Immunosuppression and Transplantation

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

E-mail: shiyu@umdnj.edu

Transplantation in ClinicTransplantation in Clinic

Body parts: Facial, Limbs,

Organs: Heart, kidney, liver

Tissue: Islets, hair follicles, bone, bone marrow

Cells: Stem cells, lymphocytes

Most surgical procedures are well established Most 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 difficult Skin is most difficult

Most surgical procedures are well established Most 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 difficult Skin is most difficult

Transplantation Hurdles Transplantation Hurdles

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

The 3rd Century,Saints Cosmas and Damian

Relationships between Donor and Relationships between Donor and RecipientRecipient

Relationships between Donor and Relationships 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.

Immunological Rejection Immunological 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 rejectione.g., Blood type mismatche.g., Blood type mismatch

Acute Graft RejectionAcute Graft RejectionDirect recognition of allogeinic MHC; rejection about 10 daysDirect recognition of allogeinic MHC; rejection about 10 days

Chronic rejectionChronic rejectionTake many months to years. Due to failure of Take many months to years. Due to failure of immunosuppressantsimmunosuppressants

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 rejectione.g., Blood type mismatche.g., Blood type mismatch

Acute Graft RejectionAcute Graft RejectionDirect recognition of allogeinic MHC; rejection about 10 daysDirect recognition of allogeinic MHC; rejection about 10 days

Chronic rejectionChronic rejectionTake many months to years. Due to failure of Take many months to years. Due to failure of immunosuppressantsimmunosuppressants

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 on immunologic 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 years later, 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, South Africa.

Milestones In Organ Transplantation (1)Source: National Kidney Foundation, Inc.

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 kidneys transplanted from these animals.

Milestones In Organ Transplantation (2)

Source: National Kidney Foundation, Inc.

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 of a combination of a specific fusion protein and a specific monoclonal antibody. Further trials are necessary to determine future applicability of the technique to humans.

Milestones In Organ Transplantation (3)

Source: National Kidney Foundation, Inc.

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

Simplified Schematic Representation of an Immune Response

Simplified Schematic Representation of an Immune Response

Class IClass I

MHC class II/peptidesMHC class II/peptidesAPCsAPCs

Protein antigens

CD8+ T cells

CD4+ T cells

B cellsB cells Plasma cellsPlasma cells

CD8+ cytolytic T cells

CD4CD4++ immune cells immune cells(delayed hypersensitivity)(delayed hypersensitivity)

antibodyproduction

proliferation & differentiation

IFN, IL-2

Cytokines

Costim. Mol.IL-4,-5,-6

proliferation & differentiation

APCClass II

proliferation & differentiation

© 2003 by LIPPINCOTT WILLIAMS & WILKINSFundamental Immunology

TCR Costimulation

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:CD244CD150, CD84, CD299, Ly-108, and BLAM

Some integrins: CD44, CD43, and heat-stable antigen (HSA).

CD

4

lck

fyn

Zap-70

Ras

Raf

Mek

MapK

Csk

PI3K

PLC

CD

28

PIP2

DAGIP3

Ca++ PKCGrb-2-SoS

CalcineurinCsA FK506

NF-AT

Immediate Early Genes

IL-2 Gene

Vav

SLP-76SHP-1

TCR Activation

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 T-cells to inhibit T-cell receptor CsA and FK506 act on T-cells to inhibit T-cell receptor activation and induction of cytokinesactivation and induction of cytokines

CsA may also inhibit IgE-stimulated mast cell degranulation CsA may also inhibit IgE-stimulated mast cell degranulation and stimulate TGF-and stimulate TGF- expression expression

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

Rapamycin and analogues are also used to sensitize cancer Rapamycin and analogues are also used to sensitize cancer cells to chemotherapeutic reagentscells to chemotherapeutic reagents

CsA and FK506 act on T-cells to inhibit T-cell receptor CsA and FK506 act on T-cells to inhibit T-cell receptor activation and induction of cytokinesactivation and induction of cytokines

CsA may also inhibit IgE-stimulated mast cell degranulation CsA may also inhibit IgE-stimulated mast cell degranulation and stimulate TGF-and stimulate TGF- expression expression

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

Rapamycin and analogues are also used to sensitize cancer Rapamycin and analogues are also used to sensitize cancer cells to chemotherapeutic reagentscells to chemotherapeutic reagents

FKBP

Rapamycin

mTor

FK506 Cyclosporine

Cyclophilin

Calcineurin

Cytokine Signaling NFAT Translocation

Genes lead to T cell Activation

Targets of Immunosuppressants

Target of Rapamycin

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

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

Newton, Thorax 2000;55:603-613

Biology of Glucocorticoids

Newton, Thorax 2000;55:603-613

Mechanisms of Glucocorticoid Action

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

Glucocorticoid-sensitive sites of the immune response

Glucocorticoid-sensitive sites of the immune response

MHC Class I/peptidesMHC Class I/peptidesAPCsAPCs

MHC Class II/peptidesMHC Class II/peptidesAPCsAPCs

Protein antigenProtein antigen

CD8 T-cellCD8 T-cell

CD4 T-cell(helper T-cells)

B-cellB-cell Plasma cellPlasma cell

CD8 cytolytic T-cellsCD8 cytolytic T-cells

CD4 immune cellCD4 immune cell(delayed hypersensitivity)(delayed hypersensitivity)

antibodyantibodyproductionproduction

proliferation & differentiation

proliferation

IL-2IL-2

IL-1IL-1

IL-1, -4,-5,-6IL-1, -4,-5,-6

proliferation & differentiation

GCX

X

GC

X

X

Use of Glucocorticoid as ImmunosuppressantsUse of Glucocorticoid as Immunosuppressants

Most widely used effective anti-inflammatory drugsMost widely used effective anti-inflammatory drugs Used with other immunophilin inhibitors to prevent Used with other immunophilin inhibitors to prevent

transplant rejection and GVHDtransplant rejection and GVHDnatural glucocorticoids not used due to natural glucocorticoids not used due to

mineralocorticoid activitymineralocorticoid activity PPrednisone and prednisolone are used orally at moderate rednisone and prednisolone are used orally at moderate

to high doses; Very high doses of to high doses; Very high doses of methylprednisolonemethylprednisolone used i.v. during acute organ rejectionused i.v. during acute organ rejection

Used before and after anti-thymocyte Abs to inhibit allergic Used before and after anti-thymocyte Abs to inhibit allergic reactionsreactions

Most widely used effective anti-inflammatory drugsMost widely used effective anti-inflammatory drugs Used with other immunophilin inhibitors to prevent Used with other immunophilin inhibitors to prevent

transplant rejection and GVHDtransplant rejection and GVHDnatural glucocorticoids not used due to natural glucocorticoids not used due to

mineralocorticoid activitymineralocorticoid activity PPrednisone and prednisolone are used orally at moderate rednisone and prednisolone are used orally at moderate

to high doses; Very high doses of to high doses; Very high doses of methylprednisolonemethylprednisolone used i.v. during acute organ rejectionused i.v. during acute organ rejection

Used before and after anti-thymocyte Abs to inhibit allergic Used before and after anti-thymocyte Abs to inhibit allergic reactionsreactions

General Principles of ImmunosuppressionGeneral Principles of Immunosuppression

Primary immune responses are more easily Primary immune responses are more easily suppressed than secondary (memory)suppressed than secondary (memory)

Different immunosuppressants have Different immunosuppressants have different effects on different immune different effects on different immune reactionsreactions

Suppression is more likely achieved if Suppression is more likely achieved if therapy begins before exposure to the therapy begins before exposure to the immunogenimmunogen

Primary immune responses are more easily Primary immune responses are more easily suppressed than secondary (memory)suppressed than secondary (memory)

Different immunosuppressants have Different immunosuppressants have different effects on different immune different effects on different immune reactionsreactions

Suppression is more likely achieved if Suppression is more likely achieved if therapy begins before exposure to the therapy begins before exposure to the immunogenimmunogen

Uses of Calcineurin inhibitors (TCR activation blockers)

Uses of Calcineurin inhibitors (TCR activation blockers)

Cyclosporine commonly used with prednisone Cyclosporine commonly used with prednisone and other immunosuppressants to prevent and other immunosuppressants to prevent allograft rejections in renal, hepatic and cardiac allograft rejections in renal, hepatic and cardiac transplants, and in RA and psoriasistransplants, and in RA and psoriasis use is delayed posttransplantation due to use is delayed posttransplantation due to

neurotoxicity concernsneurotoxicity concernsFK506 (Tacrolimus) is approved for prevention FK506 (Tacrolimus) is approved for prevention

of solid-organ allograft rejection, and eczema of solid-organ allograft rejection, and eczema (topical)(topical) Treatment begins prior to surgery, and is maintained Treatment begins prior to surgery, and is maintained

well afterwardswell afterwards

Cyclosporine commonly used with prednisone Cyclosporine commonly used with prednisone and other immunosuppressants to prevent and other immunosuppressants to prevent allograft rejections in renal, hepatic and cardiac allograft rejections in renal, hepatic and cardiac transplants, and in RA and psoriasistransplants, and in RA and psoriasis use is delayed posttransplantation due to use is delayed posttransplantation due to

neurotoxicity concernsneurotoxicity concernsFK506 (Tacrolimus) is approved for prevention FK506 (Tacrolimus) is approved for prevention

of solid-organ allograft rejection, and eczema of solid-organ allograft rejection, and eczema (topical)(topical) Treatment begins prior to surgery, and is maintained Treatment begins prior to surgery, and is maintained

well afterwardswell afterwards

Glucocorticoid effects related to Glucocorticoid effects related to immunosuppressionimmunosuppression

Glucocorticoid effects related to Glucocorticoid 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, but lymphopenia, monocytopenia, eosinopenia, but neutrophilia

Interference with APC, T-cell and macrophage Interference with APC, T-cell 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, but lymphopenia, monocytopenia, eosinopenia, but neutrophilia

Interference with APC, T-cell and macrophage Interference with APC, T-cell and macrophage functionsfunctions

Sirolimus (Rapamycin, Rapamune): Sirolimus (Rapamycin, Rapamune): a new T-cell blockera new T-cell blocker

Sirolimus (Rapamycin, Rapamune): Sirolimus (Rapamycin, Rapamune): a new T-cell blockera new T-cell blocker

different mechanism of actiondifferent mechanism of action blocks mTOR kinaseblocks mTOR kinase

similar poor bioavailability as cyclosporine and similar poor bioavailability as cyclosporine and tacrolimus, much longer half-life; 62 h v. 18 and 12 htacrolimus, much longer half-life; 62 h v. 18 and 12 h

same metabolism (CYP3A) and potential drug same metabolism (CYP3A) and potential drug interactionsinteractions

used for prophylaxis of organ transplant rejection in used for prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and combination with a calcineurin inhibitor and glucocorticoids glucocorticoids

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

thrombocytopenia, fever, GI effects, hyper- or thrombocytopenia, fever, GI effects, hyper- or hypokalemiahypokalemia

different mechanism of actiondifferent mechanism of action blocks mTOR kinaseblocks mTOR kinase

similar poor bioavailability as cyclosporine and similar poor bioavailability as cyclosporine and tacrolimus, much longer half-life; 62 h v. 18 and 12 htacrolimus, much longer half-life; 62 h v. 18 and 12 h

same metabolism (CYP3A) and potential drug same metabolism (CYP3A) and potential drug interactionsinteractions

used for prophylaxis of organ transplant rejection in used for prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and combination with a calcineurin inhibitor and glucocorticoids glucocorticoids

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

thrombocytopenia, fever, GI effects, hyper- or thrombocytopenia, fever, GI effects, hyper- or hypokalemiahypokalemia

Toxicity of GlucocorticoidsToxicity of GlucocorticoidsToxicity of GlucocorticoidsToxicity of Glucocorticoids

Major side effects are common due to high Major 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 high Major 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

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

Antineoplastic drugs will also prevent clonal Antineoplastic drugs will also prevent clonal

expansion of T- and B-cellsexpansion of T- and B-cells

azathioprine (prodrug of nucleotide anti-metabolite)azathioprine (prodrug of nucleotide anti-metabolite) mycophenolate mofetilmycophenolate mofetil

» becomes MPA; inhibits IMP dehydrogenasebecomes MPA; inhibits IMP dehydrogenase

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

Antineoplastic drugs will also prevent clonal Antineoplastic drugs will also prevent clonal

expansion of T- and B-cellsexpansion of T- and B-cells

azathioprine (prodrug of nucleotide anti-metabolite)azathioprine (prodrug of nucleotide anti-metabolite) mycophenolate mofetilmycophenolate mofetil

» becomes MPA; inhibits IMP dehydrogenasebecomes MPA; inhibits IMP dehydrogenase

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

Uses of cytotoxic agentsUses of cytotoxic agents

Azathioprine; with cyclosporine and/or prednisone Azathioprine; 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 and prednisone for renal transplantsprednisone for renal transplants

Cyclophosphamide; for BMTCyclophosphamide; for BMT

Methotrexate; GVHD prophylaxis Methotrexate; GVHD prophylaxis

Azathioprine; with cyclosporine and/or prednisone Azathioprine; 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 and prednisone for renal transplantsprednisone for renal transplants

Cyclophosphamide; for BMTCyclophosphamide; for BMT

Methotrexate; GVHD prophylaxis Methotrexate; GVHD prophylaxis

Bioactive Immunosuppressants Bioactive Immunosuppressants Bioactive Immunosuppressants Bioactive Immunosuppressants

Anti-thymocyte antibodiesAnti-thymocyte antibodies

3 types available3 types available» all derived from non-human sourcesall derived from non-human sources

Rh(D) immune globulinRh(D) immune globulin

OKT3, OKT4, Anti-CD20, anti-TNF, anti-ICAMs, and CTLA4-OKT3, OKT4, Anti-CD20, anti-TNF, anti-ICAMs, and CTLA4-IgIg

Repeated blood transfusion; transfusion of apoptotic cellsRepeated blood transfusion; transfusion of apoptotic cells

Anti-thymocyte antibodiesAnti-thymocyte antibodies

3 types available3 types available» all derived from non-human sourcesall derived from non-human sources

Rh(D) immune globulinRh(D) immune globulin

OKT3, OKT4, Anti-CD20, anti-TNF, anti-ICAMs, and CTLA4-OKT3, OKT4, Anti-CD20, anti-TNF, anti-ICAMs, and CTLA4-IgIg

Repeated blood transfusion; transfusion of apoptotic cellsRepeated blood transfusion; transfusion of apoptotic cells

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 Graft Inhibition of Antibody Production, Prolongation of Skin Graft SurvivalSurvival

6-MP6-MPSchwartz,DameshekSchwartz,Dameshek19591959

Prolongation of Mouse Skin Graft SurvivalProlongation of Mouse Skin Graft SurvivalX-irradiation+BMTX-irradiation+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 Clinical Experiment or Clinical applicationapplication

authorauthorTimeTime

Became a Clinical RoutineBecame a Clinical RoutineAza+CorticosteroidAza+CorticosteroidStarzlStarzl19631963

Prolongation of Cadaveric Kidney Graft SurvivalProlongation of Cadaveric Kidney Graft SurvivalTLI+6-MPTLI+6-MPKussKuss19601960

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

ResultsResultsExperiment or Experiment 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 Graft Enhanced Survival Rate of Cadaveric Kidney Graft by 20%by 20%

Prooperative Blood Prooperative Blood TransfusionTransfusion

OpelzOpelz19731973

To Replace Aza When Severely ToxicTo Replace Aza When Severely ToxicCHXCHXStarzlStarzl19701970

No Obvious EffectNo Obvious EffectIrradiation of Cadaveric Irradiation of Cadaveric KidneyKidney

WolfWolf19691969

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

Prolongation of Graft Survival of Mouse Skin and Prolongation of Graft Survival of Mouse Skin and Canine KidneyCanine Kidney

ALSALSRussell MonacoRussell Monaco19671967

Transient EffectTransient Effect ，， Technical DifficultyTechnical DifficultyThoracic Duct DrainageThoracic Duct DrainageMcGregor,GowansMcGregor,Gowans19641964

Not so Good, Seldom UsedNot so Good, Seldom UsedPreoperative Preoperative SplenectomySplenectomy

SrarzlSrarzl19631963

Currently Used ImmunosuppressantsCurrently Used ImmunosuppressantsCurrently Used ImmunosuppressantsCurrently Used Immunosuppressants

Chinese MedicineChinese Medicine

CsA FK506CsA FK506 RapamicinRapamicin ，， Cellcept Cellcept ((mycophenolate mofetil )

Fungus ProductsFungus Products

ALG (anti-lymphocyte globulinsALG (anti-lymphocyte globulins), ), ATG (anti-ATG (anti-thymocyte globulins), OKT3thymocyte globulins), OKT3

Biological AgentsBiological Agents

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

Azathioprin (Azathioprin (Aza)Aza)Antimetabolic AgentAntimetabolic Agent

CyclophosphamideCyclophosphamideAlkyl AgentAlkyl Agent

DrugsDrugs CategoryCategory

Ideal ImmunosuppressantIdeal Immunosuppressant

Strongly ImmunosuppressiveStrongly ImmunosuppressiveSpecific, No Overall ImmunosuppressionSpecific, No Overall ImmunosuppressionAnti-infection abilityAnti-infection abilityLow Toxicity for Vital OrgansLow Toxicity for Vital OrgansLow costLow costLong Long in vivoin vivo bioactivity bioactivityEasy to useEasy to use

Strongly ImmunosuppressiveStrongly ImmunosuppressiveSpecific, No Overall ImmunosuppressionSpecific, No Overall ImmunosuppressionAnti-infection abilityAnti-infection abilityLow Toxicity for Vital OrgansLow Toxicity for Vital OrgansLow costLow costLong Long in vivoin vivo bioactivity bioactivityEasy to useEasy to use

Clinical Tolerance EstablishedClinical Tolerance Established

Absence of Pathogenic Immune Response Against Absence of Pathogenic Immune Response Against Graft TissueGraft Tissue

With little or no Immune SuppressantWith little or no Immune Suppressant

With the Retention of Immune Responses Against With the Retention of Immune Responses Against Other Infectious AntigensOther Infectious Antigens

Absence of Pathogenic Immune Response Against Absence of Pathogenic Immune Response Against Graft TissueGraft Tissue

With little or no Immune SuppressantWith little or no Immune Suppressant

With the Retention of Immune Responses Against With the Retention of Immune Responses Against Other Infectious AntigensOther Infectious Antigens

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. The patient 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.