Transplantation Transplantation ImmunologyImmunology

Laura StacyLaura Stacy

March 22, 2006March 22, 2006

ObjectivesObjectives Name the different types of graftsName the different types of grafts Distinguish among the first-set, Distinguish among the first-set,

second-set, and chronic rejectionsecond-set, and chronic rejection Differentiate between host vs. graft Differentiate between host vs. graft

rejectionrejection Describe serologic tests used for Describe serologic tests used for

transplantationtransplantation Understand the molecular basis of Understand the molecular basis of

immune responseimmune response Appreciate the different tissues and Appreciate the different tissues and

organs that can be transplantedorgans that can be transplanted

OutlineOutline IntroductionIntroduction The Immunology of Allogeneic TransplantationThe Immunology of Allogeneic Transplantation

Recognition of AlloantigensRecognition of Alloantigens Activation of Alloreactive T Cells and RejectionActivation of Alloreactive T Cells and Rejection

Effector Mechanisms of Allograft RejectionEffector Mechanisms of Allograft Rejection Hyperacute RejectionHyperacute Rejection Acute RejectionAcute Rejection Chronic RejectionChronic Rejection

Xenogeneic TransplantationXenogeneic Transplantation Blood TransfusionBlood Transfusion Bone Marrow TransplantationBone Marrow Transplantation

Graft vs. Host DiseaseGraft vs. Host Disease Immunologic AnalysisImmunologic Analysis

IntroductionIntroduction

A major limitation to the success of A major limitation to the success of transplantation is the immune transplantation is the immune response of the recipient to the response of the recipient to the donor tissue. (Abbas pg 369)donor tissue. (Abbas pg 369)

TermsTerms

Autologous graftAutologous graft Syngeneic graftSyngeneic graft Allogeneic graftAllogeneic graft Xenogeneic graftXenogeneic graft AlloantigensAlloantigens XenoantigensXenoantigens AlloreactiveAlloreactive xenoreactivexenoreactive

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

Figure 16.1

The Immunology of The Immunology of Allogeneic TransplantationAllogeneic Transplantation

Alloantigens elicit both cell-mediated Alloantigens elicit both cell-mediated and humoral immune responses. and humoral immune responses. (Abbas pg 371)(Abbas pg 371)

Recognition of transplanted cells Recognition of transplanted cells that are self or foreign is determined that are self or foreign is determined by polymorphic genes that are by polymorphic genes that are inherited from both parents and are inherited from both parents and are expressed co-dominantly. (Abbas pg expressed co-dominantly. (Abbas pg 371)371)

Recognition of Recognition of AlloantigensAlloantigens

Direct PresentationDirect Presentation Recognition of an intact MHC molecule Recognition of an intact MHC molecule

displayed by donor APC in the graftdisplayed by donor APC in the graft Basically, self MHC molecule Basically, self MHC molecule

recognizes the structure of an intact recognizes the structure of an intact allogeneic MHC moleculeallogeneic MHC molecule

Indirect PresentationIndirect Presentation Donor MHC is processed and presented Donor MHC is processed and presented

by recipient APCby recipient APC Basically, donor MHC molecule is Basically, donor MHC molecule is

handled like any other foreign antigenhandled like any other foreign antigen

MoleculaMolecular Basis of r Basis of

Direct Direct RecognitiRecogniti

onon

Figure 16-4Figure 16-4

Direct and Indirect Direct and Indirect RecognitionRecognition

Figure 16-3

Activation of Alloreactive T Activation of Alloreactive T cells and Rejection of cells and Rejection of

AllograftsAllografts Donor APCs migrate to regional Donor APCs migrate to regional

lymph nodes and are recognized by lymph nodes and are recognized by the recipient’s T cells (Abbas pg the recipient’s T cells (Abbas pg 375)375)

Alloreactive T cells in the recipient Alloreactive T cells in the recipient may be activated by both pathways, may be activated by both pathways, and they migrate into the graft and and they migrate into the graft and cause graft rejection (Abbas pg 375)cause graft rejection (Abbas pg 375)

CD4CD4++ and CD8 and CD8++

CD4CD4++ differentiate into cytokine differentiate into cytokine producing effector cellsproducing effector cells Damage graft by reactions similar to Damage graft by reactions similar to

DTHDTH CD8CD8++ cells activated by direct cells activated by direct

pathway kill nucleated cells in the pathway kill nucleated cells in the graftgraft

CD8CD8++ cells activated by the indirect cells activated by the indirect pathway are self MHC-restrictedpathway are self MHC-restricted

Effector Mechanisms of Effector Mechanisms of Allograft RejectionAllograft Rejection

Hyperacute Hyperacute RejectionRejection

Acute RejectionAcute Rejection Chronic Chronic

RejectionRejection

Hyperacute RejectionHyperacute Rejection

Characterized by thrombotic Characterized by thrombotic occlusion of the graftocclusion of the graft

Begins within minutes or hours after Begins within minutes or hours after anastamosisanastamosis

Pre-existing antibodies in the host Pre-existing antibodies in the host circulation bind to donor endothelial circulation bind to donor endothelial antigensantigens

Activates Complement CascadeActivates Complement Cascade Xenograft ResponseXenograft Response

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

Hyperacute RejectionHyperacute Rejection

1. Preformed Ab, 2. complement activation, 3. neutrophil margination, 4. inflammation, 5. Thrombosis formation

Acute RejectionAcute Rejection

Vascular and parenchymal injury Vascular and parenchymal injury mediated by T cells and antibodies mediated by T cells and antibodies that usually begin after the first that usually begin after the first week of transplantation if there is no week of transplantation if there is no immunosuppressant therapyimmunosuppressant therapy

Incidence is high (30%) for the first Incidence is high (30%) for the first 90 days90 days

Acute RejectionAcute Rejection

1.1. T-cell, macrophage and Ab mediated,T-cell, macrophage and Ab mediated,

2.2. myocyte and endothelial damage, myocyte and endothelial damage,

3.3. InflammationInflammation

Chronic RejectionChronic Rejection

Occurs in most solid organ transplantsOccurs in most solid organ transplants HeartHeart KidneyKidney LungLung LiverLiver

Characterized by fibrosis and vascular Characterized by fibrosis and vascular abnormalities with loss of graft function abnormalities with loss of graft function over a prolonged period (Abbas 381)over a prolonged period (Abbas 381)

Chronic RejectionChronic Rejection

1.1. Macrophage – T cell mediatedMacrophage – T cell mediated

2.2. Concentric medial hyperplasiaConcentric medial hyperplasia

3.3. Chronic DTH reactionChronic DTH reaction

Types of RejectionTypes of Rejection Acute RejectionAcute Rejection: : CD4 controlled CD8 CD4 controlled CD8

mediated (8-11 days)mediated (8-11 days) Hyperacute RejectionHyperacute Rejection: : pre-existing pre-existing

antibodies to donor tissue (7 min)antibodies to donor tissue (7 min) Chronic RejectionChronic Rejection: : Mixed CD4 and Mixed CD4 and

antibody – ”DTH like” (3 m to 10 years) antibody – ”DTH like” (3 m to 10 years) Xenograft RejectionXenograft Rejection: : pre-existing pre-existing

antibodies to donor tissue (7 min)antibodies to donor tissue (7 min)

Xenogeneic Xenogeneic TransplantationTransplantation

A major barrier to xenogeneic A major barrier to xenogeneic transplantation is the presence of transplantation is the presence of natural antibodies that cause natural antibodies that cause hyperacute rejection. (Abbas pg 386)hyperacute rejection. (Abbas pg 386)

Most Common Most Common TransplantationTransplantation

-Blood Transfusion--Blood Transfusion-

Transfuse Not transfused

QuestionQuestion

Why are antibodies Why are antibodies normallynormally formed formed in response to ABO blood in response to ABO blood groups?groups?

1.1. Due to prior exposure to bloodDue to prior exposure to blood

2.2. Maternal exposureMaternal exposure

3.3. Gut floraGut flora

4.4. Plant pollenPlant pollen

QuestionQuestion

Why are antibodies Why are antibodies normallynormally formed formed in response to ABO blood in response to ABO blood groups?groups?

1.1. Prior exposure to bloodPrior exposure to blood

2.2. Maternal exposureMaternal exposure

3.3. Gut floraGut flora

4.4. Plant pollenPlant pollen

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

Acute GVHDAcute GVHD Characterized by epithelial cell death in Characterized by epithelial cell death in

the skin, GI tract, and liverthe skin, GI tract, and liver Chronic GVHDChronic GVHD

Characterized by atrophy and fibrosis of Characterized by atrophy and fibrosis of one or more of these same target organs one or more of these same target organs as well as the lungsas well as the lungs

Heart TransplantationHeart Transplantation

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

ejection fractions of <20%, ejection fractions of <20%, maximal oxygen consumption of (VOmaximal oxygen consumption of (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%.

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.

TransplantationTransplantation

KidneyKidney 25,000 patients are waiting for 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.

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

Pancreas TransplantationPancreas Transplantation Graft survivalGraft survival is 72% at one-year and this 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 The overall goaloverall goal of pancreas transplantation 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.

Immunologic AnalysisImmunologic Analysis

HLA Tissue HLA Tissue TypingTyping

CytoscreenCytoscreen Cross MatchCross Match

Questions?Questions?