Transplant ImmunologyTransplant Immunology

Transplantation and Transplantation and ImmunologyImmunology

Review of cytokinesReview of cytokines Cells involved in alloreactivityCells involved in alloreactivity Cell to cell interactionCell to cell interaction Major histocompatibility locus: Major histocompatibility locus:

transplant antigenstransplant antigens Clinical immunosuppressionClinical immunosuppression

Sources and Effects of CytokinesSources and Effects of CytokinesTNFTNF MMΦΦ, others, others Proliferation of T and B cells; enhances T cell function, activates Proliferation of T and B cells; enhances T cell function, activates MMΦΦ and and

PMNsPMNs

IFN-IFN-αα LeukocytesLeukocytes Increases expression of MHC class I receptors, acute inflammatory Increases expression of MHC class I receptors, acute inflammatory response and macrophage activationresponse and macrophage activation

IFN-IFN-ββ fibroblastsfibroblasts Same as IFN-Same as IFN-αα

IFN-IFN-γγ TH1TH1 Activates MActivates MΦΦ and NK cells, and NK cells, Promotes TH1 pathwayPromotes TH1 pathway

Upregulates MHC I/IIUpregulates MHC I/II

IL-1IL-1 Proliferation of T and B cells, fever, inflammationProliferation of T and B cells, fever, inflammation

IL-2IL-2 TH1TH1 Promotes T-cell and activated B-cell proliferation, stimulates cytokine Promotes T-cell and activated B-cell proliferation, stimulates cytokine secretion by T-cellssecretion by T-cells

IL-3IL-3 T cellsT cells Stimulates pluripotent stem cellsStimulates pluripotent stem cells

IL-4IL-4 TH2TH2 Promotes TH2 differentiationPromotes TH2 differentiation

B cell growth and differentiationB cell growth and differentiation

IGE production, mast cell growth factorIGE production, mast cell growth factor

Inhibits secretion of proinflammatory cytokinesInhibits secretion of proinflammatory cytokines

Il-5Il-5 T-cells, mast T-cells, mast cellscells

Growth/differentiation of eosinophilsGrowth/differentiation of eosinophils

B cell proliferationB cell proliferation

IL-6IL-6 MMΦΦ, TH2, TH2 Induces fever, promotes B-cell maturation and differentiation, stimulates Induces fever, promotes B-cell maturation and differentiation, stimulates hypothalamic-pituitary-adrenal axis, induces hepatic production of acute hypothalamic-pituitary-adrenal axis, induces hepatic production of acute phase proteins; levels are increased in sepsis and traumaphase proteins; levels are increased in sepsis and trauma

IL-8IL-8 MMΦΦ, endothelial , endothelial cellscells

Stimulates chemotaxis and oxidative burst by PMNs, high circulating Stimulates chemotaxis and oxidative burst by PMNs, high circulating levels associated with fatal outcome in sepsislevels associated with fatal outcome in sepsis

IL-9IL-9 TH2TH2 Promotes proliferation of activated T-cellsPromotes proliferation of activated T-cells

IL-10IL-10 TH2TH2 Inhibits proinflammatory cytokines by MInhibits proinflammatory cytokines by MΦΦ

IL-11IL-11 Neurons, fibroblasts, epithelial cellsNeurons, fibroblasts, epithelial cells Increases platelet production, inhibits Increases platelet production, inhibits proliferation of enterocytes; increased proliferation of enterocytes; increased levels in sepsis and DIClevels in sepsis and DIC

IL-12IL-12 MMΦΦ Promotes differentiation of CD4 cells to Promotes differentiation of CD4 cells to TH1 cells, enhances TH1 cells, enhances IFN-IFN-γγ secretion by secretion by TH1 cells and NK cells; implicated in TH1 cells and NK cells; implicated in inflammatory bowel diseaseinflammatory bowel disease

IL-13IL-13 TH2TH2 Inhibits proinflammatory cytokines by MInhibits proinflammatory cytokines by MΦΦ

IL-18IL-18 TH2TH2 Costimulation of IL-12 of Costimulation of IL-12 of IFN-IFN-γγ secretion by secretion by TH1 cells and NK cellsTH1 cells and NK cells

Cells involved in Cells involved in alloreactivityalloreactivity

Key componentsKey components T cellsT cells B cellsB cells Antigen presenting cells (APC)Antigen presenting cells (APC)

Development of lymphoid system begins with Development of lymphoid system begins with pluripotential stem cells in liver and bone marrow of pluripotential stem cells in liver and bone marrow of fetus. As fetus matures, bone marrow is primary fetus. As fetus matures, bone marrow is primary site for lymphopoiesis .site for lymphopoiesis .

Pre T cells migrate to thymus, where CD3+ cells Pre T cells migrate to thymus, where CD3+ cells mature and become “educated” to selfmature and become “educated” to self Learn to restrict to self MHC and learn tolerance to self Learn to restrict to self MHC and learn tolerance to self

antigensantigens Mature T cells then populate lymph nodes, spleen, Mature T cells then populate lymph nodes, spleen,

gutgut

Development of tolerance occurs Development of tolerance occurs centrally and peripherallycentrally and peripherally

Central tolerance occurs through Central tolerance occurs through clonal deletion in the thymusclonal deletion in the thymus

Pre-T cells (CD3+) enter thymus, Pre-T cells (CD3+) enter thymus, proliferate and become CD4+ and proliferate and become CD4+ and CD8+CD8+

Undergo “education” by self MHC Undergo “education” by self MHC class I or IIclass I or II

POSITIVE SELECTIONPOSITIVE SELECTION T cells that have a TCR receptor molecule T cells that have a TCR receptor molecule

with intermediate affinity for self MHC with intermediate affinity for self MHC survivesurvive

If affinity too high or low, cells undergo If affinity too high or low, cells undergo apoptosisapoptosis

NEGATIVE SELECTIONNEGATIVE SELECTION Occurs when T cells exposed to self antigensOccurs when T cells exposed to self antigens Undergo apoptosis if react too stronglyUndergo apoptosis if react too strongly

ApoptosisApoptosis

Regulated cell deathRegulated cell death Cell condenses, fragments, Cell condenses, fragments,

phagocytosis occursphagocytosis occurs Occurs through Fas Ligand systemOccurs through Fas Ligand system Fas- receptor expressed on activated Fas- receptor expressed on activated

T cellsT cells Expression of Fas and FasL lead to Expression of Fas and FasL lead to

apoptosisapoptosis

Cell to Cell InteractionsCell to Cell Interactions

APCs- dendritic cells and APCs- dendritic cells and macrophages-macrophages- Bind antigen and present it to B and T Bind antigen and present it to B and T

cellscells Protein antigens need to be digested by Protein antigens need to be digested by

phagocytes before presented to phagocytes before presented to lymphocytes for self and non self lymphocytes for self and non self recognition by MHCrecognition by MHC

T cell activationT cell activation

TCR- T cell receptor recognizes antigens only if TCR- T cell receptor recognizes antigens only if presented as peptide/MHC complexes presented presented as peptide/MHC complexes presented on surface of APCson surface of APCs

TCR (heterodimer) binds covalently with CD3 TCR (heterodimer) binds covalently with CD3 moleculemolecule

Foreign antigen causes conformational change; Foreign antigen causes conformational change; causes intracellular signalingcauses intracellular signaling

When T cell activated, TCRs decrease; IL-2/IL-2R When T cell activated, TCRs decrease; IL-2/IL-2R release increases(thru phospholipase C release increases(thru phospholipase C activation)activation)

T cell proliferates T cell proliferates

T cell activation also requires co-stimulatory signals (CD 28/B-7 T cell activation also requires co-stimulatory signals (CD 28/B-7 interaction)interaction)Without this, T cell anergy results (basis for monoclonal Ab)Without this, T cell anergy results (basis for monoclonal Ab)

T cell effector functionsT cell effector functions

Cytotoxic T cells (CD8)- interact with Cytotoxic T cells (CD8)- interact with MHC class I/peptide complexes and MHC class I/peptide complexes and lead to cell lysislead to cell lysis

Helper T cells (CD4)- recognize Helper T cells (CD4)- recognize antigen in context of MHC class II antigen in context of MHC class II moleculesmolecules Leads to cell mediated (TH1) or humoral Leads to cell mediated (TH1) or humoral

(TH2) response(TH2) response

B lymphocytesB lymphocytes

IL-7- growth factor for pre B cellsIL-7- growth factor for pre B cells IL-4, 5, 6 stimulate maturation and proliferation of IL-4, 5, 6 stimulate maturation and proliferation of

B cellsB cells Responsible for antibody mediated immune Responsible for antibody mediated immune

response against foreign antigenresponse against foreign antigen Express immunoglobulin antibody on cell surfaceExpress immunoglobulin antibody on cell surface One antigen specific antibody produced per One antigen specific antibody produced per

mature B cellmature B cell Naïve B cells express IgD and IgMNaïve B cells express IgD and IgM After antigen stimulation, undergo isotype After antigen stimulation, undergo isotype

switching to produce IgG (memory B cells)switching to produce IgG (memory B cells)

MacrophagesMacrophages

Role of monocyte/macrophageRole of monocyte/macrophage PhagocytosisPhagocytosis Presentation of processed antigen to Presentation of processed antigen to

lymphocytes results in production of lymphocytes results in production of cytokinescytokines

MHC locus/transplant MHC locus/transplant antigensantigens

Major histocompatibility locus located on Major histocompatibility locus located on Chromosome 6Chromosome 6

Produces Human Leukocyte Antigens Produces Human Leukocyte Antigens (HLA)(HLA)

Class I molecules are expressions of HLA-Class I molecules are expressions of HLA-A, HLA-B, HLA-CA, HLA-B, HLA-C

Class II molecules are expressions of HLA-Class II molecules are expressions of HLA-DR, HLA-DQ, HLA-DPDR, HLA-DQ, HLA-DP

Class III- contains mediators of immune Class III- contains mediators of immune function (TNF, heat shock protein)function (TNF, heat shock protein)

Comparing MHC Class I and Comparing MHC Class I and IIII

PropertiesProperties Class IClass I Class IIClass IIANTIGENSANTIGENS HLA-A, B, CHLA-A, B, C HLA-D-DR/Q/P HLA-D-DR/Q/P

TISSUETISSUE On all nucleated cells involved inOn all nucleated cells involved inDISTRIBUTION DISTRIBUTION cellscells immune systemimmune system

FUNCTIONSFUNCTIONS Endogenous AgEndogenous Ag Exogenous AgExogenous Agpresented to CD8presented to CD8 presented to presented to (cytotoxic) T-cells(cytotoxic) T-cells CD4 (T-helpers)CD4 (T-helpers)

HLA-Typing: Prevention and HLA-Typing: Prevention and RejectionRejection

Must make graft less antigenic so host Must make graft less antigenic so host doesn’t reject itdoesn’t reject it

Major strategy: minimize alloantigen Major strategy: minimize alloantigen differences between donor and hostdifferences between donor and host

1.1. ABO compatibility to prevent hyperacute rejectionABO compatibility to prevent hyperacute rejection

2.2. HLA (tissue) typing: HLA-A, HLA-B, HLA-DR most HLA (tissue) typing: HLA-A, HLA-B, HLA-DR most importantimportant

More alleles matched, greater survival of graft in 1More alleles matched, greater survival of graft in 1stst year year Appears to only matter if 6 allele match Appears to only matter if 6 allele match

HLA-typingHLA-typing

SerologicSerologic Uses antigen specific serum to bind cells Uses antigen specific serum to bind cells

expressing antigenexpressing antigen Not very accurateNot very accurate

MolecularMolecular PCRPCR

Cross match Cross match Uses flow cytometry to test for preformed Uses flow cytometry to test for preformed

antibodiesantibodies

RejectionRejection Three typesThree types

Hyperacute- due to preformed Ab Hyperacute- due to preformed Ab ABO incompatibilityABO incompatibility Minutes to hoursMinutes to hours Prevented by screeningPrevented by screening Result of prior pregnancy, transplant, blood Result of prior pregnancy, transplant, blood

transfusiontransfusion Cannot be treated with anti rejection medsCannot be treated with anti rejection meds Mechanism- complement cascade; mediated Mechanism- complement cascade; mediated

by IgGby IgG Characterized by rapid Characterized by rapid

thromobosis/occlusion of graft vasculaturethromobosis/occlusion of graft vasculature

Hyperacute RejectionHyperacute Rejection

Acute rejection Acute rejection Mediated by T lymphocytesMediated by T lymphocytes Occurs 1-3 weeks after transplantation Occurs 1-3 weeks after transplantation

without immunosuppressionwithout immunosuppression Most common 3-6 months post Most common 3-6 months post

transplantation but can occur anytimetransplantation but can occur anytime Characterized by Characterized by

macrophage/lymphycyte infiltrationmacrophage/lymphycyte infiltration

Acute RejectionAcute Rejection Two formsTwo forms

1.1.Acute vascular rejectionAcute vascular rejection IgG responseIgG response Leads to lysis of endothelial cells and Leads to lysis of endothelial cells and

cytokine productioncytokine production Endothelial necrosisEndothelial necrosis

2.2.Acute cellular rejectionAcute cellular rejection Necrosis of parenchymal cells due to Necrosis of parenchymal cells due to

infiltration of T cells and macrophagesinfiltration of T cells and macrophages

Acute Rejection Acute Rejection

Chronic rejectionChronic rejection Appears as fibrosis and scarringAppears as fibrosis and scarring

Atherosclerosis in heart patientsAtherosclerosis in heart patientsBOOP in lung patientsBOOP in lung patients““vanishing bile duct syndrome” vanishing bile duct syndrome” in liver patientsin liver patients

Fibrosis, glomerulonephropathy Fibrosis, glomerulonephropathy in kidney patientsin kidney patients

Due to ischemia and inflammationDue to ischemia and inflammation

Chronic RejectionChronic Rejection

Risk factorsRisk factors Previous acute rejection (Previous acute rejection ( risk with more risk with more

episodes)episodes) Inadequate immunosuppressionInadequate immunosuppression Initial delayed graft functionInitial delayed graft function Donor factors (age, HTN) Donor factors (age, HTN) Procurement issues (ischemia time, Procurement issues (ischemia time,

reperfusion injury)reperfusion injury) Recipient issues (DM, HTN, infections)Recipient issues (DM, HTN, infections)

Chronic Rejection

Risks of immunosuppressionRisks of immunosuppression InfectionInfection

Environmental pathogens and reactivation of host Environmental pathogens and reactivation of host pathogens (CMV, EBV)pathogens (CMV, EBV)

Requires prophylaxis with gangcyclovir; hep B Requires prophylaxis with gangcyclovir; hep B vaccine, Bactrim to prevent PCP, UTIvaccine, Bactrim to prevent PCP, UTI

MalignancyMalignancy No increase in lung, breast, prostate, colon, uterine No increase in lung, breast, prostate, colon, uterine

CACA Skin tumors, cervical CA, Kaposi’s, lymphoma, other Skin tumors, cervical CA, Kaposi’s, lymphoma, other

virus mediated tumors more common in Tx patientsvirus mediated tumors more common in Tx patients Cardiovascular diseaseCardiovascular disease

Pretransplant risk factors (DM, HTN, CAD) amplified Pretransplant risk factors (DM, HTN, CAD) amplified by immunosuppressionby immunosuppression

Pts need good pre-op workupPts need good pre-op workup

Clinical immunosuppressionClinical immunosuppression

Objectives of Objectives of ImmunosuppressionImmunosuppression

Facilitate acceptance of the allograft Facilitate acceptance of the allograft SpecificSpecific Low toxicityLow toxicity

Basic Strategies of Basic Strategies of ImmunosuppressionImmunosuppression

Induction (High dose initial Induction (High dose initial immunosuppression) immunosuppression)

Facilitate graft acceptanceFacilitate graft acceptance Minimize early rejectionMinimize early rejection Favor induction of toleranceFavor induction of tolerance

Maintenance therapy for chronic Maintenance therapy for chronic acceptanceacceptance

Augmentation to reverse acute Augmentation to reverse acute rejection.rejection.

Graft RejectionGraft Rejection

Highly dependent on T cell activation Highly dependent on T cell activation and proliferation.and proliferation.

Signaling pathways and control Signaling pathways and control points for entry into cell cycle are points for entry into cell cycle are appropriate targets for appropriate targets for immunsuppression.immunsuppression.

Broad Mechanisms of Broad Mechanisms of ImmunosuppressionImmunosuppression

T cell depletion. (induction)T cell depletion. (induction) Inhibition of T cell activation.Inhibition of T cell activation.

Block antigen binding.Block antigen binding. Block accessory molecules.Block accessory molecules. Inhibition of IL-2 production.Inhibition of IL-2 production.

Inhibition of T cell proliferation.Inhibition of T cell proliferation. Inhibition of B cell proliferation.Inhibition of B cell proliferation.

Induction Agents-Induction Agents-ThymoglobulinThymoglobulin

Antithymocyte globulin- polyclonal sera Antithymocyte globulin- polyclonal sera produced when human lymphocytes produced when human lymphocytes injected into animals (rabbit or horse)injected into animals (rabbit or horse)

Interferes with cell-mediated reactions: Interferes with cell-mediated reactions: allograft rejection, graft v host diseaseallograft rejection, graft v host disease

Used in early post transplant period or to Used in early post transplant period or to reverse ongoing rejectionreverse ongoing rejection

Can cause anemia, thrombocytopeniaCan cause anemia, thrombocytopenia Allergic reaction most common problemAllergic reaction most common problem

Induction Agents-Induction Agents-Monoclonal AntibodyMonoclonal Antibody

OKT3- engages CD3 TCR receptorOKT3- engages CD3 TCR receptor TCR receptor internalized by cell and no TCR receptor internalized by cell and no

longer expressed on cell surfacelonger expressed on cell surface T cells removed by spleen and T cells removed by spleen and

reticuloendothelial cellsreticuloendothelial cells Less effective over timeLess effective over time Cytokine release syndromeCytokine release syndrome

Induction Agents-Induction Agents-IL-2R inhibitorsIL-2R inhibitors

Basiliximab/ daclizumab (CD25 Ab)Basiliximab/ daclizumab (CD25 Ab) Bind to IL-2 receptors without activating Bind to IL-2 receptors without activating

themthem Cells can’t bind IL-2; can’t proliferateCells can’t bind IL-2; can’t proliferate Must be combined with other Must be combined with other

immunosuppressantsimmunosuppressants Well toleratedWell tolerated

Induction Agents-Induction Agents-

Rituximab- Anti-CD 20 AbRituximab- Anti-CD 20 Ab Treats humoral rejection due to B cell Treats humoral rejection due to B cell

depleting abilitydepleting ability Campath 1H- Anti CD52 AbCampath 1H- Anti CD52 Ab

Acts against B/T cells, macrophagesActs against B/T cells, macrophages Depletes lymphocytes for 2-6 monthsDepletes lymphocytes for 2-6 months

Maintenance AgentsMaintenance Agents

Adrenal Corticosteroid- prednisoneAdrenal Corticosteroid- prednisone AntiproliferativeAntiproliferative

AzathioprineAzathioprine Mycophenolate mofetilMycophenolate mofetil LeflunomideLeflunomide

T cell directedT cell directed Calcineurin inhibitors: cyclosporine, tacrolimusCalcineurin inhibitors: cyclosporine, tacrolimus Cell cycle arrest: sirolimusCell cycle arrest: sirolimus

Lymphocyte Sequestration- FTY720Lymphocyte Sequestration- FTY720

Adrenal CorticosteroidsAdrenal Corticosteroids Suppresses transcription and secretion of Suppresses transcription and secretion of

IL-1, IL-6, TNFIL-1, IL-6, TNF Inhibits IL-2 production and binding of IL-2RInhibits IL-2 production and binding of IL-2R Blocks ability of macrophages to respond to Blocks ability of macrophages to respond to

signals such as migration inhibition and signals such as migration inhibition and activation factorsactivation factors

Side effectsSide effects Cushingoid featuresCushingoid features Ulcer/GI bleedUlcer/GI bleed DiabetesDiabetes Avascular necrosisAvascular necrosis

Antiproliferative AgentsAntiproliferative AgentsAntimetabolitesAntimetabolites

Lymphocytes depend on de novo purine Lymphocytes depend on de novo purine synthesis rather than salvage pathwaysynthesis rather than salvage pathway

Azathioprine (6 mercaptopurine)Azathioprine (6 mercaptopurine) Blocks de novo purine synthesis, impedes T Blocks de novo purine synthesis, impedes T

cell replicationcell replication Mycophenolate (Cellcept) Mycophenolate (Cellcept)

Blocks inosine monophosphate dehydrogenase Blocks inosine monophosphate dehydrogenase (Rate limiting step for de novo sythesis)(Rate limiting step for de novo sythesis)

Side effects- diarrhea, vomiting, bone marrow Side effects- diarrhea, vomiting, bone marrow suppression, opportunitistic infectionssuppression, opportunitistic infections

Antiproliferative AgentsAntiproliferative AgentsAntimetabolitesAntimetabolites

LeflunomideLeflunomide Blocks dihydro-orotate dehydrogenase Blocks dihydro-orotate dehydrogenase

(necessary for de novo pyrimidine (necessary for de novo pyrimidine synthesis)synthesis)

Inhibitors of T cell Receptor Inhibitors of T cell Receptor SignalingSignaling

Cyclosporine-binds to cyclophilinCyclosporine-binds to cyclophilin Complex binds/inhibits calcineurinComplex binds/inhibits calcineurin Blocks cytokine production, esp IL-2, but does Blocks cytokine production, esp IL-2, but does

not inhibit proliferationnot inhibit proliferation P 450 metabolismP 450 metabolism

Side EffectsSide Effects Gingival HyperplasiaGingival Hyperplasia InfectionInfection NephrotoxicityNephrotoxicity HypertensionHypertension Tremors, Nightmares, InsomniaTremors, Nightmares, Insomnia HirsutismHirsutism Fibrous Breast TissueFibrous Breast Tissue

Inhibitors of T cell Receptor Inhibitors of T cell Receptor SignalingSignaling

Tacrolimus (FK506, Prograf)Tacrolimus (FK506, Prograf) Also inhibits calcineurin, thus inhibiting Also inhibits calcineurin, thus inhibiting

IL-2 productionIL-2 production Inhibits production of cytotoxic T cellsInhibits production of cytotoxic T cells Side effects: alopecia, risk of post Side effects: alopecia, risk of post

transplant diabetestransplant diabetes

Inhibitors of T cell Receptor Inhibitors of T cell Receptor SignalingSignaling

SirolimusSirolimus Macrolide antibioticMacrolide antibiotic Causes cell cycle arrestCauses cell cycle arrest Blocks transduction of signals from IL-2R Blocks transduction of signals from IL-2R

to nucleus rather than blocking cytokine to nucleus rather than blocking cytokine gene expressiongene expression

T cell Receptor Signaling T cell Receptor Signaling PathwayPathway

FynZap-70

PLCPIP 2

D AGIP 3

C a 2+

CaM

C alcineurin

T cell Signaling: T cell Signaling: CalcineurinCalcineurin

N F-ATP

N ucleus

P

P

N F-ATN

Transcrip tion

N F-AT

C ytokine G ene

CalcineurinCaM

C alcineurin

C yclophilin

C yclosporine

Lymphocyte SequestrationLymphocyte Sequestration

FTY720FTY720 Sequesters lymphocytes in Peyer’s Sequesters lymphocytes in Peyer’s

patchespatches Can cause bradycardiaCan cause bradycardia

Treatment of Acute Treatment of Acute RejectionRejection

Need prompt diagnosis from biopsyNeed prompt diagnosis from biopsy Treat mild rejection with steroidsTreat mild rejection with steroids Thymoglobulin or OKT3 for severe Thymoglobulin or OKT3 for severe

rejectionrejection CMV prophylaxis during treatment of CMV prophylaxis during treatment of

acute rejectionacute rejection

Now for a Quick Review:Now for a Quick Review:

The correct terminology for a graft The correct terminology for a graft between genetically nonidentical between genetically nonidentical members of the same species is:members of the same species is:

A.A. Allogeneic graftAllogeneic graftB.B. Autogeneic graftAutogeneic graftC.C. Isogeneic graftIsogeneic graftD.D. Syngeneic graftSyngeneic graftE.E. Xenogeneic graftXenogeneic graft

Which of the following Which of the following statements correctly statements correctly

characterize the genetic basis characterize the genetic basis of histocompatibility?of histocompatibility? A. Histocompatibility is determined by a series of A. Histocompatibility is determined by a series of

genes inherited as a complex and subject to the genes inherited as a complex and subject to the mendelian rules that characterize recessive traitsmendelian rules that characterize recessive traits

B. Histocompatibility depeds in part on the B. Histocompatibility depeds in part on the inheritance of histocompatibility genes and in inheritance of histocompatibility genes and in part of the inheritance of T-cell receptor genespart of the inheritance of T-cell receptor genes

C. Major histocompatibility genes are C. Major histocompatibility genes are polymorphicpolymorphic

D. Major histocompatibility genes are D. Major histocompatibility genes are independently segregating and co-dominantindependently segregating and co-dominant

E. Histocompatibility is learnedE. Histocompatibility is learned

Which of the following Which of the following distinguish MHC classs I from distinguish MHC classs I from

MHC class II antigens?MHC class II antigens? A. MHC class I and class II antigens are encoded A. MHC class I and class II antigens are encoded

in different regions of the MHC complexin different regions of the MHC complex B. MHC class I antigens are expressed on B. MHC class I antigens are expressed on

specialized antigen presenting cells, whereas specialized antigen presenting cells, whereas MHC class II antigens are expressed on all cellsMHC class II antigens are expressed on all cells

C. MHC class I and class II are members of C. MHC class I and class II are members of different supergene familiesdifferent supergene families

D. MHC class I are considered to be the major D. MHC class I are considered to be the major histocompatibility antigens and MHC class II the histocompatibility antigens and MHC class II the minor antigensminor antigens

MHC class I is recognized by the CD8 MHC class I is recognized by the CD8 glycoprotein, whereas MHC class II is recognized glycoprotein, whereas MHC class II is recognized by the CD4 glycoproteinby the CD4 glycoprotein

Which of the following Which of the following characterize the role of the characterize the role of the

major histocompatibility major histocompatibility antigens in immune antigens in immune

responses?responses? A. The major histocompatibility antigens are A. The major histocompatibility antigens are critical in antigen processing and presentationcritical in antigen processing and presentation

B. Major histocompatibilty antigens contribute to B. Major histocompatibilty antigens contribute to the maturation of T cells in the thymusthe maturation of T cells in the thymus

C. T cells recognize only foreign antigens that are C. T cells recognize only foreign antigens that are complexed with major histocompatibility antigenscomplexed with major histocompatibility antigens

D. Expression of major histocompatiblity D. Expression of major histocompatiblity antigens is increased in inflammationantigens is increased in inflammation

E. Recognition of major histocompatibility E. Recognition of major histocompatibility antigens is critical to the development of antigens is critical to the development of tolerancetolerance

Which of the following Which of the following statements correctly statements correctly

characterize the role of characterize the role of histocompatibility typing in histocompatibility typing in

transplantation?transplantation? A. Histocompatibility typing must be carried out A. Histocompatibility typing must be carried out before transplantation can be safely undertaken.before transplantation can be safely undertaken.

B. The “rules” of histocompatibility wre established B. The “rules” of histocompatibility wre established shrotly after the advent of immunosuppressive shrotly after the advent of immunosuppressive therapy made transplantation feasibletherapy made transplantation feasible

C. Histocompatibility typing may involve serologic, C. Histocompatibility typing may involve serologic, cellular, and molecular procedures for typingcellular, and molecular procedures for typing

D. The role of histocompatibility matching in D. The role of histocompatibility matching in transplantation is controversialtransplantation is controversial

E. The cross match test is carried out to determine E. The cross match test is carried out to determine whether a potential graft recipient has antibodies whether a potential graft recipient has antibodies against the donoragainst the donor

Activation of T cells Activation of T cells requires:requires:

A. Stimulation of the antigen A. Stimulation of the antigen receptorreceptor

B. Stimulation of the MHC antigenB. Stimulation of the MHC antigen C. Co-stimulation (CD28/B7)C. Co-stimulation (CD28/B7) D. AnergyD. Anergy E. CD3E. CD3

Which of the following Which of the following statements characterize the statements characterize the

biology of allotransplantation?biology of allotransplantation? A. The rejection response is systemicA. The rejection response is systemic B. The rejection response is learnedB. The rejection response is learned C. The rejection response involves a C. The rejection response involves a

constellation of immunologic and constellation of immunologic and enviromental factorsenviromental factors

D. Allotransplantation evokes a cellular D. Allotransplantation evokes a cellular immune responseimmune response

E. Allotransplantation evokes a humoral E. Allotransplantation evokes a humoral immune responseimmune response

Allograft rejection may involve Allograft rejection may involve which of the following?which of the following?

A. Helper T cellsA. Helper T cells B. Veto cellsB. Veto cells C. CytotoxicityC. Cytotoxicity D. CytokinesD. Cytokines E. The Arthus reactionE. The Arthus reaction

Which of the following Which of the following statements about allograft statements about allograft

rejection are true?rejection are true? A. In the absence of immunosuppression, the time A. In the absence of immunosuppression, the time

and intensity of rejection of transplants between and intensity of rejection of transplants between unrelated donors and recipients is highly variable.unrelated donors and recipients is highly variable.

B. Allograft rejection may be mediated by B. Allograft rejection may be mediated by antibodies or by cellsantibodies or by cells

C. Allograft rejection is thought to be caused by C. Allograft rejection is thought to be caused by Th2 cellsTh2 cells

D. Acute cellular rejection is the major cause for D. Acute cellular rejection is the major cause for loss of clinical organ transplantsloss of clinical organ transplants

E. An individual with “tolerance” is unable to reject E. An individual with “tolerance” is unable to reject an allograftan allograft

The presence of donor reactive The presence of donor reactive lymphocytotoxic antiboies in lymphocytotoxic antiboies in

the serum of a potential kidney the serum of a potential kidney transplant recipient:transplant recipient:

A. Can be detected by in vitro A. Can be detected by in vitro testing with recipient leukocytes and testing with recipient leukocytes and donor serumdonor serum

B. Is a contraindication of kidney B. Is a contraindication of kidney transplantationtransplantation

C. Can be found in all male patients C. Can be found in all male patients older than 20 yearsolder than 20 years

Utilization of a living related donor instead of Utilization of a living related donor instead of a cadaver donor is no longer an advantage a cadaver donor is no longer an advantage

in rental transplantation beause:in rental transplantation beause:

A. Public recognition of transplantation as a A. Public recognition of transplantation as a successful therapy has facilitated obtaining family successful therapy has facilitated obtaining family permission of recovery of transplantable organs. permission of recovery of transplantable organs. Thus, there is no need to use related donors.Thus, there is no need to use related donors.

B. Cyclosporine therapy after cadaveric renal B. Cyclosporine therapy after cadaveric renal transplants has improved their outcome, which is transplants has improved their outcome, which is now comparable to related-donor transplantsnow comparable to related-donor transplants

C. Modern preservation techniques can maintain C. Modern preservation techniques can maintain viability of kidneys from cadaver donors for many viability of kidneys from cadaver donors for many hours, consistently allowing their function to be hours, consistently allowing their function to be as good as that of kidneys from living donorsas good as that of kidneys from living donors

D. None of the aboveD. None of the above

As compared with the early As compared with the early immunosuppressive drugs (azathioprine, immunosuppressive drugs (azathioprine,

steriods, antilyphocyte serum), some newer steriods, antilyphocyte serum), some newer agents have the following specific agents have the following specific

advantages:advantages: A. Cyclosporine, which interferes with A. Cyclosporine, which interferes with

lymphokine production, exhibits neither lymphokine production, exhibits neither bone marrow nor renal toxicitybone marrow nor renal toxicity

B. Monoclonal antibody (OKT3) is more B. Monoclonal antibody (OKT3) is more available and has greater specificity and available and has greater specificity and few side effects than antilymphocyte serumfew side effects than antilymphocyte serum

C. Tacrolimus (FK506) has properties C. Tacrolimus (FK506) has properties similar to those of cyclosporine but is similar to those of cyclosporine but is especially valuable for rescue of grafts that especially valuable for rescue of grafts that are failing on cyclosporine therapyare failing on cyclosporine therapy

D. None of the aboveD. None of the above

Which of the following Which of the following statements about statements about

posttransplantation posttransplantation malignancy is correct?malignancy is correct? A. Certain immunosuppressive agents A. Certain immunosuppressive agents

increase the incidence of malignancy increase the incidence of malignancy whereas others do notwhereas others do not

B. Those malignancies most commonly B. Those malignancies most commonly seen in the general population (breast, seen in the general population (breast, colon) are substantially more common in colon) are substantially more common in transplant recipientstransplant recipients

C. Lymphoproliferative states and B-cell C. Lymphoproliferative states and B-cell lymphomas are associated with Epstein-lymphomas are associated with Epstein-Barr virusBarr virus

D. None of the aboveD. None of the above