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Immunology Immunology 1 Transplantation Transplantation Immunology Immunology
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  • Immunology* Transplantation Immunology

    Immunology

  • Immunology*Introduction

    Immunology

  • Immunology*ConceptionsTransplantationGraftsDonorsRecipients or hostsOrthotopic transplantationHeterotopic transplantation

    Immunology

  • Immunology*Nobel Prize in Physiology or Medicine 1912Alexis Carrel (France)Work on vascular suture and the transplantation of blood vessels and organs

    Great events in history of transplantation

    Immunology

  • Immunology*Nobel Prize in Physiology or Medicine 1960Peter Brian Medawar (1/2) Discovery of acquired immunological tolerance The graft reaction is an immunity phenomenon 1950s, induced immunological tolerance to skin allografts in mice by neonatal injection of allogeneic cellsGreat events in history of transplantation

    Immunology

  • Immunology*Nobel Prize in Physiology or Medicine 1990Joseph E. Murray (1/2) Discoveries concerning organ transplantation in the treatment of human disease In 1954, the first successful human kidney transplant was performed between twins in Boston. Transplants were possible in unrelated people if drugs were taken to suppress the body's immune reactionGreat events in history of transplantation

    Immunology

  • Immunology*Nobel Prize in Physiology or Medicine 1980George D. Snell (1/3), Jean Dausset (1/3) Discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions H-genes (histocompatibility genes), H-2 gene Human transplantation antigens (HLA) ----MHCGreat events in history of transplantation

    Immunology

  • Immunology*Nobel Prize in Physiology or Medicine 1988Gertrude B. Elion (1/3) , George H. Hitchings (1/3) Discoveries of important principles for drug treatment Immunosuppressant drug (The first cytotoxic drugs) ----- azathioprineGreat events in history of transplantation

    Immunology

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

    Immunology

  • Immunology*Classification of graftsAutologous grafts (Autografts)Grafts transplanted from one part of the body to another in the same individualSyngeneic grafts (Isografts) Grafts transplanted between two genetically identical individuals of the same species Allogeneic grafts (Allografts)Grafts transplanted between two genetically different individuals of the same species Xenogeneic grafts (Xenografts) Grafts transplanted between individuals of different species

    Immunology

  • Immunology*

    Immunology

  • Immunology*Grafts rejection is a kind of specific immune responseSpecificityImmune memory Grafts rejectionFirst set rejectionSecond set rejection

    Immunology

  • First- and Second-set Allograft RejectionImmunology*

    Immunology

  • Immunology*Part one Immunological Basis of Allograft Rejection

    Immunology

  • Immunology*Major histocompatibility antigens (MHC molecules)Minor histocompatibility antigensOther alloantigens

    I. Transplantation antigens

    Immunology

  • Immunology*1. Major histocompatibility antigensMain antigens of grafts rejection Cause fast and strong rejectionDifference of HLA types is the main cause of human grafts rejection

    Immunology

  • Immunology*2. Minor histocompatibility antigensAlso cause grafts rejection, but slow and weakMouse H-Y antigens encoded by Y chromosome HA-1HA-5 linked with non-Y chromosome

    Immunology

  • Immunology*

    Immunology

  • Immunology*3. Other alloantigens Human ABO blood group antigens Some tissue specific antigensSkinkidneyheartpancreas liverVEC antigen SK antigen

    Immunology

  • Immunology*Cell-mediated Immunity Humoral Immunity Role of NK cellsII. Mechanism of allograft rejection

    Immunology

  • Immunology*1. Cell-mediated ImmunityRecipient's T cell-mediated cellular immune response against alloantigens on grafts

    Immunology

  • Immunology*Molecular Mechanisms of Allogeneic Recognition T cells of the recipient recognize the allogenetic MHC moleculesMany T cells can recognize allogenetic MHC molecules10-5-10-4 of specific T cells recognize conventional antigens 1%-10% of T cells recognize allogenetic MHC molecules

    Immunology

  • Immunology*The recipient T cells recognize the allogenetic MHC moleculesDirect Recognition Indirect Recognition

    Immunology

  • Immunology*Direct RecognitionRecognition of an intact allogenetic MHC molecule displayed by donor APC in the graftCross recognitionAn allogenetic MHC molecule with a bound peptide can mimic the determinant formed by a self MHC molecule plus foreign peptideA cross-reaction of a normal TCR, which was selected to recognize a self MHC molecules plus foreign peptide, with an allogenetic MHC molecule plus peptide

    Immunology

  • Immunology*Cross recognition

    Immunology

  • Immunology*Passenger leukocytesDonor APCs that exist in grafts, such as DC, MEarly phase of acute rejectionFast and strong

    Immunology

  • Immunology*Many T cells can recognize allogenetic MHC moleculesAllogenetic MHC molecules (different residues)Allogenetic MHC moleculesdifferent peptidesAll allogenetic MHC molecules on donor APC can be epitopes recognized by TCR

    Immunology

  • Immunology*Indirect recognitionUptake and presentation of allogeneic donor MHC molecules by recipient APC in normal wayRecognition by T cells like conventional foreign antigens

    Immunology

  • Immunology*

    Immunology

  • Immunology*Slow and weakLate phase of acute rejection and chronic rejection Coordinated function with direct recognition in early phase of acute rejection

    Immunology

  • Immunology*Difference between Direct Recognition and Indirect Recognition

    Direct RecognitionIndirect RecognitionAllogeneic MHC moleculeIntact allogeneic MHC moleculePeptide of allogeneic MHC moleculeAPCsRecipient APCs are not necessaryRecipient APCsActivated T cellsCD4T cells and/or CD8T cellsCD4T cells and/or CD8T cellsRoles in rejectionAcute rejectionChronic rejectionDegree of rejectionVigorousWeak

    Immunology

  • Immunology*Activated CD4+T by direct and indirect recognitionCK secretionM activation and recruitment Activated CD8+T by direct recognition Kill the graft cells directlyActivated CD8+T by indirect recognitionCan not kill the graft cells directly Role of CD4T cells and CD8T cells

    Immunology

  • Immunology*

    Immunology

  • Immunology*Important role in hyperacute rejection (Preformed antibodies)Complements activationADCCOpsonizationEnhancing antibodies /Blocking antibodies2. Humoral immunity

    Immunology

  • Immunology*3 .Role of NK cellsCKs secreted by activated Th cells can promote NK activation

    Immunology

  • Immunology*Part two Classification and Effector Mechanisms of Allograft Rejection

    Immunology

  • Immunology*Host versus graft reaction (HVGR) Conventional organ transplantationGraft versus host reaction (GVHR)Bone marrow transplantationImmune cells transplantationClassification of Allograft Rejection

    Immunology

  • Immunology*I. Host versus graft reaction (HVGR) Hyperacute rejection Acute rejection Chronic rejection

    Immunology

  • Immunology*Occurrence timeOccurs within minutes to hours after host blood vessels are anastomosed to graft vesselsPathology Thrombotic occlusion of the graft vasculature Ischemia, denaturation, necrosis 1. Hyperacute rejection

    Immunology

  • Immunology*MechanismsPreformed antibodies Antibody against ABO blood type antigenAntibody against VEC antigen Antibody against HLA antigen

    Immunology

  • Immunology*Complement activationEndothelial cell damagePlatelets activationThrombosis, vascular occlusion, ischemic damage

    Immunology

  • Immunology*Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus

    Immunology

  • Immunology*Occurrence timeOccurs within days to 2 weeks after transplantation, 80-90% of cases occur within 1 month PathologyAcute humoral rejectionAcute vasculitis manifested mainly by endothelial cell damageAcute cellular rejectionParenchymal cell necrosis along with infiltration of lymphocytes and M2. Acute rejection

    Immunology

  • Hyperacute Rejection: the early daysMediated by pre-existing IgM alloantibodiesAntibodies come from carbohydrate antigens expressed by bacteria in intestinal floraABO blood group antigensNot really a problem anymore

  • Hyperacute Rejection: TodayMediated by IgG antibodies directed against protein alloantigensAntibodies generally arise fromPast blood transfusionMultiple pregnanciesPrevious transplantation

  • Immunology*Mechanisms Vasculitis IgG antibodies against alloantigens on endothelial cell

    Parenchymal cell damage Delayed hypersensitivity mediated by CD4+Th1Killing of graft cells by CD8+Tc

    Immunology

  • Immunology*

    Immunology

  • Immunology*Acute rejection of a kidney with inflammatory cells in the interstitium and between epithelial cells of the tubules

    Immunology

  • Immunology*Occurrence in timeDevelops months or years after acute rejection reactions have subsidedPathologyFibrosis and vascular abnormalities with loss of graft function3. Chronic rejection

    Immunology

  • Immunology*Mechanisms Not clearExtension and results of cell necrosis in acute rejectionChronic inflammation mediated by CD4+T cell/MOrgan degeneration induced by non immune factors

    Immunology

  • Immunology*

    Immunology

  • Immunology*Kidney Transplantation----Graft Rejection

    Immunology

  • Immunology*Chronic rejection in a kidney allograft with arteriosclerosis

    Immunology

  • Immunology*II.Graft versus host reaction (GVHR)Graft versus host reaction (GVHR) Allogenetic bone marrow transplantationRejection to host alloantigensMediated by immune competent cells in bone marrowGraft versus host disease (GVHD)A disease caused by GVHR, which can damage the host

    Immunology

  • Immunology*Graft versus host disease

    Immunology

  • Immunology*Graft versus host disease

    Immunology

  • Immunology*Conditions Enough immune competent cells in graftsImmunocompromised hostHistocompatability differences between host and graft

    Immunology

  • Immunology*Bone marrow transplantation Thymus transplantationSpleen transplantationBlood transfusion of neonate

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

    Immunology

  • Immunology*1. Acute GVHDEndothelial cell death in the skin, liver, and gastrointestinal tractRash, jaundice, diarrhea, gastrointestinal hemorrhage Mediated by mature T cells in the grafts

    Immunology

  • Immunology*Acute graft-versus-host reaction with vivid palmar erythema

    Immunology

  • Immunology*2. Chronic GVHDFibrosis and atrophy of one or more of the organsEventually complete dysfunction of the affected organ

    Immunology

  • Immunology*Early, chronic graft-versus-host reaction with widespread, almost confluent hyperpigmented lichenoid papules and toxic epidermal necrosis-like appearance on knee Late, chronic graft-versus -host reaction with hyperpigmented sclerotic plaques on the back

    Immunology

  • Immunology* Both acute and chronic GVHD are commonly treated with intense immunosuppresionUncertainFatal

    Immunology

  • Immunology*Part threePrevention and Therapy of Allograft Rejection

    Immunology

  • Immunology*Tissue Typing Immunosuppressive TherapyInduction of Immune Tolerance

    Immunology

  • Immunology*I. Tissue Typing ABO and Rh blood typingCrossmatching (Preformed antibodies)HLA typing HLA-A and HLA-BHLA-DR

    Immunology

  • Immunology*Laws of transplantation

    Immunology

  • Immunology*II. Immunosuppressive TherapyCyclosporine(CsA), FK506Inhibits NFAT transcription factorAzathioprine, CyclophosphamideBlock the proliferation of lymphocytes Ab against T cell surface molecules Anti-CD3 mAb----Deplete T cellsAnti-inflammatory agents Corticosteroids----Block the synthesis and secretion of cytokines

    Immunology

  • Immunology*Removal of T cells from marrow graft

    Immunology

  • Immunology*III. Induction of Immune Tolerance Inhibition of T cell activationSoluble MHC moleculesCTLA4-Ig Anti-IL2R mAbTh2 cytokinesAnti-TNF-Anti-IL-2Anti-IFN- mAbMicrochimerismThe presence of a small number of cells of donor, genetically distinct from those of the host individual

    Immunology

  • Immunology*Part IVXenotransplantation

    Immunology

  • Immunology*Lack of organs for transplantationPig-human xenotransplantationBarrier

    Immunology

  • Immunology*Hyperacute xenograft rejection (HXR) Human anti-pig nature Abs reactive with Gal1,3GalConstruct transgenic pigs expressing human proteins that inhibit complement activationDelayed xenograft rejection (DXR) Acute vascular rejectionIncompletely understood T cell-mediated xenograft rejection

    Immunology

  • Bone Marrow TransplantationRescue procedure for hemopoietic reconstitution subsequent to cancer chemo- or radio- therapy

  • Graft vs. Host DiseaseCaused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the hostAcute GVHDCharacterized by epithelial cell death in the skin, GI tract, and liverChronic GVHDCharacterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs

  • Heart TransplantationHeart transplantation is indicated for those in end-stage heart disease with a New York Heart Association of class III or IV, ejection fractions of
  • IntroductionMore than 4000 patients in the United States are registered with the United Organ Sharing Network (UNOS) for cardiac transplantation.There are only about 2500 heart donors yearly.Scarcity of donors is complicated by the use of single organs, heart injury with common brain-death injuries, difficulty with ex-vivo preservation, heart disease among donors, and the complexity of the operation.

  • Matching Donor and RecipientBecause ischemic time during cardiac transplantation is crucial, donor recipient matching is based primarily not on HLA typing but on the severity of illness, ABO blood type (match or compatible), response to PRA, donor weight to recipient ratio (must be 75% to 125%), geographic location relative to donor, and length of time at current status. The PRA is a rapid measurement of preformed reactive anti-HLA antibodies in the transplant recipient. In general PRA < 10 to 20% then no cross-match is necessary. If PRA is > 20% then a T and B-cell cross-match should be performed. Patients with elevated PRA will need plasmapheresis, immunoglobulins, or immunosuppresive agents to lower PRA.

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

  • Immunosuppressive AgentsAzathioprine: purine analogue that works by nonspecific suppression of T and B-cell lymphocyte proliferation.Dosage is 1 to 2 mg/kg per day.Side effects are bone marrow suppression (dose related), increased incidence of skin cancer (use sunscreen), cutaneous fungal infections, and rarely liver toxicity and pancreatitis.Drug interactions: allopurinol (decrease dose by 75%) and TMP/Sulfa (worsens thrombocytopenia).

  • Immunosuppressive AgentsCyclosporin: inhibits T-cell lymphokine production. Highly lipophilic.Dosage is 8 to 10mg/kg/day in 2 divided doses. IV doses are 1/3 of oral doses in a continuous infusion. Drug levels are frequently measured for dosage and toxicity, but levels are not highly predictive of actual immunosuppressive effect. Drug levels are reflected for 5 to 10 days because of a long half life. Side effects: nephrotoxicity caused by afferent arteriolar constriction and manifested by oliguria. Loop diuretics may exacerbate this side effect. Dosage adjustments should only be made if creatinine level is >3.0mg/dL (some renal insufficiency is expected). Other side effects include hypertension, hypertrichosis, tremor, hyperkalemia, hyperlipidemia, and hyperuricemia. Multiple drug interactions.

  • Immunosuppressive AgentsCorticosteroids: immunosuppressives of uncertain mechanism. Used for maintenance of immunosuppression and to manage acute rejections.High doses used initially tapered over the 1st 6 months to 5 to 15mg/d prednisone.Side effects include mood and sleep disturbances, acne, weight gain, obesity, hypertension, osteopenia, and hyperglycemia.

  • Immunosuppressive AgentsMycophenolate mofetil: selectively inhibits lymphocyte proliferation. Dosage is 2g/d po. Side effects include GI disturbances. Does not cause significant bone marrow suppression. FK-506 (tacrolimus): Lymphophilic macrolide that inhibits lymphokine production similar to cyclosporine. More toxic than cyclosporine. Side effects include nephrotoxicity and neuotoxicity.

  • Immunosuppressive AgentsAntilymphocyte globulin: Horse polyclonal antibody designed to inhibit T cells by binding to surface antigens. It is generally used at the time of transplantation for induction therapy or during acute rejections. Dosage is 10 to 15 mg/kg qd through a central venous catheter. Goal is to keep T lymphocyte count ~200cells/microL. Side effects include fevers, chills, urticaria, serum sickness, and thrombocytopenia.

  • Immunosuppressive AgentsMuromonab-CD3 (OKT3): a murine monoclonal antibody to the CD3 complex on the T-cell lymphocyte designed for selective T-cell depletion. Usual dose is 5mg/d IV bolus over 10 to 14 days. CD3 cells are monitored with goal
  • Basic Drug RegimenImmunosuppressivesAntibiotic prophylaxis PCP: TMP/Sulfa or Dapsone or Pentamidine aerosols. CMV infection: Ganglyclovir, acyclovir. Fungal infections: Nystatin.AntihypertensivesDiuretics as neededPotassium and Magnesium replacement (cyclosporin leads to wasting of thes electrolytes.Lipid-lowering agents. (Avoid allograft vasculopathy).Glucose lowering agents (DM and steroids)Anticoagulation if transplant heterotopic.Cyclosporin dose lowering meds (Diltiazem / Verapamil / Theophyilline)

  • Complications - RejectionAvoidance with preoperative therapy with cyclosporin, corticosteroids, and azathioprine.If rejection is suspected then workup should include: measurement of cyclosporine level CKMB level, echocardiography for LV function, and endomyocardial biopsy. Signs and symptoms of rejection only manifest in the late stages and usually as CHF (rarely arrhythmias). Due to close surveillance, most rejection is picked up in asymptomatic patients.

  • Staging of Acute RejectionIf acute rejection is found, histologic review of endomyocardial biopsy is performed to determine the grade of rejection. Grade 0 no evidence of cellular rejectionGrade 1A focal perivascular or interstitial infiltrate without myocyte injury.Grade 1B multifocal or diffuse sparse infiltrate without myocyte injury.Grade 2 single focus of dense infiltrate with myocyte injury.Grade 3A multifocal dense infiltrates with myocyte injury.Grade 3B diffuse, dense infiltrates with myocyte injury.Grade 4 diffuse and extensive polymorphous infiltrate with myocyte injury; may have hemorrhage, edema, and microvascular injury.

  • Treatment of Acute RejectionGrade 1A and Grade 1B: No treatment is necessary. Grade 2: Probably no treatment is necessary. Short course of steriods (Prednisone 100mg qd x 3 days) is optional.Grade 3A and Grade 3B: High dose corticosteroids (Solumedrol 1mg/kg IV). If no response then ATGAM (OTK3 also an option, but causes more intense cytokine reaction). Grade 3 with hemodynamic compromise or Grade 4: High dose corticosteriods plus ATGAM or OTK3. It is critical that an endomyocardial biopsy be performed to document reversal of rejection after treatment. Otherwise additional agents will need to be added. A biopsy is obtained 1 week after initial biopsy showed rejection and then 1 week after therapy complete. If ATGAM or OTK3 is used biopsy should be obtained at the end of a course of therapy (usually 7 to 14 days) and then again 1 week later off therapy.

  • Complications - RejectionAllograft vasculopathy (Chronic rejection): Transplant coronary artery disease that is the leading cause of death in patients more than 1 year after transplantation. Likely a result of a proliferative response to immunologically mediated endothelial injury (chronic humoral rejection). It differs from native CAD in that it is manifested by concentric stenoses, predominately subendocardial location, lack of calcification, can be rapidly progressive and lack of angina pectoris. Risk factors include degree of histocompatibility, hypertension, hyperlipidemia, obesity, and CMV infection.

  • Complications Rejection Allograft VasculopathyTreatment is mainly prevention with statins, diltiazem, and antioxidant vitamins. Rapamycin is an agent that has shown promise in preventing this complication. Treatment with percutaneous interventions and CABG is limited due to its diffuse nature and subendocardial locations.Retransplantation for this disorder is an option, but retrospective analysis have shown this approach does not improve mortality as patients do significantly worse with a second transplant as compared with the first.

  • Complications - InfectionThere are two peak infection periods after transplantation: The first 30 days postoperatively: nosocomial infections related to indwelling catheters and wound infections. Two to six months postoperatively: opportunistic immunosuppresive-related infections.There is considerable overlap, however as fungal infections and toxoplasmosis can be seen during the first month.It is important to remember that immunosuppressed transplant patients can develop severe infections in unusual locations and remain afebrile.

  • Opportunistic InfectionsCMV: most common infection transmitted donor to recipient. Manifested by fever, malaise, and anorexia. Severe infection can affect the lungs, gastrointestinal tract, and retina.If donor is CMV positive and the recipient is CMV negative, prophylaxis with IV ganciclovir or foscarnet is given for 6 weeks and followed by longterm oral prophylaxis with acyclovir. If the recipient is CMV positive a less potent regimen can be used. Bone marrow toxicity related to treatment can occur and be confused with that due to azathioprine treatment.

  • Complications - MalignancyTransplant recipients have a 100-fold increase in the prevalence of malignant tumors as compared with age-matched controls.Most common tumor is posttransplantation lymphoproliferative disorder (PTLD), a type of non-Hodgkins lymphoma believed to be related to EBV. The incidence is as high as 50% in EBV-negative recipients of EBV-positive hearts. Treatment involves reduction of immunosuppressive agents, administration of acyclovir, and chemotherapy for widespread disease. Skin cancer is common with azathioprine use. Any malignant tumor present before transplantation carries the risk for growth once immunosuppresion is initiated because of the negative effects on the function of T-cells.

  • TransplantationKidney 25,000 patients are waiting for kidney transplantation savings in three years compared to the cost of three years of renal dialysis.

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

  • Pancreas TransplantationGraft survival is 72% at one-year and this is further improved if a kidney is transplanted simultaneously. The overall goal of pancreas transplantation is to prevent the typical diabetic secondary complications: neuropathy, retinopathy, and cardiovascular disease.

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