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Transplantation Immunology


Title: transplantation Subject: 7year Author: wangqun Last modified by: Saverio Minucci Created Date: 9/9/2003 3:55:24 AM Document presentation format – PowerPoint PPT presentation

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Title: Transplantation Immunology

Transplantation Immunology
  • Transplantation
  • Grafts
  • Donors
  • Recipients or hosts
  • Orthotopic transplantation
  • Heterotopic transplantation

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

Great events in history of transplantation
Nobel Prize in Physiology or Medicine 1960
  • Peter 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 cells

Great events in history of transplantation
Nobel Prize in Physiology or Medicine 1990
  • Joseph 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

Great events in history of transplantation
Nobel Prize in Physiology or Medicine 1980
  • George 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) ----MHC

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

Great events in history of transplantation
  • Today, kidney, pancreas, heart, lung,
    liver, bone marrow, and cornea transplantations
    are performed among non-identical individuals
    with ever increasing frequency and success

Classification of grafts
  • Autologous grafts (Autografts)
  • Grafts transplanted from one part of the body to
    another in the same individual
  • Syngeneic 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

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  • Grafts rejection is a kind of specific immune
  • Specificity
  • Immune memory
  • Grafts rejection
  • First set rejection
  • Second set rejection

First- and Second-set Allograft Rejection
Part one
  • Immunological Basis of Allograft Rejection

I. Transplantation antigens
  • Major histocompatibility antigens (MHC molecules)
  • Minor histocompatibility antigens
  • Other alloantigens

1. Major histocompatibility antigens
  • Main antigens of grafts rejection
  • Cause fast and strong rejection
  • Difference of HLA types is the main cause of
    human grafts rejection

2. Minor histocompatibility antigens
  • Also cause grafts rejection, but slow and weak
  • Mouse H-Y antigens encoded by Y chromosome
  • HA-1HA-5 linked with non-Y chromosome

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3. Other alloantigens
  • Human ABO blood group antigens
  • Some tissue specific antigens
  • Skingtkidneygtheartgtpancreas gtliver
  • VEC antigen
  • SK antigen

II. Mechanism of allograft rejection
  • Cell-mediated Immunity
  • Humoral Immunity
  • Role of NK cells

1. Cell-mediated Immunity
  • Recipient's T cell-mediated cellular immune
    response against alloantigens on grafts

Molecular Mechanisms of Allogeneic Recognition
  • ?T cells of the recipient recognize the
    allogenetic MHC molecules
  • ?Many T cells can recognize allogenetic MHC
  • 10-5-10-4 of specific T cells recognize
    conventional antigens
  • 1-10 of T cells recognize allogenetic MHC

?The recipient T cells recognize the allogenetic
MHC molecules
  • Direct Recognition
  • Indirect Recognition

Direct Recognition
  • Recognition of an intact allogenetic MHC molecule
    displayed by donor APC in the graft
  • Cross recognition
  • An allogenetic MHC molecule with a bound peptide
    can mimic the determinant formed by a self MHC
    molecule plus foreign peptide
  • A 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

  • Cross recognition

  • Passenger leukocytes
  • Donor APCs that exist in grafts, such as DC, MF
  • Early phase of acute rejection
  • Fast and strong

?Many T cells can recognize allogenetic MHC
  • Allogenetic MHC molecules (different residues)
  • Allogenetic MHC moleculesdifferent peptides
  • All allogenetic MHC molecules on donor APC can be
    epitopes recognized by TCR

Indirect recognition
  • Uptake and presentation of allogeneic donor MHC
    molecules by recipient APC in normal way
  • Recognition by T cells like conventional foreign

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  • Slow and weak
  • Late phase of acute rejection and chronic
  • Coordinated function with direct recognition in
    early phase of acute rejection

Difference between Direct Recognition and
Indirect Recognition
Direct Recognition Indirect Recognition
Allogeneic MHC molecule Intact allogeneic MHC molecule Peptide of allogeneic MHC molecule
APCs Recipient APCs are not necessary Recipient APCs
Activated T cells CD4T cells and/or CD8T cells CD4T cells and/or CD8T cells
Roles in rejection Acute rejection Chronic rejection
Degree of rejection Vigorous Weak
Role of CD4T cells and CD8T cells
  • Activated CD4T by direct and indirect
  • CK secretion
  • MF activation and recruitment
  • Activated CD8T by direct recognition
  • Kill the graft cells directly
  • Activated CD8T by indirect recognition
  • Can not kill the graft cells directly

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2. Humoral immunity
  • Important role in hyperacute rejection
  • (Preformed antibodies)
  • Complements activation
  • ADCC
  • Opsonization
  • Enhancing antibodies
  • /Blocking antibodies

3 .Role of NK cells
  • CKs secreted by activated Th cells can promote NK

Part two
  • Classification and Effector Mechanisms of
    Allograft Rejection

Classification of Allograft Rejection
  • Host versus graft reaction (HVGR)
  • Conventional organ transplantation
  • Graft versus host reaction (GVHR)
  • Bone marrow transplantation
  • Immune cells transplantation

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

1. Hyperacute rejection
  • Occurrence time
  • Occurs within minutes to hours after host blood
    vessels are anastomosed to graft vessels
  • Pathology
  • Thrombotic occlusion of the graft vasculature
  • Ischemia, denaturation, necrosis

  • Mechanisms
  • Preformed antibodies
  • Antibody against ABO blood type antigen
  • Antibody against VEC antigen
  • Antibody against HLA antigen

  • Complement activation
  • Endothelial cell damage
  • Platelets activation
  • Thrombosis, vascular occlusion, ischemic damage

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

2. Acute rejection
  • Occurrence time
  • Occurs within days to 2 weeks after
    transplantation, 80-90 of cases occur within 1
  • Pathology
  • Acute humoral rejection
  • Acute vasculitis manifested mainly by endothelial
    cell damage
  • Acute cellular rejection
  • Parenchymal cell necrosis along with
    infiltration of lymphocytes and MF

Hyperacute Rejection the early days
  • Mediated by pre-existing IgM alloantibodies
  • Antibodies come from carbohydrate antigens
    expressed by bacteria in intestinal flora
  • ABO blood group antigens
  • Not really a problem anymore

Hyperacute Rejection Today
  • Mediated by IgG antibodies directed against
    protein alloantigens
  • Antibodies generally arise from
  • Past blood transfusion
  • Multiple pregnancies
  • Previous transplantation

  • Mechanisms
  • Vasculitis
  • IgG antibodies against alloantigens on
    endothelial cell
  • Parenchymal cell damage
  • Delayed hypersensitivity mediated by CD4Th1
  • Killing of graft cells by CD8Tc

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Acute rejection of a kidney with inflammatory
cells in the interstitium and between epithelial
cells of the tubules
3. Chronic rejection
  • Occurrence in time
  • Develops months or years after acute rejection
    reactions have subsided
  • Pathology
  • Fibrosis and vascular abnormalities with loss of
    graft function

  • Mechanisms
  • Not clear
  • Extension and results of cell necrosis in acute
  • Chronic inflammation mediated by CD4T cell/MF
  • Organ degeneration induced by non immune factors

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Kidney Transplantation----Graft Rejection
Chronic rejection in a kidney allograft with
II.Graft versus host reaction (GVHR)
  • Graft versus host reaction (GVHR)
  • Allogenetic bone marrow transplantation
  • Rejection to host alloantigens
  • Mediated by immune competent cells in bone marrow
  • Graft versus host disease (GVHD)
  • A disease caused by GVHR, which can damage the

  • Graft versus host disease

  • Graft versus host disease

  • Enough immune competent cells in grafts
  • Immunocompromised host
  • Histocompatability differences between host and

  • Bone marrow transplantation
  • Thymus transplantation
  • Spleen transplantation
  • Blood transfusion of neonate
  • In most cases the reaction is directed against
    minor histocompatibility antigens of the host

1. Acute GVHD
  • Endothelial cell death in the skin, liver, and
    gastrointestinal tract
  • Rash, jaundice, diarrhea, gastrointestinal
  • Mediated by mature T cells in the grafts

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

2. Chronic GVHD
  • Fibrosis and atrophy of one or more of the organs
  • Eventually complete dysfunction of the affected

  • 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

  • Both acute and chronic GVHD are commonly
    treated with intense immunosuppresion
  • Uncertain
  • Fatal

Part three
  • Prevention and Therapy of Allograft Rejection

  • Tissue Typing
  • Immunosuppressive Therapy
  • Induction of Immune Tolerance

I. Tissue Typing
  • ABO and Rh blood typing
  • Crossmatching (Preformed antibodies)
  • HLA typing
  • HLA-A and HLA-B
  • HLA-DR

  • Laws of transplantation  

II. Immunosuppressive Therapy
  • Cyclosporine(CsA), FK506
  • Inhibits NFAT transcription factor
  • Azathioprine, Cyclophosphamide
  • Block the proliferation of lymphocytes
  • Ab against T cell surface molecules
  • Anti-CD3 mAb----Deplete T cells
  • Anti-inflammatory agents
  • Corticosteroids----Block the synthesis and
    secretion of cytokines

  • Removal of T cells from marrow graft

III. Induction of Immune Tolerance
  • Inhibition of T cell activation
  • Soluble MHC molecules
  • CTLA4-Ig
  • Anti-IL2R mAb
  • Th2 cytokines
  • Anti-TNF-a,Anti-IL-2,Anti-IFN-? mAb
  • Microchimerism
  • The presence of a small number of cells of donor,
    genetically distinct from those of the host

Part IV
  • Xenotransplantation

  • Lack of organs for transplantation
  • Pig-human xenotransplantation
  • Barrier

  • Hyperacute xenograft rejection (HXR)
  • Human anti-pig nature Abs reactive with
  • Construct transgenic pigs expressing human
    proteins that inhibit complement activation
  • Delayed xenograft rejection (DXR)
  • Acute vascular rejection
  • Incompletely understood
  • T cell-mediated xenograft rejection

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

Graft vs. Host Disease
  • Caused by the reaction of grafted mature T-cells
    in the marrow inoculum with alloantigens of the
  • Acute GVHD
  • Characterized by epithelial cell death in the
    skin, GI tract, and liver
  • Chronic GVHD
  • Characterized by atrophy and fibrosis of one or
    more of these same target organs as well as the

Heart Transplantation
  • Heart transplantation is indicated for those in
    end-stage heart disease with a New York Heart
    Association of class III or IV,
  • ejection fractions of lt20,
  • maximal oxygen consumption of (VO2) lt14
    ml/kg/min, and
  • expected 1-year life expectancy of lt50.

  • More 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 Recipient
  • Because 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 lt 10 to 20 then no
    cross-match is necessary. If PRA is gt 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 Transplantation
  • Survival is 80 at five years but at five year
    50 also have coronary vascular disease due to
    chronic rejection.

Immunosuppressive Agents
  • Azathioprine 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 Agents
  • Cyclosporin 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
  • 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 gt3.0mg/dL (some renal
    insufficiency is expected). Other side effects
    include hypertension, hypertrichosis, tremor,
    hyperkalemia, hyperlipidemia, and hyperuricemia.
  • Multiple drug interactions.

Immunosuppressive Agents
  • Corticosteroids 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 Agents
  • Mycophenolate 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
  • More toxic than cyclosporine.
  • Side effects include nephrotoxicity and

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

Immunosuppressive Agents
  • Muromonab-CD3 (OKT3) a murine monoclonal
    antibody to the CD3 complex on the T-cell
    lymphocyte designed for selective T-cell
  • Usual dose is 5mg/d IV bolus over 10 to 14 days.
  • CD3 cells are monitored with goal lt25cells/mL.
  • Used in patients with renal insufficiency.
  • Side effects include cytokine release syndrome
    (fever, chills, nausea, vomiting, mylagia,
    diarrhea, weakness, bronchospasm, and
    hypotension), pulmonary edema.
  • Rapamycin Similar mechanism of action of FK-506
    except that it antagonizes the proliferation of
    nonimmune cells such as endothelial cells,
    fibroblasts, and smooth muscle cells.
  • Not routinely used at present.
  • May have a roal in prevention of immunologically
    mediated coronary allograft vasculopathy.

Basic Drug Regimen
  • Immunosuppressives
  • Antibiotic prophylaxis
  • PCP TMP/Sulfa or Dapsone or Pentamidine
  • CMV infection Ganglyclovir, acyclovir.
  • Fungal infections Nystatin.
  • Antihypertensives
  • Diuretics as needed
  • Potassium and Magnesium replacement (cyclosporin
    leads to wasting of thes electrolytes.
  • Lipid-lowering agents. (Avoid allograft
  • Glucose lowering agents (DM and steroids)
  • Anticoagulation if transplant heterotopic.
  • Cyclosporin dose lowering meds (Diltiazem /
    Verapamil / Theophyilline)

Complications - Rejection
  • Avoidance 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 Rejection
  • If acute rejection is found, histologic review of
    endomyocardial biopsy is performed to determine
    the grade of rejection.  
  • Grade 0 no evidence of cellular rejection
  • Grade 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 Rejection
  • Grade 1A and Grade 1B No treatment is
  • 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 - Rejection
  • Allograft 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
  • Risk factors include degree of histocompatibility,
    hypertension, hyperlipidemia, obesity, and CMV

Complications Rejection Allograft Vasculopathy
  • Treatment 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 - Infection
  • There are two peak infection periods after
  • 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 Infections
  • CMV most common infection transmitted donor to
  • 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 - Malignancy
  • Transplant 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
  • 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.

  • Kidney 25,000 patients are waiting for kidney
  • 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 Transplantation
  • Graft survival is 72 at one-year and this is
    further improved if a kidney is transplanted
  • The overall goal of pancreas transplantation is
    to prevent the typical diabetic secondary
    complications neuropathy, retinopathy, and
    cardiovascular disease.