Immunology1 Transplantation Immunology Transplantation Immunology.

ImmunologyImmunology 11

Transplantation Transplantation

ImmunologyImmunology


IntroductionIntroduction


ConceptionsConceptions

• TransplantationTransplantation

• GraftsGrafts

• DonorsDonors

• Recipients or hostsRecipients or hosts

• Orthotopic transplantationOrthotopic transplantation

• Heterotopic transplantation Heterotopic transplantation


Nobel Prize in Physiology or Medicine Nobel Prize in Physiology or Medicine 19121912

• Alexis Carrel (France)Alexis Carrel (France)

• Work on vascular suture Work on vascular suture and the transplantation and the transplantation of blood vessels and of blood vessels and organsorgans

Great events in history of transplantation



• Peter Brian Medawar Peter Brian Medawar (1/2) (1/2)

• Discovery of acquired Discovery of acquired immunological tolerance immunological tolerance – The graft reaction is an The graft reaction is an

immunity phenomenon immunity phenomenon – 1950s,1950s, induced induced

immunological tolerance to immunological tolerance to skin allografts in mice by skin allografts in mice by neonatal injection of neonatal injection of allogeneic cellsallogeneic cells




• Joseph E. Murray Joseph E. Murray (1/2)(1/2) • Discoveries concerning Discoveries concerning

organ transplantation in organ transplantation in the treatment of human the treatment of human disease disease – In 1954, the first successful In 1954, the first successful

human kidney transplant human kidney transplant was performed between was performed between twins in Boston. twins in Boston.

– Transplants were possible in Transplants were possible in unrelated people if drugs unrelated people if drugs were taken to suppress the were taken to suppress the body's immune reactionbody's immune reactionGreat events in history of transplantation


Nobel Prize in Physiology or Nobel Prize in Physiology or Medicine 1980Medicine 1980

• George D. Snell George D. Snell (1/3),(1/3), Jean Dausset Jean Dausset (1/3)(1/3)

• Discoveries concerning genetically Discoveries concerning genetically determined structures on the cell surface determined structures on the cell surface that regulate immunological reactions that regulate immunological reactions – H-genes (histocompatibility genes), H-2 gene H-genes (histocompatibility genes), H-2 gene – Human transplantation antigens (HLA) ----MHCHuman transplantation antigens (HLA) ----MHC



Nobel Prize in Physiology or Nobel Prize in Physiology or Medicine 1988Medicine 1988

• Gertrude B. Elion Gertrude B. Elion (1/3)(1/3) , George H. Hitchings , George H. Hitchings (1/3)(1/3)

• Discoveries of important principles for drug Discoveries of important principles for drug treatment treatment – Immunosuppressant drug (The first cytotoxic drugs) Immunosuppressant drug (The first cytotoxic drugs)

----- azathioprine----- azathioprine



Today, kidney, pancreas, heart, Today, kidney, pancreas, heart, lung, liver, bone marrow, and lung, liver, bone marrow, and cornea transplantations are cornea transplantations are performed among non-identical performed among non-identical individuals with ever increasing individuals with ever increasing frequency and successfrequency and success


Classification of graftsClassification of grafts• Autologous grafts (Autografts)Autologous grafts (Autografts)

– Grafts transplanted from one part of the Grafts transplanted from one part of the body to another in the same individualbody to another in the same individual

• Syngeneic grafts (Isografts) Syngeneic grafts (Isografts) – Grafts transplanted between two genetically Grafts transplanted between two genetically

identical individuals of the same species identical individuals of the same species

• Allogeneic grafts (Allografts)Allogeneic grafts (Allografts)– Grafts transplanted between two genetically Grafts transplanted between two genetically

different individuals of the same species different individuals of the same species

• Xenogeneic grafts (Xenografts) Xenogeneic grafts (Xenografts) – Grafts transplanted between individuals of Grafts transplanted between individuals of

different speciesdifferent species



• Grafts rejection is a kind of specific Grafts rejection is a kind of specific immune responseimmune response– SpecificitySpecificity– Immune memory Immune memory

• Grafts rejectionGrafts rejection– First set rejectionFirst set rejection– Second set rejectionSecond set rejection

First- and Second-set Allograft First- and Second-set Allograft RejectionRejection



Part onePart one

Immunological Basis of Immunological Basis of Allograft RejectionAllograft Rejection


• Major histocompatibility antigens Major histocompatibility antigens (MHC molecules)(MHC molecules)

• Minor histocompatibility antigensMinor histocompatibility antigens

• Other alloantigensOther alloantigens

I. Transplantation antigensI. Transplantation antigens


1. Major histocompatibility 1. Major histocompatibility antigensantigens

• Main antigens of grafts rejection Main antigens of grafts rejection

• Cause fast and strong rejectionCause fast and strong rejection

• Difference of HLA types is the main Difference of HLA types is the main cause of human grafts rejectioncause of human grafts rejection


2. Minor histocompatibility 2. Minor histocompatibility antigensantigens

• Also cause grafts rejection, but slow Also cause grafts rejection, but slow and weakand weak

• Mouse H-Y antigens encoded by Y Mouse H-Y antigens encoded by Y chromosome chromosome

• HA-1HA-1 ～～ HA-5 linked with non-Y HA-5 linked with non-Y chromosome chromosome



3. Other alloantigens3. Other alloantigens

• Human ABO blood group antigens Human ABO blood group antigens

• Some tissue specific antigensSome tissue specific antigens– SkinSkin ＞＞ kidneykidney ＞＞ heartheart ＞＞ pancreas pancreas ＞＞

liverliver– VEC antigen VEC antigen – SK antigen SK antigen


• Cell-mediated Immunity Cell-mediated Immunity

• Humoral Immunity Humoral Immunity

• Role of NK cellsRole of NK cells

II. Mechanism of allograft II. Mechanism of allograft rejectionrejection


1. Cell-mediated Immunity1. Cell-mediated Immunity

• Recipient's T cell-mediated cellular Recipient's T cell-mediated cellular immune response against immune response against alloantigens on graftsalloantigens on grafts


Molecular Mechanisms of Molecular Mechanisms of Allogeneic RecognitionAllogeneic Recognition

？？ T cells of the recipient recognize the T cells of the recipient recognize the allogenetic MHC moleculesallogenetic MHC molecules

？？ Many T cells can recognize Many T cells can recognize allogenetic MHC moleculesallogenetic MHC molecules– 1010-5-5-10-10-4 -4 of specific T cells recognize of specific T cells recognize

conventional antigensconventional antigens– 1%-10% of T cells recognize allogenetic 1%-10% of T cells recognize allogenetic

MHC moleculesMHC molecules


？？ The recipientThe recipient’’ T cells recognize T cells recognize the the allogeneticallogenetic MHC molecules MHC molecules

• Direct Recognition Direct Recognition

• Indirect RecognitionIndirect Recognition


Direct RecognitionDirect Recognition

• Recognition of an intact allogenetic MHC Recognition of an intact allogenetic MHC molecule displayed by donor APC in the graftmolecule displayed by donor APC in the graft

• Cross recognitionCross recognition– An allogenetic MHC molecule with a bound An allogenetic MHC molecule with a bound

peptide can mimic the determinant formed by a peptide can mimic the determinant formed by a self MHC molecule plus foreign peptideself MHC molecule plus foreign peptide

– A cross-reaction of a normal TCR, which was A cross-reaction of a normal TCR, which was selected to recognize a self MHC molecules plus selected to recognize a self MHC molecules plus foreign peptide, with an allogenetic MHC foreign peptide, with an allogenetic MHC molecule plus peptidemolecule plus peptide


• Cross recognitionCross recognition


• Passenger leukocytesPassenger leukocytes– Donor APCs that exist in grafts, such as Donor APCs that exist in grafts, such as

DC, MΦDC, MΦ– Early phase of acute rejectionEarly phase of acute rejection– Fast and strongFast and strong


？？ Many T cells can recognize Many T cells can recognize allogenetic MHC moleculesallogenetic MHC molecules

• Allogenetic MHC molecules (different Allogenetic MHC molecules (different residues)residues)

• Allogenetic MHC molecules–different Allogenetic MHC molecules–different peptidespeptides

• All allogenetic MHC molecules on donor APC All allogenetic MHC molecules on donor APC can be epitopes recognized by TCRcan be epitopes recognized by TCR


Indirect recognitionIndirect recognition

• Uptake and presentation of Uptake and presentation of allogeneic donor MHC molecules by allogeneic donor MHC molecules by recipient APC in recipient APC in ““ normal waynormal way””

• Recognition by T cells like Recognition by T cells like conventional foreign antigensconventional foreign antigens



• Slow and weakSlow and weak

• Late phase of acute rejection and chronic Late phase of acute rejection and chronic rejection rejection

• Coordinated function with direct recognition Coordinated function with direct recognition in early phase of acute rejectionin early phase of acute rejection


Difference between Direct Recognition Difference between Direct Recognition and Indirect Recognitionand Indirect Recognition

Direct Direct RecognitionRecognition

Indirect Indirect RecognitionRecognition

Allogeneic MHC Allogeneic MHC moleculemolecule

Intact allogeneic Intact allogeneic MHC moleculeMHC molecule

Peptide of allogeneic Peptide of allogeneic MHC moleculeMHC molecule

APCsAPCs Recipient APCs are Recipient APCs are not necessarynot necessary

Recipient APCsRecipient APCs

Activated T cellsActivated T cells CD4CD4 ＋＋ T cells and/or T cells and/or CD8CD8 ＋＋ T cellsT cells

CD4CD4 ＋＋ T cells and/or T cells and/or CD8CD8 ＋＋ T cellsT cells

Roles in rejectionRoles in rejection Acute rejectionAcute rejection Chronic rejectionChronic rejection

Degree of rejectionDegree of rejection VigorousVigorous WeakWeak


• Activated CD4Activated CD4++T by direct and indirect T by direct and indirect recognitionrecognition– CK secretionCK secretion– MMΦΦ activation and recruitment activation and recruitment

• Activated CD8Activated CD8++T by direct recognitionT by direct recognition– Kill the graft cells directlyKill the graft cells directly

• Activated CD8Activated CD8++T by indirect recognitionT by indirect recognition– Can not kill the graft cells directlyCan not kill the graft cells directly

Role of CD4Role of CD4 ＋＋ T cells and CD8T cells and CD8 ＋＋ T T cellscells



• Important role in hyperacute Important role in hyperacute rejectionrejection

(Preformed antibodies)(Preformed antibodies)– Complements activationComplements activation– ADCCADCC– OpsonizationOpsonization

• Enhancing antibodiesEnhancing antibodies

/Blocking antibodies/Blocking antibodies

2. Humoral immunity2. Humoral immunity


3 .Role of NK cells3 .Role of NK cells

• CKs secreted by activated Th cells CKs secreted by activated Th cells can promote NK activationcan promote NK activation


Part twoPart two

Classification and Classification and Effector Mechanisms of Effector Mechanisms of

Allograft RejectionAllograft Rejection


• Host versus graft reaction (HVGR) Host versus graft reaction (HVGR) – Conventional organ transplantationConventional organ transplantation

• Graft versus host reaction (GVHR)Graft versus host reaction (GVHR)– Bone marrow transplantationBone marrow transplantation– Immune cells transplantationImmune cells transplantation

Classification of AllograftClassification of Allograft RejectionRejection


I. Host versus graft I. Host versus graft reaction (HVGR)reaction (HVGR)

• Hyperacute rejectionHyperacute rejection

• Acute rejectionAcute rejection

• Chronic rejectionChronic rejection


• Occurrence timeOccurrence time– Occurs within minutes to hours after host Occurs within minutes to hours after host

blood vessels are anastomosed to graft blood vessels are anastomosed to graft vesselsvessels

• Pathology Pathology – Thrombotic occlusion of the graft Thrombotic occlusion of the graft

vasculature vasculature – Ischemia, denaturation, necrosis Ischemia, denaturation, necrosis

1. Hyperacute rejection1. Hyperacute rejection


• MechanismsMechanisms– Preformed antibodies Preformed antibodies

•Antibody against ABO blood type Antibody against ABO blood type antigenantigen

•Antibody against VEC antigen Antibody against VEC antigen

•Antibody against HLA antigenAntibody against HLA antigen


– Complement activationComplement activation•Endothelial cell damageEndothelial cell damage

– Platelets activationPlatelets activation•Thrombosis, vascular occlusion, ischemic Thrombosis, vascular occlusion, ischemic

damage damage


• Occurrence timeOccurrence time– Occurs within days to 2 weeks after Occurs within days to 2 weeks after

transplantation, 80-90% of cases occur transplantation, 80-90% of cases occur within 1 month within 1 month

• PathologyPathology– Acute humoral rejectionAcute humoral rejection

•Acute vasculitis manifested mainly by Acute vasculitis manifested mainly by endothelial cell damageendothelial cell damage

– Acute cellular rejectionAcute cellular rejection•Parenchymal cell necrosis along with Parenchymal cell necrosis along with

infiltration of lymphocytes and MΦinfiltration of lymphocytes and MΦ

2. Acute rejection2. Acute rejection

Hyperacute Rejection: the Hyperacute Rejection: the early daysearly days

• Mediated by pre-existing IgM Mediated by pre-existing IgM alloantibodiesalloantibodies

• Antibodies come from carbohydrate Antibodies come from carbohydrate antigens expressed by bacteria in antigens expressed by bacteria in intestinal floraintestinal flora– ABO blood group antigensABO blood group antigens

• Not really a problem anymoreNot really a problem anymore

Hyperacute Rejection: Hyperacute Rejection: TodayToday

• Mediated by IgG antibodies directed Mediated by IgG antibodies directed against protein alloantigensagainst protein alloantigens

• Antibodies generally arise fromAntibodies generally arise from– Past blood transfusionPast blood transfusion– Multiple pregnanciesMultiple pregnancies– Previous transplantationPrevious transplantation


• Mechanisms Mechanisms – Vasculitis Vasculitis

• IgG antibodies against alloantigens on IgG antibodies against alloantigens on endothelial cell endothelial cell

– Parenchymal cell damage Parenchymal cell damage •Delayed hypersensitivity mediated by Delayed hypersensitivity mediated by

CD4+Th1CD4+Th1•Killing of graft cells by CD8+TcKilling of graft cells by CD8+Tc



• Occurrence in timeOccurrence in time– Develops months or years after acute Develops months or years after acute

rejection reactions have subsidedrejection reactions have subsided

• PathologyPathology– Fibrosis and vascular abnormalities with Fibrosis and vascular abnormalities with

loss of graft functionloss of graft function

3. Chronic rejection3. Chronic rejection


• Mechanisms Mechanisms – Not clearNot clear– Extension and results of cell necrosis in Extension and results of cell necrosis in

acute rejectionacute rejection– Chronic inflammation mediated by Chronic inflammation mediated by

CD4+T cell/MΦCD4+T cell/MΦ– Organ degeneration induced by non Organ degeneration induced by non

immune factorsimmune factors



Kidney Transplantation----Graft Rejection


Chronic rejection in a kidney allograft with arteriosclerosis


II.Graft versus host II.Graft versus host reaction (GVHR)reaction (GVHR)

• Graft versus host reaction (GVHR) Graft versus host reaction (GVHR) – Allogenetic bone marrow transplantationAllogenetic bone marrow transplantation– Rejection to host alloantigensRejection to host alloantigens– Mediated by immune competent cells in Mediated by immune competent cells in

bone marrowbone marrow

• Graft versus host disease (GVHD)Graft versus host disease (GVHD)– A disease caused by GVHR, which can A disease caused by GVHR, which can

damage the hostdamage the host


• Graft versus host disease Graft versus host disease


• Graft versus host diseaseGraft versus host disease


ConditionsConditions

• Enough immune competent cells in Enough immune competent cells in graftsgrafts

• Immunocompromised hostImmunocompromised host

• Histocompatability differences between Histocompatability differences between host and grafthost and graft


• Bone marrow transplantation Bone marrow transplantation

• Thymus transplantationThymus transplantation

• Spleen transplantationSpleen transplantation

• Blood transfusion of neonateBlood transfusion of neonate

In most cases the reaction is directed In most cases the reaction is directed against minor histocompatibility against minor histocompatibility antigens of the hostantigens of the host


1. Acute GVHD1. Acute GVHD

• Endothelial cell death in the skin, Endothelial cell death in the skin, liver, and gastrointestinal tractliver, and gastrointestinal tract

• Rash, jaundice, diarrhea, Rash, jaundice, diarrhea, gastrointestinal hemorrhage gastrointestinal hemorrhage

• Mediated by mature T cells in the Mediated by mature T cells in the graftsgrafts


• Acute graft-versus-host reaction with Acute graft-versus-host reaction with vivid palmar erythemavivid palmar erythema


2. Chronic GVHD2. Chronic GVHD

• Fibrosis and atrophy of one or more Fibrosis and atrophy of one or more of the organsof the organs

• Eventually complete dysfunction of Eventually complete dysfunction of the affected organ the affected organ


Both acute and chronic GVHD are Both acute and chronic GVHD are commonly treated with intense commonly treated with intense immunosuppresionimmunosuppresion

• UncertainUncertain

• Fatal Fatal


Part threePart three

Prevention and Therapy Prevention and Therapy of Allograft Rejectionof Allograft Rejection


• Tissue TypingTissue Typing

• Immunosuppressive TherapyImmunosuppressive Therapy

• Induction of Immune ToleranceInduction of Immune Tolerance


I. Tissue TypingI. Tissue Typing

• ABO and Rh blood typingABO and Rh blood typing

• Crossmatching (Preformed Crossmatching (Preformed antibodies)antibodies)

• HLA typing HLA typing – HLA-A and HLA-BHLA-A and HLA-B– HLA-DRHLA-DR


• Laws of transplantationLaws of transplantation


II. Immunosuppressive II. Immunosuppressive TherapyTherapy

• Cyclosporine(CsA), FK506Cyclosporine(CsA), FK506– Inhibits NFAT transcription factorInhibits NFAT transcription factor

• Azathioprine, CyclophosphamideAzathioprine, Cyclophosphamide– Block the proliferation of lymphocytes Block the proliferation of lymphocytes

• Ab against T cell surface molecules Ab against T cell surface molecules – Anti-CD3 mAb----Deplete T cellsAnti-CD3 mAb----Deplete T cells

• Anti-inflammatory agents Anti-inflammatory agents – Corticosteroids----Block the synthesis and Corticosteroids----Block the synthesis and

secretion of cytokinessecretion of cytokines


Removal of T cells from marrow graft


III.III. Induction of Immune Induction of Immune ToleranceTolerance

• Inhibition of T cell activationInhibition of T cell activation– SSoluble MHC moleculesoluble MHC molecules– CTLA4-Ig CTLA4-Ig – Anti-IL2R mAbAnti-IL2R mAb

• Th2 cytokinesTh2 cytokines– Anti-TNF-αAnti-TNF-α ，， Anti-IL-2Anti-IL-2 ，， Anti-IFN-γ mAbAnti-IFN-γ mAb

• MicrochimerismMicrochimerism– The presence of a small number of cells of The presence of a small number of cells of

donor, genetically distinct from those of donor, genetically distinct from those of the host individualthe host individual


Part IVPart IV

XenotransplantationXenotransplantation


•Lack of organs for Lack of organs for transplantationtransplantation

•Pig-human xenotransplantationPig-human xenotransplantation

•Barrier Barrier


• Hyperacute xenograft rejection (HXR)Hyperacute xenograft rejection (HXR)– Human anti-pig nature Abs reactive Human anti-pig nature Abs reactive

with Galα1,3Galwith Galα1,3Gal– Construct transgenic pigs expressing Construct transgenic pigs expressing

human proteins that inhibit complement human proteins that inhibit complement activationactivation

• Delayed xenograft rejection (DXR) Delayed xenograft rejection (DXR) – Acute vascular rejectionAcute vascular rejection– Incompletely understood Incompletely understood

• T cell-mediated xenograft rejectionT cell-mediated xenograft rejection

Bone Marrow Bone Marrow TransplantationTransplantation

• Rescue procedure for hemopoietic Rescue procedure for hemopoietic reconstitution subsequent to cancer reconstitution subsequent to cancer chemo- or radio- therapychemo- or radio- therapy

Graft vs. Host DiseaseGraft vs. Host Disease

• Caused by the reaction of grafted mature Caused by the reaction of grafted mature T-cells in the marrow inoculum with T-cells in the marrow inoculum with alloantigens of the hostalloantigens of the host

• Acute GVHDAcute GVHD– Characterized by epithelial cell death in the Characterized by epithelial cell death in the

skin, GI tract, and liverskin, GI tract, and liver

• Chronic GVHDChronic GVHD– Characterized by atrophy and fibrosis of one Characterized by atrophy and fibrosis of one

or more of these same target organs as well or more of these same target organs as well as the lungsas the lungs

Heart TransplantationHeart Transplantation

Heart transplantation is indicated Heart transplantation is indicated for those in end-stage heart for those in end-stage heart disease with a New York Heart disease with a New York Heart Association of class III or IV,Association of class III or IV,

ejection fractions of <20%, ejection fractions of <20%, maximal oxygen consumption of maximal oxygen consumption of

(VO(VO22) <14 ml/kg/min, and ) <14 ml/kg/min, and expected 1-year life expectancy of expected 1-year life expectancy of

<50%. <50%.

IntroductionIntroduction

• More than 4000 patients in the United States More than 4000 patients in the United States are registered with the United Organ Sharing are registered with the United Organ Sharing Network (UNOS) for cardiac transplantation.Network (UNOS) for cardiac transplantation.

• There are only about 2500 heart donors There are only about 2500 heart donors yearly.yearly.

• Scarcity of donors is complicated by the use Scarcity of donors is complicated by the use of single organs, heart injury with common of single organs, heart injury with common brain-death injuries, difficulty with ex-vivo brain-death injuries, difficulty with ex-vivo preservation, heart disease among donors, preservation, heart disease among donors, and the complexity of the operation. and the complexity of the operation.

Matching Donor and RecipientMatching Donor and Recipient

• Because ischemic time during cardiac transplantation Because ischemic time during cardiac transplantation is crucial, donor recipient matching is based primarily is crucial, donor recipient matching is based primarily not on HLA typing but on the severity of illness, ABO not on HLA typing but on the severity of illness, ABO blood type (match or compatible), response to PRA, blood type (match or compatible), response to PRA, donor weight to recipient ratio (must be 75% to 125%), donor weight to recipient ratio (must be 75% to 125%), geographic location relative to donor, and length of geographic location relative to donor, and length of time at current status. time at current status.

• The PRA is a rapid measurement of preformed reactive The PRA is a rapid measurement of preformed reactive anti-HLA antibodies in the transplant recipient. In anti-HLA antibodies in the transplant recipient. In general PRA < 10 to 20% then no cross-match is general PRA < 10 to 20% then no cross-match is necessary. If PRA is > 20% then a T and B-cell cross-necessary. If PRA is > 20% then a T and B-cell cross-match should be performed. match should be performed.

• Patients with elevated PRA will need plasmapheresis, Patients with elevated PRA will need plasmapheresis, immunoglobulins, or immunosuppresive agents to immunoglobulins, or immunosuppresive agents to lower PRA. lower PRA.

Heart TransplantationHeart Transplantation

Survival is 80% at five years but at five Survival is 80% at five years but at five year 50% also have coronary vascular year 50% also have coronary vascular disease due to chronic rejection.disease due to chronic rejection.

Immunosuppressive AgentsImmunosuppressive Agents

• Azathioprine: purine analogue that works Azathioprine: purine analogue that works by nonspecific suppression of T and B-cell by nonspecific suppression of T and B-cell lymphocyte proliferation.lymphocyte proliferation.

• Dosage is 1 to 2 mg/kg per day.Dosage is 1 to 2 mg/kg per day.

• Side effects are bone marrow suppression (dose Side effects are bone marrow suppression (dose related), increased incidence of skin cancer (use related), increased incidence of skin cancer (use sunscreen), cutaneous fungal infections, and rarely sunscreen), cutaneous fungal infections, and rarely liver toxicity and pancreatitis.liver toxicity and pancreatitis.

• Drug interactions: allopurinol (decrease dose by 75%) Drug interactions: allopurinol (decrease dose by 75%) and TMP/Sulfa (worsens thrombocytopenia).and TMP/Sulfa (worsens thrombocytopenia).


• Cyclosporin: inhibits T-cell lymphokine production. Cyclosporin: inhibits T-cell lymphokine production. Highly lipophilic.Highly lipophilic.

• Dosage is 8 to 10mg/kg/day in 2 divided doses. IV doses are 1/3 of Dosage is 8 to 10mg/kg/day in 2 divided doses. IV doses are 1/3 of oral doses in a continuous infusion. oral doses in a continuous infusion.

• Drug levels are frequently measured for dosage and toxicity, but Drug levels are frequently measured for dosage and toxicity, but levels are not highly predictive of actual immunosuppressive levels are not highly predictive of actual immunosuppressive effect. Drug levels are reflected for 5 to 10 days because of a long effect. Drug levels are reflected for 5 to 10 days because of a long half life. half life.

• Side effects: nephrotoxicity caused by afferent arteriolar Side effects: nephrotoxicity caused by afferent arteriolar constriction and manifested by oliguria. Loop diuretics may constriction and manifested by oliguria. Loop diuretics may exacerbate this side effect. Dosage adjustments should only be exacerbate this side effect. Dosage adjustments should only be made if creatinine level is >3.0mg/dL (some renal insufficiency is made if creatinine level is >3.0mg/dL (some renal insufficiency is expected). Other side effects include hypertension, hypertrichosis, expected). Other side effects include hypertension, hypertrichosis, tremor, hyperkalemia, hyperlipidemia, and hyperuricemia. tremor, hyperkalemia, hyperlipidemia, and hyperuricemia.

• Multiple drug interactions. Multiple drug interactions.


• Corticosteroids: immunosuppressives of Corticosteroids: immunosuppressives of uncertain mechanism. Used for uncertain mechanism. Used for maintenance of immunosuppression and maintenance of immunosuppression and to manage acute rejections.to manage acute rejections.

• High doses used initially tapered over the 1High doses used initially tapered over the 1stst 6 6 months to 5 to 15mg/d prednisone.months to 5 to 15mg/d prednisone.

• Side effects include mood and sleep disturbances, Side effects include mood and sleep disturbances, acne, weight gain, obesity, hypertension, osteopenia, acne, weight gain, obesity, hypertension, osteopenia, and hyperglycemia.and hyperglycemia.


• Mycophenolate mofetil: selectively inhibits Mycophenolate mofetil: selectively inhibits lymphocyte proliferation. lymphocyte proliferation.

• Dosage is 2g/d po. Dosage is 2g/d po.

• Side effects include GI disturbances. Does not cause Side effects include GI disturbances. Does not cause significant bone marrow suppression. significant bone marrow suppression.

• FK-506 (tacrolimus): Lymphophilic FK-506 (tacrolimus): Lymphophilic macrolide that inhibits lymphokine macrolide that inhibits lymphokine production similar to cyclosporine. production similar to cyclosporine.

• More toxic than cyclosporine. More toxic than cyclosporine.

• Side effects include nephrotoxicity and neuotoxicity. Side effects include nephrotoxicity and neuotoxicity.


• Antilymphocyte globulin: Horse polyclonal Antilymphocyte globulin: Horse polyclonal antibody designed to inhibit T cells by antibody designed to inhibit T cells by binding to surface antigens. binding to surface antigens.

• It is generally used at the time of transplantation for It is generally used at the time of transplantation for induction therapy or during acute rejections. induction therapy or during acute rejections.

• Dosage is 10 to 15 mg/kg qd through a central Dosage is 10 to 15 mg/kg qd through a central venous catheter.venous catheter.

• Goal is to keep T lymphocyte count Goal is to keep T lymphocyte count ~200cells/microL. ~200cells/microL.

• Side effects include fevers, chills, urticaria, serum Side effects include fevers, chills, urticaria, serum sickness, and thrombocytopenia.sickness, and thrombocytopenia.


• Muromonab-CD3 (OKT3): a murine monoclonal Muromonab-CD3 (OKT3): a murine monoclonal antibody to the CD3 complex on the T-cell antibody to the CD3 complex on the T-cell lymphocyte designed for selective T-cell lymphocyte designed for selective T-cell depletion.depletion.

• Usual dose is 5mg/d IV bolus over 10 to 14 days. Usual dose is 5mg/d IV bolus over 10 to 14 days. • CD3 cells are monitored with goal <25cells/mL. CD3 cells are monitored with goal <25cells/mL. • Used in patients with renal insufficiency. Used in patients with renal insufficiency. • Side effects include cytokine release syndrome (fever, Side effects include cytokine release syndrome (fever,

chills, nausea, vomiting, mylagia, diarrhea, weakness, chills, nausea, vomiting, mylagia, diarrhea, weakness, bronchospasm, and hypotension), pulmonary edema. bronchospasm, and hypotension), pulmonary edema.

• Rapamycin: Similar mechanism of action of FK-Rapamycin: Similar mechanism of action of FK-506 except that it antagonizes the proliferation of 506 except that it antagonizes the proliferation of nonimmune cells such as endothelial cells, nonimmune cells such as endothelial cells, fibroblasts, and smooth muscle cells. fibroblasts, and smooth muscle cells.

• Not routinely used at present. Not routinely used at present. • May have a roal in prevention of immunologically mediated May have a roal in prevention of immunologically mediated

coronary allograft vasculopathy.coronary allograft vasculopathy.

Basic Drug RegimenBasic Drug Regimen

• ImmunosuppressivesImmunosuppressives

• Antibiotic prophylaxis Antibiotic prophylaxis • PCP: TMP/Sulfa or Dapsone or Pentamidine aerosols. PCP: TMP/Sulfa or Dapsone or Pentamidine aerosols.

• CMV infection: Ganglyclovir, acyclovir. CMV infection: Ganglyclovir, acyclovir.

• Fungal infections: Nystatin.Fungal infections: Nystatin.

• AntihypertensivesAntihypertensives

• Diuretics as neededDiuretics as needed

• Potassium and Magnesium replacement (cyclosporin leads to Potassium and Magnesium replacement (cyclosporin leads to wasting of thes electrolytes.wasting of thes electrolytes.

• Lipid-lowering agents. (Avoid allograft vasculopathy).Lipid-lowering agents. (Avoid allograft vasculopathy).

• Glucose lowering agents (DM and steroids)Glucose lowering agents (DM and steroids)

• Anticoagulation if transplant heterotopic.Anticoagulation if transplant heterotopic.

• Cyclosporin dose lowering meds (Diltiazem / Verapamil / Cyclosporin dose lowering meds (Diltiazem / Verapamil / Theophyilline)Theophyilline)

Complications - RejectionComplications - Rejection

• Avoidance with preoperative therapy with Avoidance with preoperative therapy with cyclosporin, corticosteroids, and azathioprine.cyclosporin, corticosteroids, and azathioprine.

• If rejection is suspected then workup should If rejection is suspected then workup should include: measurement of cyclosporine level include: measurement of cyclosporine level CKMB level, echocardiography for LV function, CKMB level, echocardiography for LV function, and endomyocardial biopsy. and endomyocardial biopsy.

• Signs and symptoms of rejection only manifest Signs and symptoms of rejection only manifest in the late stages and usually as CHF (rarely in the late stages and usually as CHF (rarely arrhythmias). Due to close surveillance, most arrhythmias). Due to close surveillance, most rejection is picked up in asymptomatic patients. rejection is picked up in asymptomatic patients.

Staging of Acute RejectionStaging of Acute Rejection

• If acute rejection is found, histologic review of If acute rejection is found, histologic review of endomyocardial biopsy is performed to determine the grade endomyocardial biopsy is performed to determine the grade of rejection.of rejection.

• Grade 0 — no evidence of cellular rejectionGrade 0 — no evidence of cellular rejection

• Grade 1A — focal perivascular or interstitial infiltrate without Grade 1A — focal perivascular or interstitial infiltrate without myocyte injury.myocyte injury.

• Grade 1B — multifocal or diffuse sparse infiltrate without myocyte Grade 1B — multifocal or diffuse sparse infiltrate without myocyte injury.injury.

• Grade 2 — single focus of dense infiltrate with myocyte injury.Grade 2 — single focus of dense infiltrate with myocyte injury.

• Grade 3A — multifocal dense infiltrates with myocyte injury.Grade 3A — multifocal dense infiltrates with myocyte injury.

• Grade 3B — diffuse, dense infiltrates with myocyte injury.Grade 3B — diffuse, dense infiltrates with myocyte injury.

• Grade 4 — diffuse and extensive polymorphous infiltrate with Grade 4 — diffuse and extensive polymorphous infiltrate with myocyte injury; may have hemorrhage, edema, and microvascular myocyte injury; may have hemorrhage, edema, and microvascular injury. injury.

Treatment of Acute RejectionTreatment of Acute Rejection

• Grade 1A and Grade 1B: No treatment is necessary. Grade 1A and Grade 1B: No treatment is necessary. • Grade 2: Probably no treatment is necessary. Short course Grade 2: Probably no treatment is necessary. Short course

of steriods (Prednisone 100mg qd x 3 days) is optional.of steriods (Prednisone 100mg qd x 3 days) is optional.• Grade 3A and Grade 3B: High dose corticosteroids Grade 3A and Grade 3B: High dose corticosteroids

(Solumedrol 1mg/kg IV). If no response then ATGAM (OTK3 (Solumedrol 1mg/kg IV). If no response then ATGAM (OTK3 also an option, but causes more intense cytokine reaction). also an option, but causes more intense cytokine reaction).

• Grade 3 with hemodynamic compromise or Grade 4: High Grade 3 with hemodynamic compromise or Grade 4: High dose corticosteriods plus ATGAM or OTK3. dose corticosteriods plus ATGAM or OTK3.

• It is critical that an endomyocardial biopsy be performed to It is critical that an endomyocardial biopsy be performed to document reversal of rejection after treatment. Otherwise document reversal of rejection after treatment. Otherwise additional agents will need to be added. A biopsy is additional agents will need to be added. A biopsy is obtained 1 week after initial biopsy showed rejection and obtained 1 week after initial biopsy showed rejection and then 1 week after therapy complete. If ATGAM or OTK3 is then 1 week after therapy complete. If ATGAM or OTK3 is used biopsy should be obtained at the end of a course of used biopsy should be obtained at the end of a course of therapy (usually 7 to 14 days) and then again 1 week later therapy (usually 7 to 14 days) and then again 1 week later off therapy. off therapy.

Complications - RejectionComplications - Rejection• Allograft vasculopathy (Chronic rejection): Transplant Allograft vasculopathy (Chronic rejection): Transplant

coronary artery disease that is the leading cause of coronary artery disease that is the leading cause of death in patients more than 1 year after transplantation. death in patients more than 1 year after transplantation.

• Likely a result of a proliferative response to Likely a result of a proliferative response to immunologically mediated endothelial injury (chronic immunologically mediated endothelial injury (chronic humoral rejection). humoral rejection).

• It differs from native CAD in that it is manifested by It differs from native CAD in that it is manifested by concentric stenoses, predominately subendocardial concentric stenoses, predominately subendocardial location, lack of calcification, can be rapidly progressive location, lack of calcification, can be rapidly progressive and lack of angina pectoris. and lack of angina pectoris.

• Risk factors include degree of histocompatibility, Risk factors include degree of histocompatibility, hypertension, hyperlipidemia, obesity, and CMV hypertension, hyperlipidemia, obesity, and CMV infection. infection.

Complications – Rejection Complications – Rejection Allograft VasculopathyAllograft Vasculopathy

• Treatment is mainly prevention with statins, diltiazem, Treatment is mainly prevention with statins, diltiazem, and antioxidant vitamins. Rapamycin is an agent that and antioxidant vitamins. Rapamycin is an agent that has shown promise in preventing this complication. has shown promise in preventing this complication.

• Treatment with percutaneous interventions and CABG Treatment with percutaneous interventions and CABG is limited due to its diffuse nature and subendocardial is limited due to its diffuse nature and subendocardial locations.locations.

• Retransplantation for this disorder is an option, but Retransplantation for this disorder is an option, but retrospective analysis have shown this approach does retrospective analysis have shown this approach does not improve mortality as patients do significantly not improve mortality as patients do significantly worse with a second transplant as compared with the worse with a second transplant as compared with the first. first.

Complications - InfectionComplications - Infection

• There are two peak infection periods after There are two peak infection periods after transplantation: transplantation:

• The first 30 days postoperatively: nosocomial infections related to The first 30 days postoperatively: nosocomial infections related to indwelling catheters and wound infections. indwelling catheters and wound infections.

• Two to six months postoperatively: opportunistic Two to six months postoperatively: opportunistic immunosuppresive-related infections.immunosuppresive-related infections.

• There is considerable overlap, however as fungal There is considerable overlap, however as fungal infections and toxoplasmosis can be seen during the infections and toxoplasmosis can be seen during the first month.first month.

• It is important to remember that immunosuppressed It is important to remember that immunosuppressed transplant patients can develop severe infections in transplant patients can develop severe infections in unusual locations and remain afebrile. unusual locations and remain afebrile.

Opportunistic InfectionsOpportunistic Infections

• CMV: most common infection transmitted CMV: most common infection transmitted donor to recipient. donor to recipient.

• Manifested by fever, malaise, and anorexia. Severe Manifested by fever, malaise, and anorexia. Severe infection can affect the lungs, gastrointestinal tract, and infection can affect the lungs, gastrointestinal tract, and retina.retina.

• If donor is CMV positive and the recipient is CMV negative, If donor is CMV positive and the recipient is CMV negative, prophylaxis with IV ganciclovir or foscarnet is given for 6 prophylaxis with IV ganciclovir or foscarnet is given for 6 weeks and followed by longterm oral prophylaxis with weeks and followed by longterm oral prophylaxis with acyclovir. acyclovir.

• If the recipient is CMV positive a less potent regimen can If the recipient is CMV positive a less potent regimen can be used. be used.

• Bone marrow toxicity related to treatment can occur and Bone marrow toxicity related to treatment can occur and be confused with that due to azathioprine treatment. be confused with that due to azathioprine treatment.

Complications - MalignancyComplications - Malignancy

• Transplant recipients have a 100-fold increase in the Transplant recipients have a 100-fold increase in the prevalence of malignant tumors as compared with age-prevalence of malignant tumors as compared with age-matched controls.matched controls.

• Most common tumor is posttransplantation lymphoproliferative Most common tumor is posttransplantation lymphoproliferative disorder (PTLD), a type of non-Hodgkindisorder (PTLD), a type of non-Hodgkin ’’s lymphoma believed to s lymphoma believed to be related to EBV. be related to EBV.

• The incidence is as high as 50% in EBV-negative recipients of EBV-The incidence is as high as 50% in EBV-negative recipients of EBV-positive hearts. positive hearts.

• Treatment involves reduction of immunosuppressive agents, Treatment involves reduction of immunosuppressive agents, administration of acyclovir, and chemotherapy for widespread disease. administration of acyclovir, and chemotherapy for widespread disease.

• Skin cancer is common with azathioprine use. Skin cancer is common with azathioprine use.

• Any malignant tumor present before transplantation carries the Any malignant tumor present before transplantation carries the risk for growth once immunosuppresion is initiated because of risk for growth once immunosuppresion is initiated because of the negative effects on the function of T-cells. the negative effects on the function of T-cells.

TransplantationTransplantation

Kidney 25,000 patients are waiting for Kidney 25,000 patients are waiting for kidney transplantation kidney transplantation

savings in three years compared to the cost savings in three years compared to the cost of three years of renal dialysis. of three years of renal dialysis.

Liver One-year survival exceeds 75% and Liver One-year survival exceeds 75% and five-year is 70%. five-year is 70%.

Pancreas TransplantationPancreas Transplantation Graft survival is 72% at one-year and this Graft survival is 72% at one-year and this

is further improved if a kidney is is further improved if a kidney is transplanted simultaneously. transplanted simultaneously.

The overall goal of pancreas transplantation The overall goal of pancreas transplantation is to prevent the typical diabetic secondary is to prevent the typical diabetic secondary complications: neuropathy, retinopathy, complications: neuropathy, retinopathy, and cardiovascular disease. and cardiovascular disease.

Immunology1 Transplantation Immunology Transplantation Immunology.

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Immunology1 Transplantation Immunology Transplantation Immunology.