Immunosuppression and Transplantation
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Transcript of Immunosuppression and Transplantation
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.