Immunosuppression and Transplantatio

8/8/2019 Immunosuppression and Transplantatio

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Immunosuppression and Transplantation

Yufang Shi, D.V.M, Ph.D.

E-mail: [email protected]


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Transplantation in ClinicTransplantation in Clinic

Body parts: Facial, Limbs,

Organs: Heart, kidney, liver

Tissue: Islets, hair follicles, bone, bone marrow

Cells: Stem cells, lymphocytes


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Most surgical procedures are well establishedMost surgical procedures are well established

**Immunosuppression**Immunosuppression

Organ variation: liver is easier to tolerizeOrgan variation: liver is easier to tolerize

Cornea very little rejectionCornea very little rejection

Skin is most difficultSkin is most difficult

Most surgical procedures are well establishedMost surgical procedures are well established

**Immunosuppression**Immunosuppression

Organ variation: liver is easier to tolerizeOrgan variation: liver is easier to tolerize

Cornea very little rejectionCornea very little rejection

Skin is most difficultSkin is most difficult

Transplantation HurdlesTransplantation Hurdles


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The dream of transplantsThe dream of transplantsThe dream of transplantsThe dream of transplants

The 3rd Century,

Saints Cosmas and Damian


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Relationships between Donor andRelationships between Donor and

RecipientRecipient

Relationships between Donor andRelationships between Donor and

RecipientRecipient

Syngeneic -between genetically identical individuals, usually the

same individual, identical twins or isogenic strains

Allogeneic - from one individual to another of the same species

Xenogeneic -between individuals of different species.


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Immunological RejectionImmunological Rejection

Major Histocompatibility Complex (MHC) is the major concern.Major Histocompatibility Complex (MHC) is the major concern.

Rejections:Rejections:

Antibody mediatedAntibody mediated

T cells mediatedT cells mediated

Hyperacute rejectionHyperacute rejection

e.g.,e.g., Blood type mismatchBlood type mismatch

Acute Graft RejectionAcute Graft Rejection

Direct recognition of allogeinic MHC; reDirect recognition of allogeinic MHC; rejjection about 10 daysection about 10 daysChronic rejectionChronic rejection

Take many months to years. Due to failure ofTake many months to years. Due to failure ofimmunosuppressantimmunosuppressantss

Major Histocompatibility Complex (MHC) is the major concern.Major Histocompatibility Complex (MHC) is the major concern.

Rejections:Rejections:

Antibody mediatedAntibody mediated

T cells mediatedT cells mediated

Hyperacute rejectionHyperacute rejection

e.g.,e.g., Blood type mismatchBlood type mismatch

Acute Graft RejectionAcute Graft Rejection

Direct recognition of allogeinic MHC; reDirect recognition of allogeinic MHC; rejjection about 10 daysection about 10 daysChronic rejectionChronic rejection

Take many months to years. Due to failure ofTake many months to years. Due to failure ofimmunosuppressantimmunosuppressantss


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1906 The first kidney transplantations were done without anti-rejection drugs. Kidneys from sheep, pigs,

goats and primates are used.

1936 Dr. Voronoy, a Russian, reports the first human-to-human kidney transplant, when a kidney from a

cadaver is transplanted to a recipient with a different blood type.

**1944 A British scientist, Sir Peter Medawar, reports that rejection of a transplant is based onimmunologic factors. This discovery eventually transforms transplant surgery from a largely

unsuccessful experiment to an accepted form of treatment.

1954 Surgeons Joseph E. Murray and John Hartwell Harrison, in collaboration with nephrologist John P.

Merrill, perform the first successful kidney transplant -- between identical twins -- at the Peter Bent

Brigham Hospital in Boston.

1963 Dr. Thomas E. Starzl performs the first human liver transplant at the University of Colorado

Medical School; however, lack of effective immunosuppressives limits the success. Four yearslater, the availability of more effective immunosuppressives enables Dr. Starzl to perform the first

successful liver transplant.

1963 Dr. James D. Hardy performs the first lung transplant at the University of Mississippi at Jackson;

however, the patient survives only a few days because of the lack of effective immunosuppression

drugs. Twenty years later, with improved immunosuppressives, Dr. Joel Cooper performs the first

successful lung transplant at Toronto General Hospital.

1967 Dr. Christiaan Barnard performs the first heart transplant at Groote Shuur in Cape Town, SouthAfrica.

Milestones In Organ Transplantation (1)

Source: National Kidney Foundation, Inc.


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1968 Dr. Norman Shumway performs the first U.S. heart transplant at Stanford University.

1968 Drs. Richard Lillehei and William Kelly perform the first pancreas transplant at the University of

Minnesota Hospital.

**1979 U.S. trials of Sandimmune (cyclosporine) in cadaver kidney transplants begin at the Peter Bent

Brigham Hospital in Boston and at the University of Colorado. The results show that Sandimmune(cyclosporine), combined with steroids, controls rejection better than any drug therapy in the past.

1983 The Federal Drug Administration releases Sandimmune (cyclosporine) for general use in the U.S.,

heralding a new era for kidney, liver and heart transplantation.

1986 Dr. A. Benedict Cosimi and his associates at Massachusetts General Hospital introduce monoclonal

antibodies into clinical medicine in the form of OKT3 antibodies, which have a selective effect on the

immune system and are intended primarily for reversing kidney transplant rejection.

1989 Clinical investigators begin using an experimental drug called FK 506 for kidney, liver, heart and lung

recipients. Results suggest that this drug is effective, but clinical trials continue to assess its safety

and efficacy.

1993 Continuing shortages in organ donation lead to renewed interest in transplanting organs from animals

such as baboons (often referred to as xenografting). Baboon-to-human liver and heart transplants

have been attempted, with limited success. A new research strategy involves developing a line of pigs

with the appropriate human genes to help prevent rejection of organs such as hearts, livers and

kidne s trans lanted from these animals.




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1994 The FDA approves a new medication for use in transplant recipients: Prograf (formerly known as FK506)

marks a significant advance in the understanding and suppression of the human rejection response and in

the lessening of unwanted side effects.

1995 A new study by Dr. Paul Terasaki and colleagues at UCLA shows that spouses are an important source of

living-donor kidney transplants. According to the Terasaki study, the 3-year graft survival rate for spouse-

to-spouse transplants (85%) is comparable to that seen in parent-to-child transplants (82%) and better

than that seen in transplants from cadaver donors (70%). Living donation is becoming an increasingly

important source of kidney and other transplants because of continuing shortages of cadaver donors.1995 Two more new medicines are approved by the FDA for use in transplant recipients. These are: CellCept

(mycophenolate mofetil), and Neoral, a new formulation of cyclosporine. These drugs hold promise for

providing even better control of rejection with fewer side effects.

1995 At Johns Hopkins Bayview Medical Center, Lloyd Ratner, M.D. and Louis Kavoussi, M.D., perform the

world's first laparoscopic live-donor nephrectomy in which a patient's kidney is removed through a hole

slightly larger than a silver dollar. Laparoscopic live-donor nephrectomies mean fewer post-op days in the

hospital, speedier recovery, less scarring and decreased post-operative pain.1996 The number of kidney transplants using living donors (both related and unrelated) continues to grow. A

total of 11,099 kidney transplants were performed in 1996 -- 3,389 of which involved kidneys recovered

from living donors.

1997 The Department of the Navy Bureau of Medicine and Surgery announces a research breakthrough that

they are now able to prevent kidney transplant rejection in primates with different histocompatibility factors

through the use ofa combination of a specific fusion protein and a specific monoclonal antibody. Further

trials are necessary to determine future applicability of the technique to humans.




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Anti-inflammatory and Immunosuppressive Drugs

Nonsteroid anti-inflammatory drugs: Aspirin, Vioxxx (no longer

used), and Celebrex. Work through COX1/2

(cylooxygeneases, which are involved in the

synthesis of prostaglandins)

Antihistamines: Blockers of histamine receptors: Allegra,Claritin, Clarinex, Benadryl

*Steroid hormones: Glucocorticoid derivatives: prednisone,

dexamethasone, and hydrocortisone

*Lymphocyte specific immunosuppressants: Cyclosoprine, FK506,

rapamycin, FTY720, specific antibodies

and receptors (bioactive).

Cytotoxic agents: cyclophosphamidecyclophosphamide


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Simplified Schematic Representation of an Immune

Response

Simplified Schematic Representation of an Immune

Response

Class IClass I

MHC class II/peptidesMHC class II/peptides

APCs

APCs

Protein antigens

CD8+ T cells

CD4+ T cells

B cellsB cells Plasma cellsPlasma cells

CD8+ cytolytic T cells

CD4CD4++ immune cellsimmune cells

(delayed hypersensitivity)(delayed hypersensitivity)

antibody

production

proliferation &

differentiation

Cytokines

Costim. Mol.

IL-4,-5,-6

proliferation &

differentiation

APCClass II

proliferation &

differentiation


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2003 by LIPPINCOTT WILLIAMS & WILKINS

Fundamental Immunology

TCR Costimulation


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Families of Costimulation Molecules

B7:CD28 superfamily: B7.1/B7.2:CD28/CTLA4; ICOSL:ICOS;

PD-L1/PD-L2:PD-1; B7-H3:?

TNF:TNFR superfamily: CD134 (OX40):CD134L; CD27:CD70;4-1BB:4-1BBL; CD30:CD30L;

RANK (OPG):RANKL; LIGHT:HVEM,

and GITR:GITRL

CD2 superfamily: CD2:CD58/CD48; CD48:CD244

CD150, CD84, CD299, Ly-108, and

BLAM

Some integrins: CD44, CD43, and heat-stable antigen

(HSA).


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E F

K IH

^^

I

CD4

5C

D4

lck

fy

Zap-70

Ras

Raf

Mek

MapK

Csk

PI3K

PLC K

CD28 PIP2

DAG

IP3

Ca ++ PKCGrb 2 SoS

CalcineurinCsA

K506

F AT

Immediate

arly Genes

IL 2Gene

Vav

SLP 76SHP 1

TCRActivation


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T-cell Activation Blockers: Cyclosporine, Tacrolimus

(FK506), and Sirolimus (Rapamycin)

T-cell Activation Blockers: Cyclosporine, Tacrolimus

(FK506), and Sirolimus (Rapamycin)

CsA and FK506 act on TCsA and FK506 act on T--cells to inhibit Tcells to inhibit T--cell receptorcell receptoractivation and induction of cytokinesactivation and induction of cytokines

CsA may also inhibit IgECsA may also inhibit IgE--stimulated mast cell degranulationstimulated mast cell degranulationand stimulate TGFand stimulate TGF--FF expressionexpression

Rapamycin acts to inhibit lymphocyte response to cytokinesRapamycin acts to inhibit lymphocyte response to cytokines

Rapamycin and analogues are also used to sensitize cancerRapamycin and analogues are also used to sensitize cancercells to chemotherapeutic reagentscells to chemotherapeutic reagents

CsA and FK506 act on TCsA and FK506 act on T--cells to inhibit Tcells to inhibit T--cell receptorcell receptoractivation and induction of cytokinesactivation and induction of cytokines

CsA may also inhibit IgECsA may also inhibit IgE--stimulated mast cell degranulationstimulated mast cell degranulationand stimulate TGFand stimulate TGF--FF expressionexpression

Rapamycin acts to inhibit lymphocyte response to cytokinesRapamycin acts to inhibit lymphocyte response to cytokines

Rapamycin and analogues are also used to sensitize cancerRapamycin and analogues are also used to sensitize cancercells to chemotherapeutic reagentscells to chemotherapeutic reagents


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FKBP

Rapamycin

mTor

FK506 Cyclosporine

Cyclophilin

Calcineurin

Cytokine Signaling NFAT Translocation

Genes lead to T cell Activation

Targets of Immunosuppressants


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Target of Rapamycin


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Mechanism of Action of

Helper T-cell blockers

Mechanism of Action of

Helper T-cell blockers

XX

From Hardman and Limbird, The Pharmacological Basis of Therapeutics


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Cyclophilin is a peptidyl-prolyl cis-trans-isomerase which catalyzes the cis-trans

isomerization of proline imidic peptide bonds. Helps protein folding.

FKBPs are also known to participate in many cellular processes such as cell

signaling, protein transport (such as Notch) and transcription.

Immunophilins


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-

Biology of Glucocorticoids


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Newton, Thorax 2000;55:603-613

Mechanisms of GlucocorticoidAction

1. Inhibit the production of

proinflammatory cytokines

2. Promote the production of

inflammatory cytokines

3. Induce apoptosis in

inflammatory cells

4. Interfere with cytokine signals


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Glucocorticoid-sensitive sites of

the immune response

Glucocorticoid-sensitive sites of

the immune response

MHC Class I/peptidesMHC Class I/peptides

APCsAPCs

MHC Class II/peptidesMHC Class II/peptides

APCsAPCs

Protein antigenProtein antigen

CD8 TCD8 T--cellcell

CD4 T-cell

(helper T-cells)

BB--cellcell Plasma cellPlasma cell

CD8 cytolytic TCD8 cytolytic T--cellscells

CD4 immune cellCD4 immune cell

(delayed hypersensitivity)(delayed hypersensitivity)

antibodyantibody

productionproduction

proliferation &

differentiation

proliferation

ILIL--11

ILIL--1,1, --4,4,--5,5,--66

proliferation &

differentiation

GC

X

X

GC

X

X


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Use of Glucocorticoid as ImmunosuppressantsUse of Glucocorticoid as Immunosuppressants

Most widely used effective antiMost widely used effective anti--inflammatory drugsinflammatory drugs

Used with other immunophilin inhibitors to preventUsed with other immunophilin inhibitors to prevent

transplant rejection and GVHDtransplant rejection and GVHD

natural glucocorticoids not used due tonatural glucocorticoids not used due to

mineralocorticoid activitymineralocorticoid activity

PPrednisone and prednisolone are used orally at moderaterednisone and prednisolone are used orally at moderateto high doses; Very high doses ofto high doses; Very high doses ofmethylprednisolonemethylprednisolone

used i.v. during acute organ rejectionused i.v. during acute organ rejection

Used before and after antiUsed before and after anti--thymocyte Abs to inhibit allergicthymocyte Abs to inhibit allergic

reactionsreactions

Most widely used effective antiMost widely used effective anti--inflammatory drugsinflammatory drugs

Used with other immunophilin inhibitors to preventUsed with other immunophilin inhibitors to prevent

transplant rejection and GVHDtransplant rejection and GVHD

natural glucocorticoids not used due tonatural glucocorticoids not used due to

mineralocorticoid activitymineralocorticoid activity

PPrednisone and prednisolone are used orally at moderaterednisone and prednisolone are used orally at moderateto high doses; Very high doses ofto high doses; Very high doses ofmethylprednisolonemethylprednisolone

used i.v. during acute organ rejectionused i.v. during acute organ rejection

Used before and after antiUsed before and after anti--thymocyte Abs to inhibit allergicthymocyte Abs to inhibit allergic

reactionsreactions


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General Principles of ImmunosuppressionGeneral Principles of Immunosuppression

Primary immune responses are more easilyPrimary immune responses are more easilysuppressed than secondary (memory)suppressed than secondary (memory)

Different immunosuppressants haveDifferent immunosuppressants havedifferent effects on different immunedifferent effects on different immunereactionsreactions

Suppression is more likely achieved ifSuppression is more likely achieved iftherapy begins before exposure to thetherapy begins before exposure to theimmunogenimmunogen

Primary immune responses are more easilyPrimary immune responses are more easilysuppressed than secondary (memory)suppressed than secondary (memory)

Different immunosuppressants haveDifferent immunosuppressants havedifferent effects on different immunedifferent effects on different immunereactionsreactions

Suppression is more likely achieved ifSuppression is more likely achieved iftherapy begins before exposure to thetherapy begins before exposure to theimmunogenimmunogen


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Uses of Calcineurin inhibitors

(TCR activation blockers)

Uses of Calcineurin inhibitors

(TCR activation blockers)

Cyclosporine commonly used with prednisoneCyclosporine commonly used with prednisoneand otherand other immunosuppressantsimmunosuppressants to preventto preventallograft rejections in renal, hepatic and cardiacallograft rejections in renal, hepatic and cardiac

transplants, and inR

A and psoriasistransplants, and inR

A and psoriasis use is delayeduse is delayed posttransplantationposttransplantation due todue toneurotoxicity concernsneurotoxicity concerns

FK506 (FK506 (TacrolimusTacrolimus) is approved for prevention of) is approved for prevention ofsolidsolid--organ allograft rejection, and eczemaorgan allograft rejection, and eczema

(topical)(topical) Treatment begins prior to surgery, and is maintainedTreatment begins prior to surgery, and is maintained

well afterwardswell afterwards

Cyclosporine commonly used with prednisoneCyclosporine commonly used with prednisoneand otherand other immunosuppressantsimmunosuppressants to preventto preventallograft rejections in renal, hepatic and cardiacallograft rejections in renal, hepatic and cardiac

transplants, and inR

A and psoriasistransplants, and inR

A and psoriasis use is delayeduse is delayed posttransplantationposttransplantation due todue toneurotoxicity concernsneurotoxicity concerns

FK506 (FK506 (TacrolimusTacrolimus) is approved for prevention of) is approved for prevention ofsolidsolid--organ allograft rejection, and eczemaorgan allograft rejection, and eczema

(topical)(topical) Treatment begins prior to surgery, and is maintainedTreatment begins prior to surgery, and is maintained

well afterwardswell afterwards


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Glucocorticoid effects related toGlucocorticoid effects related to

immunosuppressionimmunosuppression

Glucocorticoid effects related toGlucocorticoid effects related to

immunosuppressionimmunosuppression

Reduced immune cell content of lymph nodes,Reduced immune cell content of lymph nodes,

spleen and bloodspleen and blood

lymphopenia, monocytopenia, eosinopenia, butlymphopenia, monocytopenia, eosinopenia, butneutrophilia

Interference with APC, TInterference with APC, T--cell and macrophagecell and macrophage

functionsfunctions

Reduced immune cell content of lymph nodes,Reduced immune cell content of lymph nodes,

spleen and bloodspleen and blood

lymphopenia, monocytopenia, eosinopenia, butlymphopenia, monocytopenia, eosinopenia, butneutrophilia

Interference with APC, TInterference with APC, T--cell and macrophagecell and macrophage

functionsfunctions


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Sirolimus (Rapamycin, Rapamune):Sirolimus (Rapamycin, Rapamune):

a new Ta new T--cell blockercell blocker

Sirolimus (Rapamycin, Rapamune):Sirolimus (Rapamycin, Rapamune):

a new Ta new T--cell blockercell blocker

different mechanism of actiondifferent mechanism of action

blocks mTOR kinaseblocks mTOR kinase

similar poor bioavailability as cyclosporine andsimilar poor bioavailability as cyclosporine and

tacrolimus, much longer halftacrolimus, much longer half--life; 62 h v. 18 and 12 hlife; 62 h v. 18 and 12 h

same metabolism (CYP3A) and potential drugsame metabolism (CYP3A) and potential druginteractionsinteractions

used for prophylaxis of organ transplant rejection inused for prophylaxis of organ transplant rejection in

combination with a calcineurin inhibitor andcombination with a calcineurin inhibitor and

glucocorticoidsglucocorticoids

toxicities include:toxicities include: hyperlipidemia, lymphocoele, anemia, leukopenia,hyperlipidemia, lymphocoele, anemia, leukopenia,

thrombocytopenia, fever, GI effects, hyperthrombocytopenia, fever, GI effects, hyper-- oror

hypokalemiahypokalemia

different mechanism of actiondifferent mechanism of action

blocks mTOR kinaseblocks mTOR kinase

similar poor bioavailability as cyclosporine andsimilar poor bioavailability as cyclosporine and

tacrolimus, much longer halftacrolimus, much longer half--life; 62 h v. 18 and 12 hlife; 62 h v. 18 and 12 h

same metabolism (CYP3A) and potential drugsame metabolism (CYP3A) and potential druginteractionsinteractions

used for prophylaxis of organ transplant rejection inused for prophylaxis of organ transplant rejection in

combination with a calcineurin inhibitor andcombination with a calcineurin inhibitor and

glucocorticoidsglucocorticoids

toxicities include:toxicities include: hyperlipidemia, lymphocoele, anemia, leukopenia,hyperlipidemia, lymphocoele, anemia, leukopenia,

thrombocytopenia, fever, GI effects, hyperthrombocytopenia, fever, GI effects, hyper-- oror

hypokalemiahypokalemia


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Toxicity of GlucocorticoidsToxicity of GlucocorticoidsToxicity of GlucocorticoidsToxicity of Glucocorticoids

Major side effects are common due to highMajor side effects are common due to high

doses necessary for suppressiondoses necessary for suppression

Cushings syndromeCushings syndrome

glucose intoleranceglucose intolerance

infectionsinfections

bone dissolutionbone dissolution

muscle wastingmuscle wasting

Major side effects are common due to highMajor side effects are common due to high

doses necessary for suppressiondoses necessary for suppression

Cushings syndromeCushings syndrome

glucose intoleranceglucose intolerance

infectionsinfections

bone dissolutionbone dissolution

muscle wastingmuscle wasting


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Cytotoxic Agents as immunosuppressantsCytotoxic Agents as immunosuppressantsCytotoxic Agents as immunosuppressantsCytotoxic Agents as immunosuppressants

Antineoplastic drugs will also prevent clonalAntineoplastic drugs will also prevent clonal

expansion of Texpansion of T-- and Band B--cellscells

azathioprine (prodrug of nucleotide antiazathioprine (prodrug of nucleotide anti--metabolite)metabolite)

mycophenolate mofetilmycophenolate mofetil

becomesMPA; inhibits IMP dehydrogenasebecomesMPA; inhibits IMP dehydrogenase

cyclophosphamide (DNA alkylating agent)cyclophosphamide (DNA alkylating agent) methotrexate (inhibits dihydrofolate reductase)methotrexate (inhibits dihydrofolate reductase)

Antineoplastic drugs will also prevent clonalAntineoplastic drugs will also prevent clonal

expansion of Texpansion of T-- and Band B--cellscells

azathioprine (prodrug of nucleotide antiazathioprine (prodrug of nucleotide anti--metabolite)metabolite)

mycophenolate mofetilmycophenolate mofetil

becomesMPA; inhibits IMP dehydrogenasebecomesMPA; inhibits IMP dehydrogenase

cyclophosphamide (DNA alkylating agent)cyclophosphamide (DNA alkylating agent) methotrexate (inhibits dihydrofolate reductase)methotrexate (inhibits dihydrofolate reductase)


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Uses of cytotoxic agentsUses of cytotoxic agents

Azathioprine; with cyclosporine and/or prednisoneAzathioprine; with cyclosporine and/or prednisone

for organ transplant rejection and severe RAfor organ transplant rejection and severe RA

Mycophenolate mofetil; with cyclosporine and

Mycophenolate mofetil; with cyclosporine andprednisone for renal transplantsprednisone for renal transplants

Cyclophosphamide; for BMTCyclophosphamide; for BMT

Methotrexate; GVHD prophylaxisMethotrexate; GVHD prophylaxis

Azathioprine; with cyclosporine and/or prednisoneAzathioprine; with cyclosporine and/or prednisone

for organ transplant rejection and severe RAfor organ transplant rejection and severe RA

Mycophenolate mofetil; with cyclosporine and

Mycophenolate mofetil; with cyclosporine andprednisone for renal transplantsprednisone for renal transplants

Cyclophosphamide; for BMTCyclophosphamide; for BMT

Methotrexate; GVHD prophylaxisMethotrexate; GVHD prophylaxis


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Bioactive ImmunosuppressantsBioactive ImmunosuppressantsBioactive ImmunosuppressantsBioactive Immunosuppressants

AntiAnti--thymocyte antibodiesthymocyte antibodies

3 types available3 types available

all derived from nonall derived from non--human sourceshuman sources

Rh(D) immune globulinRh(D) immune globulin

OKT3, OKT4, AntiOKT3, OKT4, Anti--CD20, antiCD20, anti--TNF, antiTNF, anti--ICAMs, andICAMs, andCTLA4CTLA4--IgIg

Repeated blood transfusion; transfusion of apoptoticRepeated blood transfusion; transfusion of apoptoticcellscells

AntiAnti--thymocyte antibodiesthymocyte antibodies

3 types available3 types available

all derived from nonall derived from non--human sourceshuman sources

Rh(D) immune globulinRh(D) immune globulin

OKT3, OKT4, AntiOKT3, OKT4, Anti--CD20, antiCD20, anti--TNF, antiTNF, anti--ICAMs, andICAMs, andCTLA4CTLA4--IgIg

Repeated blood transfusion; transfusion of apoptoticRepeated blood transfusion; transfusion of apoptoticcellscells


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History of Immunosuppressants (1)History of Immunosuppressants (1)

Significant Prolongation of canine Kidney Graft SurvivalSignificant Prolongation of canine Kidney Graft SurvivalAzathioprin(Azathioprin(Aza)Aza)Calne,ZckoskiCalne,Zckoski19601960

Prolongation of Cadaveric Kidney Graft SurvivalProlongation of Cadaveric Kidney Graft SurvivalTLI+Autogeneic BMTTLI+Autogeneic BMTHamburgerHamburger19591959

Inhibition of Antibody Production, Prolongation of Skin GraftInhibition of Antibody Production, Prolongation of Skin Graft

SurvivalSurvival

66--MPMPSchwartz,DameshekSchwartz,Dameshek19591959

Prolongation of Mouse Skin Graft SurvivalProlongation of Mouse Skin Graft SurvivalXX--irradiation+BMTirradiation+BMTLoutitLoutit19521952

Prolongation of canine Kidney Graft SurvivalProlongation of canine Kidney Graft Survivalcortisteroid+Splenectomycortisteroid+SplenectomyBakerBaker19521952

Recipient Died of Systemic InfectionRecipient Died of Systemic InfectionCadaveric Kidney Tx+ TLCCadaveric Kidney Tx+ TLCHumeHume19501950

Prolongation of Skin Graft of Rabbit and MiceProlongation of Skin Graft of Rabbit and MiceCorticosteroidsCorticosteroidsBillinghamBillingham19501950

ResultResultExperiment or ClinicalExperiment or Clinical

applicationapplication

authorauthorTimeTime

Became a Clinical RoutineBecame a Clinical RoutineAza+CorticosteroidAza+CorticosteroidStarzlStarzl19631963

Prolongation of Cadaveric Kidney Graft SurvivalProlongation of Cadaveric Kidney Graft SurvivalTLI+6TLI+6--MPMPKussKuss19601960


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History of Immunosuppressants (2)History of Immunosuppressants (2)History of Immunosuppressants (2)History of Immunosuppressants (2)

ResultsResultsExperiment orExperiment or

Clinical ApplicationClinical Application

AuthorAuthorTimeTime

Strong Immunosuppresion and Less InfectionStrong Immunosuppresion and Less InfectionThe Finding of CsAThe Finding of CsABorelBorel19761976

Enhanced Survival Rate of Cadaveric Kidney GraftEnhanced Survival Rate of Cadaveric Kidney Graft

by 20%by 20%

Prooperative BloodProoperative Blood

TransfusionTransfusion

OpelzOpelz19731973

To Replace Aza When Severely ToxicTo Replace Aza When Severely ToxicCHXCHXStarzlStarzl19701970

No Obvious EffectNo Obvious EffectIrradiation of CadavericIrradiation of CadavericKidneyKidney

WolfWolf19691969

Clinical Use of ALS, Still in Use ClinicallyClinical Use of ALS, Still in Use ClinicallyALSALSStarzlStarzl19671967

Prolongation of Graft Survival of Mouse Skin andProlongation of Graft Survival of Mouse Skin and

Canine KidneyCanine Kidney

ALSALSRussell MonacoRussell Monaco19671967

Transient EffectTransient EffectTechnical DifficultyTechnical DifficultyThoracic Duct DrainageThoracic Duct DrainageMcGregor,GowansMcGregor,Gowans19641964

Not so Good, Seldom UsedNot so Good, Seldom UsedPreoperativePreoperative

SplenectomySplenectomy

SrarzlSrarzl19631963


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Currently Used ImmunosuppressantsCurrently Used ImmunosuppressantsCurrently Used ImmunosuppressantsCurrently Used Immunosuppressants

Chinese MedicineChinese Medicine

CsA FK506CsA FK506 RapamicinRapamicinCellceptCellcept ((mycophenolate

mofetil )

Fungus ProductsFungus Products

ALG (antiALG (anti--lymphocyte globulinslymphocyte globulins),), ATG (antiATG (anti--

thymocyte globulins), OKT3thymocyte globulins), OKT3Biological AgentsBiological Agents

Predenisone,Prednisolone, Dexamethasone, etcPredenisone,Prednisolone, Dexamethasone, etcSteroidsSteroids

Azathioprin (Azathioprin (Aza)Aza)Antimetabolic AgentAntimetabolic Agent

CyclophosphamideCyclophosphamideAlkyl AgentAlkyl Agent

DrugsDrugsCategoryCategory


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Ideal ImmunosuppressantIdeal Immunosuppressant

Strongly ImmunosuppressiveStrongly Immunosuppressive

Specific, No Overall ImmunosuppressionSpecific, No Overall Immunosuppression

AntiAnti--infection abilityinfection ability

Low Toxicity for Vital OrgansLow Toxicity for Vital Organs

Low costLow cost

LongLong in vivoin vivo bioactivitybioactivity

Easy to useEasy to use

Strongly ImmunosuppressiveStrongly Immunosuppressive

Specific, No Overall ImmunosuppressionSpecific, No Overall Immunosuppression

AntiAnti--infection abilityinfection ability

Low Toxicity for Vital OrgansLow Toxicity for Vital Organs

Low costLow cost

LongLong in vivoin vivo bioactivitybioactivity

Easy to useEasy to use


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Clinical Tolerance EstablishedClinical Tolerance Established

Absence of Pathogenic Immune ResponseAbsence of Pathogenic Immune Response

Against Graft TissueAgainst Graft Tissue

With little or no Immune SuppressantWith little or no Immune Suppressant

With the Retention of Immune ResponsesWith the Retention of Immune ResponsesAgainst Other Infectious AntigensAgainst Other Infectious Antigens

Absence of Pathogenic Immune ResponseAbsence of Pathogenic Immune Response

Against Graft TissueAgainst Graft Tissue

With little or no Immune SuppressantWith little or no Immune Suppressant

With the Retention of Immune ResponsesWith the Retention of Immune ResponsesAgainst Other Infectious AntigensAgainst Other Infectious Antigens


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Help on the WayHelp on the Way

Adult bone-marrow-derived

mesenchymal stem cells are

immunosuppressive and prolong the

rejection of mismatched skin grafts in

animals. We transplanted haploidentical

mesenchymal stem cells in a patient with

severe treatment-resistant grade IV acute

graft-versus-host disease of the gut and

liver. Clinical response was striking. Thepatient is now well after 1 year. We

postulate that mesenchymal stem cells

have a potent immunosuppressive effect

in vivo.Lancet. 2004 May 1;363:1439-41.

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Immunosuppression and Transplantatio