Immunology12006-7year Chapter 19 Transplantation Immunology

ImmunologyImmunology 112006-7year2006-7year

Chapter 19 Chapter 19 Transplantation Transplantation

ImmunologyImmunology

2006-7year2006-7year ImmunologyImmunology 22

ContentsContents

• IntroductionIntroduction• Immunologic Basis of Allograft Rejection Immunologic Basis of Allograft Rejection • Classification and Effector Mechanisms Classification and Effector Mechanisms

of allograft rejectionof allograft rejection• Prevention and Treatment of Allograft RPrevention and Treatment of Allograft R

ejectionejection• XenotransplantationXenotransplantation


IntroductionIntroduction


ConceptionsConceptions

• TransplantationTransplantation• GraftsGrafts• DonorsDonors• Recipients or hostsRecipients or hosts• Orthotopic transplantationOrthotopic transplantation• Heterotopic transplantation Heterotopic transplantation


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

• Alexis Carrel (France)Alexis Carrel (France)

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

Great events in history of transplantation



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

• Discovery of acquired immunDiscovery of acquired immunological tolerance ological tolerance – The graft reaction is an immunitThe graft reaction is an immunit

y phenomenon y phenomenon – 1950s,1950s, induced immunological tinduced immunological t

olerance to skin allografts in miolerance to skin allografts in mice by neonatal injection of allogce by neonatal injection of allogeneic cellseneic cells




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

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

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

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


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

• George D. Snell George D. Snell (1/3),(1/3), Jean Dausset Jean Dausset (1/3)(1/3) • Discoveries concerning genetically determined Discoveries concerning genetically determined

structures on the cell surface that regulate immstructures on the cell surface that regulate immunological reactions unological reactions – H-genes (histocompatibility genes), H-2 gene H-genes (histocompatibility genes), H-2 gene – Human transplantation antigens (HLA) ----MHCHuman transplantation antigens (HLA) ----MHC



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

• Gertrude B. Elion Gertrude B. Elion (1/3)(1/3) , George H. Hitchings , George H. Hitchings (1/3)(1/3) • Discoveries of important principles for drug treatDiscoveries of important principles for drug treat

ment ment – Immunosuppressant drug (The first cytotoxic drugs)Immunosuppressant drug (The first cytotoxic drugs)

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



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


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

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

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

ntical individuals of the same species ntical individuals of the same species • Allogeneic grafts (Allografts)Allogeneic grafts (Allografts)

– Grafts transplanted between two genetically diffGrafts transplanted between two genetically different individuals of the same species erent individuals of the same species

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

ent speciesent species


Skin from an inbred mouse grafted onto the same strain of mouse

Skin from an inbred mouse grafted onto a different strain of mouse

ACCEPTED

REJECTED

Genetic basis of transplant rejection

Inbred mouse strains - all genes are identical

Transplantation of skin between strains showed thatrejection or acceptance was dependent upon

the genetics of each strain


6 months

Transplant rejection is due to an antigen-specific immune response with immunological memory

Immunological basis of graft rejection

Primary rejection of strain skin

e.g. 10 days

Secondary rejection of strain skin

e.g. 3 days

Primary rejection ofstrain skin

e.g. 10 days

Naïve mouse

LycTransfer lymphocytesfrom primed mouse


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

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



Part onePart one

Immunologic Basis of Immunologic Basis of Allograft RejectionAllograft Rejection


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

• Minor histocompatibility antigensMinor histocompatibility antigens• Other alloantigensOther alloantigens

I. Transplantation antigensI. Transplantation antigens


1. Major histocompatibility antigens1. Major histocompatibility antigens

• Main antigens of grafts rejection Main antigens of grafts rejection

• Cause fast and strong rejectionCause fast and strong rejection

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


2. Minor histocompatibility antigens2. Minor histocompatibility antigens

• Also cause grafts rejection, but slow and Also cause grafts rejection, but slow and weakweak

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

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



3. Other alloantigens3. Other alloantigens

• Human ABO blood group antigens Human ABO blood group antigens • Some tissue specific antigensSome tissue specific antigens

– SkinSkin ＞＞ kidneykidney ＞＞ heartheart ＞＞ pancreas pancreas ＞＞ liverliver– VEC antigen VEC antigen – SK antigen SK antigen


• Cell-mediated Immunity Cell-mediated Immunity • Humoral Immunity Humoral Immunity • Role of NK cellsRole of NK cells

II. Mechanism of allograft II. Mechanism of allograft rejectionrejection


1. Cell-mediated Immunity1. Cell-mediated Immunity

• Recipient's T cell-mediated cellular imRecipient's T cell-mediated cellular immune response against alloantigens on mune response against alloantigens on graftsgrafts


Molecular Mechanisms of Allogeneic Molecular Mechanisms of Allogeneic RecognitionRecognition

？？ T cells of the recipient recognize the allT cells of the recipient recognize the allogenetic MHC moleculesogenetic MHC molecules

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

ional antigensional antigens– 1%-10% of T cells recognize allogenetic MH1%-10% of T cells recognize allogenetic MH

C moleculesC molecules


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

• Direct Recognition Direct Recognition

• Indirect RecognitionIndirect Recognition


Direct RecognitionDirect Recognition

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

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

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

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


• Cross recognitionCross recognition


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

MΦMΦ– Early phase of acute rejectionEarly phase of acute rejection ？？– Fast and strongFast and strong ？？


？？ Many T cells can recognize allogenetMany T cells can recognize allogenetic MHC moleculesic MHC molecules

• Allogenetic MHC molecules (different residues)Allogenetic MHC molecules (different residues)• Allogenetic MHC molecules–different peptidesAllogenetic MHC molecules–different peptides• All allogenetic MHC molecules on donor APC can All allogenetic MHC molecules on donor APC can

be epitopes recognized by TCRbe epitopes recognized by TCR


Indirect recognitionIndirect recognition

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

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



Recipient T cell

TCRPeptide

Donor MHC molecule

Donor MHC molecule

Donor APC Recipient APC

Recipient MHC molecule

Peptide from donor MHC molecule


• Slow and weakSlow and weak

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

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


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

Direct Direct RecognitionRecognition

Indirect Indirect RecognitionRecognition

Allogeneic MHC molAllogeneic MHC moleculeecule

Intact allogeneic MHC Intact allogeneic MHC moleculemolecule

Peptide of allogeneic Peptide of allogeneic MHC moleculeMHC molecule

APCsAPCs Recipient APCs are not Recipient APCs are not necessarynecessary

Recipient APCsRecipient APCs

Activated T cellsActivated T cells CD4CD4 ＋＋ T cells and/or CT cells and/or CD8D8 ＋＋ T cellsT cells

CD4CD4 ＋＋ T cells and/or CT cells and/or CD8D8 ＋＋ T cellsT cells

Roles in rejectionRoles in rejection Acute rejectionAcute rejection Chronic rejectionChronic rejection

Degree of rejectionDegree of rejection VigorousVigorous WeakWeak


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

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

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

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



Role of CD4 ＋ T cells and CD8 ＋ T cellsRole of CD4 ＋ T cells and CD8 ＋ T cells

CD4+TH1

CD8+CTL

CD8+preCTL


• Important role in hyperacute rejectionImportant role in hyperacute rejection (Preformed antibodies)(Preformed antibodies)

– Complements activationComplements activation– ADCCADCC– OpsonizationOpsonization

• Enhancing antibodiesEnhancing antibodies /Blocking antibodies/Blocking antibodies

2. Humoral immunity2. Humoral immunity


3 .Role of NK cells3 .Role of NK cells

• KIR can’t recognize allogeneic MHC on KIR can’t recognize allogeneic MHC on graftgraft

• CKs secreted by activated Th cells can prCKs secreted by activated Th cells can promote NK activationomote NK activation


Inflammation

lysis

ADCC

lysis

IL2, IFN

TNF, NO2

IL2, IL4, IL5

IL2, TNF, IFN

Rejection

Mechanisms of graft rejectionMechanisms of graft rejectionMechanisms of graft rejectionMechanisms of graft rejection


Part twoPart two

Classification and Effector Classification and Effector Mechanisms of Allograft RejMechanisms of Allograft Rej

ectionection


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

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

Classification of AllograftClassification of Allograft RejectionRejection


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

• Hyperacute rejectionHyperacute rejection• Acute rejectionAcute rejection• Chronic rejectionChronic rejection


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

vessels are anastomosed to graft vesselsvessels are anastomosed to graft vessels• Pathology Pathology

– Thrombotic occlusion of the graft vasculature Thrombotic occlusion of the graft vasculature – Ischemia, denaturation, necrosis Ischemia, denaturation, necrosis

1. Hyperacute rejection1. Hyperacute rejection


• MechanismsMechanisms– Preformed antibodies Preformed antibodies

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

•Antibody against VEC antigen Antibody against VEC antigen

•Antibody against HLA antigenAntibody against HLA antigen


– Complement activationComplement activation•Endothelial cell damageEndothelial cell damage

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

damage damage


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

antation, 80-90% of cases occur within 1 moantation, 80-90% of cases occur within 1 month nth

• PathologyPathology– Acute humoral rejectionAcute humoral rejection

•Acute vasculitis manifested mainly by endotheliAcute vasculitis manifested mainly by endothelial cell damageal cell damage

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

n of lymphocytes and MΦn of lymphocytes and MΦ

2. Acute rejection2. Acute rejection


• Mechanisms Mechanisms – Vasculitis Vasculitis

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

•CDCCDC– Parenchymal cell damage Parenchymal cell damage

•Delayed hypersensitivity mediated by CD4+Th1Delayed hypersensitivity mediated by CD4+Th1•Killing of graft cells by CD8+TcKilling of graft cells by CD8+Tc



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

rejection reactions have subsidedrejection reactions have subsided

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

loss of graft functionloss of graft function

3. Chronic rejection3. Chronic rejection


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

e rejectione rejection– Chronic inflammation mediated by CD4+T cChronic inflammation mediated by CD4+T c

ell/MΦell/MΦ– Organ degeneration induced by non immunOrgan degeneration induced by non immun

e factorse factors



Kidney Transplantation----Graft Rejection


Chronic rejection in a kidney allograft with arteriosclerosis


II.Graft versus host reaction (GVII.Graft versus host reaction (GVHR)HR)• Graft versus host reaction (GVHR) Graft versus host reaction (GVHR)

– Allogenetic bone marrow transplantationAllogenetic bone marrow transplantation– Rejection to host alloantigensRejection to host alloantigens– Mediated by immune competent cells in boMediated by immune competent cells in bo

ne marrowne marrow• Graft versus host disease (GVHD)Graft versus host disease (GVHD)

– A disease caused by GVHR, which can damaA disease caused by GVHR, which can damage the hostge the host


• Graft versus host disease Graft versus host disease


• Graft versus host diseaseGraft versus host disease


ConditionsConditions

• Enough immune competent cells in graftsEnough immune competent cells in grafts• Immunocompromised hostImmunocompromised host• Histocompatability differences between hoHistocompatability differences between ho

st and graftst and graft


• Bone marrow transplantation Bone marrow transplantation • Thymus transplantationThymus transplantation• Spleen transplantationSpleen transplantation• Blood transfusion of neonateBlood transfusion of neonate

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


1. Acute GVHD1. Acute GVHD

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

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

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


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


2. Chronic GVHD2. Chronic GVHD

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

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


Both acute and chronic GVHD are commBoth acute and chronic GVHD are commonly treated with intense immunosuppronly treated with intense immunosuppresionesion

• UncertainUncertain• Fatal Fatal


Part threePart three

Prevention and Therapy Prevention and Therapy of Allograft Rejectionof Allograft Rejection


• Tissue TypingTissue Typing

• Immunosuppressive TherapyImmunosuppressive Therapy

• Induction of Immune ToleranceInduction of Immune Tolerance


I. Tissue TypingI. Tissue Typing

• ABO and Rh blood typingABO and Rh blood typing• Crossmatching (Preformed antibodies)Crossmatching (Preformed antibodies)• HLA typing HLA typing

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


• Laws of transplantationLaws of transplantation


II. Immunosuppressive II. Immunosuppressive TherapyTherapy

• Cyclosporine(CsA), FK506Cyclosporine(CsA), FK506– Inhibit NFAT transcription factorInhibit NFAT transcription factor

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

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

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

retion of cytokinesretion of cytokines


Removal of T cells from marrow graft


III.III. Induction of Immune Induction of Immune ToleranceTolerance

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

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

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

nor, genetically distinct from those of the host nor, genetically distinct from those of the host individualindividual


Part IVPart IV

XenotransplantationXenotransplantation


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


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

lα1,3Gallα1,3Gal– Construct transgenic pigs expressing humaConstruct transgenic pigs expressing huma

n proteins that inhibit complement activatin proteins that inhibit complement activationon

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

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

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Immunology12006-7year Chapter 19 Transplantation Immunology