Transplant Immuno - 2

8/11/2019 Transplant Immuno - 2

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Transplantation Unit

8/29: Basic immunology of transplantation

8/31: Pathology lab: hypersensitivity and rejection

9/5: Pharmacology of immunosuppressive drugs

9/6: Clinical Case Discussion: Transplant cases


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Terminology of Transplantation

Autograft (e.g. skin grafts for burns, etc.) Syngraft (genetically identical twins;

possibly therapeutic cloning)

No immunologic rejection for these two types Allograft (genetically distinct member of

same species; almost all medical transplants) Xenograft (different species; attractive due

to shortage of organs for transplants) Very severe rejection problems


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Histocompatability Antigens

I. ABO blood group antigensPre-existing antibodies to A or B antigens lead to

hyperacute rejection if not matched properlyII. Major histocompatability antigens

Encoded by the MHC, originally discovered for theirrole in skin graft rejection in mice

III. Minor histocompatability antigensAllelic variants of normal cellular proteins


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Structures of A, B, O blood groupantigens

The A and B alleles of theABO genetic locus encode

very similar glycosyl-transferases, the O alleleencodes a defective versionwith no activity (leaving the

H antigenic structureunmodified)

QuickTime and a

decompressorare needed to see this picture.


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Red blood cell antigens and Bloodtransfusions

The ABO antigen system provides a potentialproblem for blood transfusions People who lack A or B antigens have preexisting

antibodies to these antigens, which can combine withRBCs, fix complement, and cause transfusion reaction

QuickTime and a decompressor

are needed to see this picture.

Mostly IgM


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Rh antigen and hemolytic disease of

newborn Mother is Rh-negative and father is Rh-positive

Mother is immunized at birth of first Rh-positive child

Small amounts of antigen enter mother during pregnancy

with 2nd Rh-positive child This induces secondary antibody response, high levels of

IgG are produced, enter fetal circulation and attach toRBCs of fetus

Treated by giving anti-Rh antibody to pregnant womanonce during gestation and within 72 hr. after birth offirst child to inhibit primary response


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Histocompatability Antigens

I. ABO blood group antigensPre-existing antibodies to A or B antigens lead to

hyperacute rejection if not matched properly

II. Major histocompatability antigensEncoded by the MHC, originally discovered for their

role in skin graft rejection in mice

III. Minor histocompatability antigensAllelic variants of normal cellular proteins


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MHC Class I and Class II genes are highly polymorphic and are all closely

linked; most of the time, they are inherited as a block (called a haplotype)


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TCR specificity and self-MHC

MHC molecules are highly polymorphic During development in the thymus, T cells are selected

for moderate/weak binding to self-MHC + self-peptides (positive selection)

During development in the thymus, T cells are killed

(or become regulatory T cells) if they have strongbinding to self-MHC + a self-peptide (negativeselection)

Do the T cells of one person see MHC moleculesfrom another person?


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Do Alloreactive T cells needcostimulation?

Ordinarily immune responses require co-stimulation(B7/CD28)

Blocking costimulation with CTLA4-Ig, belatacept

protects against acute graft rejection in kidneypatients (phase III clinical trials published in 2010;FDA approval in 2011)

Most likely explanation:

-ischemia, stress to organ, release of DAMPs caninduce expression of co-stimulators-may explain why live donor organs have superioroutcomes for kidney transplants compared tocadaver donor organs


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Direct presentationin transplantation

(MHC+peptide: MHC is from graft) Graft dendritic cell is induced to mature,

express co-stimulatory molecules (B7) andmigrate to lymph node by stress of surgery, etc.

DC in lymph node activates allo-MHC recognizingCD4+T cells and/or CD8+T cells

Activated T cells expand and then home to sitesof inflammation where they find allo-MHC ongraft cells and secrete cytokines/kill graft cells

This is the critical pathway for CD8 T cellresponse


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Direct Presentation in Graft Rejection

see also Abbas and Lichtman Fig. 10-8

QuickTime and adecompressor


Blue: host cell; pink: graft cell

killing

CD8

T cell


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Indirect presentationin transplantation

(MHC+peptide: MHC is from host, peptide may

be from graft MHC) Dendritic cells, monocytes, or B cells of host entersites of inflammation of graft, pick up antigens (e.g.allo-MHCs), and load peptides from these allo-MHConto their own MHC, migrate to lymph nodes and

activate T cells CD4+T cells are activated and then migrate to sites of

inflammation where they are activated by hostmacrophages presenting graft antigens, leads to

inflammatory reaction and tissue damage Also, important for production of antibodies to MHCmolecules

This pathway is probably responsible for chronicrejection (rejection after 1 year)


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Indirect Presentation in GraftRejection

see also Abbas and Lichtman Fig. 10-8



In graft

tissue

In draining

lymph node

B cell specific

for allo-MHC


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Allografts: a medical procedure


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Allografts: a medical procedure

Except for pregnancy!

Fetus is not rejected by mother

Mechanism preventing rejection is not wellunderstood there is typically an antibody response to paternal

class I MHC molecules

but not a T cell response to allogeneic cells at thematernal-fetal interface Evidence for local suppression and low expression

of MHC I by trophoblasts


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Pre-existingantibody

T cell immuneresponse (CD4and/or CD8 T cells)

Humoral acuterejection also occursin some people(accelerated rejection)

Mechanism uncertain;does not seem to beblocked by calcineurininhibitors (worst forlung; best for liver)


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Immunosuppression to prevent acutegraft rejection

Cyclosporine and Tacrolimus (FK506): blockcalcineurin, which is important for signaling by TCR(disadvantage: has some toxicity for kidney)


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Mechanism ofimmunosuppression

by cyclosporin

NF-AT: nuclear factor of activated T cellsNF-AT is required for transcription of theIL-2 gene and some other cytokine genes

NF-AT cannot be activated in presence ofcyclosporin



QuickTime and a

decompressor



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Mechanism of immunosuppression bycalcineurin inhibitors

FK-506 (tacrolimus) has an essentially similar

mechanism of action except that the initialbinding protein is FK-506 binding protein(FKBP-12) instead of cyclophilin


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Mechanism of immunosuppression bytacrolimis and sirolimus

FK-506 (tacrolimus) binds to FK-506binding protein (FKBP) and inhibitscalcineurin

Rapamycin (sirolimus) binds FKBP andthis complex has a different target,mTOR (mammalian target ofrapamycin); mTOR regulates proteinsynthesis for a broad subset of genesinvolved in proliferation






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Cyclosporine and Tacrolimus (FK506): blockcalcineurin, which is important for signaling by TCR(disadvantage: has some toxicity for kidney)

Corticosteroids: anti-inflammatory and block T cell

activation Mycophenolate mofetil, azathioprine: inhibit purine

biosynthesis, lymphocyte proliferation (biochemistryexplained in lecture on Friday)

Sirolimus (Rapamycin): blocks T cell response to IL-2


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Cyclosporine and Tacrolimus (FK506): block calcineurin, which isimportant for signaling by TCR (disadvantage: has some toxicityfor kidney)

Corticosteroids: anti-inflammatory and block T cell activation Mycophenolate mofetil, azathioprine: inhibit purine biosynthesis,

lymphocyte proliferation Sirolimus (Rapamycin): blocks T cell response to IL-2 Antibodies that block T cells in one way or another(used to treat

acute rejection episode) Anti-thymocyte globulin (polyclonal Ab made in animals): depletes T

cells via antibody effector functions

Anti-IL-2Rmonoclonal antibody: blocks response to IL-2 and/ordepletes activated T cells

Anti-CD3 monoclonal antibody (OKT3): abortive activation of T cells

Belatacept (modified CTLA4-Ig): blocks co-stimulation (alternativeto cyclosporine in combination with next two types of drugs)


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Graft vs. Host Reaction

T cells from graft can attack host, reacting toMHC differences or minor antigens

Primarily seen in immunocompromised host(e.g., immunodeficiency patient with bonemarrow transplant or leukemia patient treatedwith chemotherapy)


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Graft vs. Host Reaction

Direct presentation pathwayQuickTime and a

decompressorare needed to see this picture.


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Stem Cell Transplantation(bone marrow transplant; future therapies)

Strategies to avoid immunological rejection1. Use stem cells from patient

Adult stem cells seem to be less useful, but workin some situations (iPS methods in development)

2. Use embryonic stem cellsA) Match MHC and use immunosuppression (?)B) Nuclear transplant of nucleus from recipient

into fertilized embryo: generate embryonicstem cells and have no immunological rejection(But: ethical issues!)

Documents

Transplant Immuno - 2