyp), cyclosporine inter-acts with calcineurin, inhibiting its catalytic domain. Thus dephos-phorylation of transcription factors is prevented, as exemplified bythe nuclear factor of activated T lymphocyte (NF-AT). Despite hav-ing a different ligand called FK-binding protein (FK-BP), tacrolimusinhibits calcineurin in a similar way. Because phosphorylated tran-scription factors cannot cross the nuclear membrane, the productionof key factors for lymphocyte activation and proliferation (
ie,
inter-leukin-2, tumor necrosis factor-
,
interferon, c-myc, and others) isinhibited [1]. NF-ATc—nuclear factor of activated T-lymphocyte-cytoplasmic form; P—phosphorus; Ca—calcium.
FIGURE 11-2
Proposed mechanism of action for rapamycin (rapa). Rapamycinbinds to FK-binding protein (FK-BP). However, the immunosup-pressive properties of rapamycin are not due to inhibition of cal-cineurin. Rapamycin blocks the activating signal delivered bygrowth factors (exemplified by the interleukin-2 [IL-2] receptor)by blocking the translation of the coding of messenger RNA(mRNA) for key proteins required for progression through theG
1
phase of the cell cycle. In this model the mammalian target of rapamycin (m-TOR, also called FRAP or RAFT1), phosphorylatesthe translational repressor PHAS-I. Arrest of the cell cycle results,and the proliferation of lymphocytes is thereby inhibited. The fullunderstanding of the mechanism(s) of action of rapamycin is thefocus of intense research at this time [2]. elF-4—translation initia-tion factor belonging to the Ets family; G
(0,1, and 2)
—quiescent;M—mitosis; S—synthesis.
 
11.3
Immunosuppressive Therapy and Protocols
PRPPIMPAMPATPGMPGTPHGPRTHGPRTEnergy, signalingGuanine + PRPP
 Azathioprine6-m-MP6-MPThiouric acid  Mycophenolate, mizoribine
EnergyRNA,DNAGlycoproteins
 Allopurinol
HGPRT
TIMP
PRPP + AdenineHypoxanthine + PRPP
I    M    P    D    
FIGURE 11-3
Mechanism of immunosuppression of azathioprine and mycophenolate mofetil(MMF). Azathioprine and MMF preventlymphocyte proliferation by way of inhibi-tion of purine base synthesis, thus resultingin decreased production of the buildingblocks of nucleic acids (
ie,
DNA and RNA).Azathioprine is metabolized to 6-mercap-topurine (6-MP), which is further convertedto 6-ionosine monophosphate. This mole-cule inhibits key enzymes in the
de novo
pathway of purine synthesis (adenosinemonophosphate [AMP] and guanosinemonophosphate [GMP]). MMF is metabo-lized to mycophenolic acid, which is a non-competitive inhibitor of the enzyme thatconverts inosine monophosphate (IMP) toGMP. The depletion of GMP may haveeffects other than inhibition of nucleic acidproduction. Some events of T-lymphocyteactivation are independent of guanosinetriphosphate (GTP), as is the assembling of certain adhesion molecules. ATP—adenosinetriphosphate; HGPRT—hypoxanthine-gua-nine phosphoribosyl transferase; IMPD—inosine-monophosphate dehydrogenase;PRPP—phosphoribosyl pyrophosphate;6-m-MP—6-methyl-mercaptopurine; TIMP—thioinosine monophosphate. (
 Adapted from
de Mattos and coworkers [3,4].)
}}}}
1 week1 month
Csa or FK-506Csa or FK-506Csa or FK-506Csa or FK-506Csa or FK-506Csa or FK-506Aza or MMFAza or MMFAza or MMFAza or MMFSteroidSteroidSteroidSteroidAntilymphocyticAntilymphocytic
MonotherapyDual therapyTriple therapyQuadrupletherapy(induction versussequential)
FIGURE 11-4
Summary of strategies for combining immunosuppressive agents.Currently, monotherapy (usually cyclosporine [Csa]) is not used inthe United States. Dual therapy (involving cyclosporine or tacrolimus)is used commonly in Europe. Most centers in the United States usetriple or quadruple therapy (induction or sequential). Some centerscontinue the induction with the antilymphocytic biologic agent fora predetermined period (usually 10–14 days), overlapping with theinitiation of cyclosporine (or tacrolimus). Alternatively, the biologicagent is discontinued and cyclosporine (or tacrolimus) begun as soonas the graft function reaches a determined threshold, resulting in nooverlap of these two agents. In living donor transplants, azathioprine(Aza) is commonly begun a few days before surgery. [5]. FK-506—tacrolimus; MMF—mycophenolate mofetil.

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