Transplantation Immunology-Cc Nsg

7/28/2019 Transplantation Immunology-Cc Nsg

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Transplantation Immunology:Organ and Tissue Transplantation

Immunosuppressive Agents,Immunosuppressive Therapy.

By

BANIQUED, Charmaine A. ARONZA, Kareen D.


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Contents

Introduction

Ethical considerations

Immunology of Transplant Rejection

Tissue and Organ Transplantation

Immunosuppressive Therapy


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IntroductionGraft or Transplant: Transfer of living cells,tissues and organs from one part of the body toanother or from one individual to another.

Transplantation immunology - sequence of events that occurs after a graft is removed fromdonor and then transplanted into a recipient.

A major limitation to the success of transplantation is the immune response of therecipient to the donor tissue.


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Ethical aspects

Organs for sale !


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Distribution of available organs

List of possible distributive justice criteria are as follows:

To each person an equal share

To each person according toneed


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To each personaccording to

effort

To each personaccording tocontribution

To each personaccording to

merit

To each personaccording tofree-marketexchanges


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secondtype of

distributive justicecriteria ismaximum

benefit

Goal: for maximumbenefit

criteria is

tomaximizethe

number of successfultransplant

s

maximum

benefitcriteriainclude

:

Medicalneed

(i.e. thesickestpeople

are giventhe first

opportunity for a

transplantableorgan)


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Successful transplants are measured bythe number of life years gained.ORGAN SHORTAGE: ETHICALQUESTIONSShould someone who has received oneorgan transplant be given a secondtransplant? Or should people who havenot had a transplant be given priority over

those who have already had one?Should people whose lifestyle choices(smoking, drinking, drug use, obesity, etc.)

damaged their organ be given a chance at


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Types of Transplant

Autograft is self-tissue transferred from

one body site to another in the sameindividual.

Isograft is tissue transferred betweengenetically identical individuals.

Allograft is tissue transferred betweengenetically different members of the samespecies.

Xenograft is tissue transferred between


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Immunology of TransplantRejection

Components of the Immune systeminvolved in graft Rejection :

1) Antigen presenting cells Dendritic cellsMacrophages

Activated B Cells


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2) B cells and antibodies Preformed antibodies

Natural antibodiesPreformed antibodies from prior sensitizationInduced antibodies


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3) T cells4) Other cells

Natural killer cellsT cells that express NK cell associated MarkersMonocytes/Macrophages


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The Immunology of AllogeneicTransplantation

Recognition of transplanted cells that

are self or foreign is determined bypolymorphic genes (MHC) that areinherited from both parents and areexpressed co-dominantly.

Alloantigens elicit both cell-mediated

and humoral immune responses.


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Transplantation antigensMajor Histocompatibility Complex (MHC):

gene complex whose alleles encodepolymorphic cell surface glycoproteinsinvolved in antigen recognition and

presentationMHC-matching between transplant donor and recipient greatly reduces likelihood of

rejectionnomenclature

HLA: human leukocyte antigen


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Transplantation antigensMajor Histocompatibility Complex (MHC):

Class I antigens: constitutivelyexpressed on surface of most cellsClass II antigens: expressed on cells of lymphoid systemExpression of MHC molecules can beupregulated by ischemia, etc.nomenclature

HLA (human) class


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Identifying MHC polymorphisms

(tissue typing)

Formerly determined by antibodiesagainst MHC molecules

HLA typingNow by DNA testing: allele-specific,sequencing


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Does MHC (HLA) matching

prevent rejection?Reduces rejection but there are stillminor histocompatibility antigens(MiHA)MiHA are probably polymorphismsaffecting peptides in the groovesBut we cannot MHC-match mostgrafts: too much polymorphism, toolittle time, too few donors

Therefore need immunosuppression


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Matching and cross-matchingMatching: finding a donor whoshares the HLA antigens of the recipient, to minimizeantigen disparities

requires donor andrecipient antigens to beidentified

Cross-matching: testing theSERUM of the recipient for antibodies against the donor

antigens


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Transplantation antigens ABO system

ABH antigens are complex carbohydrate(polysaccharide) structures on surface of many cell types including graft cells & RBC

nomenclatureH antigen: base chain; defines blood type O

A trisaccharide on H chain: blood type A or A1B trisaccharide on H chain: blood type B

A and B trisaccharides on H chains: blood type AB


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The ABO blood group barrier in organ transplantation

ABO antigens: carbohydrate structuresexpressed on many tissues and organs,including endothelium of organ transplantsRecipient preformed natural anti -A or anti-Bantibodies to non-self A/B antigens

Transplantation of ABO-incompatible organs:

Hyperacute rejection


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Pathogenesis of hyperacute rejectionFrom Silver et al .


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Isohemagglutinin ontogeny in normal humaninfants

A

6 months 1 year

Age

A n t i - A

a n t i

b o

d y t i t r e

Birth

West et al., NEJM 2001; 344

Proof of principle: ABO-incompatible transplantation is

safe in young patients withoutcirculating anti-donor antibody


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Recognition of Alloantigens

Direct PresentationRecognition of an intact MHC moleculedisplayed by donor APC in the graft

Basically, self MHC molecule recognizes thestructure of an intact allogeneic MHCmolecule

Involves both CD8+

and CD4+

T cells.


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Indirect Presentation

Donor MHC is processed and presentedby recipient APCBasically, donor MHC molecule is handled

like any other foreign antigenInvolve only CD4+ T cells.

Antigen presentation by class II MHC

molecules.


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Activation of Alloreactive T cellsand Rejection of Allografts

Donor APCs migrate to regional lymphnodes and are recognized by the

recipients T H cells. Alloreactive T H cells in the recipient inducegeneration of T DTH cell and CTLs then

migrate into the graft and cause graftrejection.


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Activation of Alloreactive T cells andRejection of Allografts

( )SENSATIZATION Passenger leukocyte

.Class II MHC antigen

2 ILH T H T

H T H T

Donar kidney

CTL DTH T

CTL

DTH T

LYMPH NODE EFFECTOR


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Role of CD4 + and CD8 + T Cells

CD4 + differentiate into cytokine producingeffector cells

Damage graft by reactions

CD8 + cells activated by direct pathway killnucleated cells in the graftCD8 + cells activated by the indirectpathway are self MHC-restricted


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Role of Cytokines in Graft RejectionIL 2, IFN , and TNF - are importantmediators of graft rejection.IL promotes T-cell proliferation andgeneration of T Lymphocytes.IFN - is central to the development of DTHresponse.TNF - has direct cytotoxic effect on thecells of graft.A number of cytokines promote graftrejection by inducing expression of class I

or class II MHC molecule on graft cell.


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Rejection mechanismsAnti-HLA alloantibody (plus C/leukocytes)

target of endothelium of interstitial capillarieslate capillary basement membrane

multilayeringlate glomerular deterioration

T cell-mediated rejectionlymphocyte infiltration into graft

cytotoxic destruction of graft parenchymalcells

key role also for macrophages and n o n - cy to tox ic destruction (DTH)target is endothelium and epithelium (and

intima of small arteries)intimal arteritis (uncommon): neointima anddisruption of elastic lamina; inflammatory cells


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Effector Mechanisms of AllograftRejection

Hyperacute RejectionAcute RejectionChronic Rejection


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Types of transplant graft rejectionChronic rejection:

Poorly defined term indicating chronicdeterioration within graftOccurs in some form in all organ allografts

Kidney: chronic allograft nephropathy

Heart: graft coronary artery diseaseLung: bronchiolitis obliterans syndromeLiver: vanishing bile duct syndromeMay (or may not) be associated withrecurrent cellular rejection episodes

Alloantibody may (or may not) play a roleNot prevented with currentimmunosuppressive drug therapies


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Allograft rejection

Effector Tcells home to

inflamedsites: CD8,

CD4

Tubulitis

Intimal arteritis

InterstitialCTL-macrophage infiltrate

Helper T cellshelp B to make

alloantibody

Nave and central memory

T cells recirculate between secondary lymphoid organs

e.g. CCR7

Host-graft

Kidney

response toinjury

antigen presenting cellsmove to lymphoid

organs APCs trigger T cells

in secondary lymphoid organs


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Discrete molecular processesin T cell-mediated rejectionCTL infiltrationIFN- production and effects on graftIFN- suppression of some gene patterns

Macrophage entry/activationInjury and repair

mild to moderate (can be restored)

severe (likely will lose graft cells)fibrosis is part of bothparenchymal de-differentiation

B cells/plasma cell infiltration


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Dendritic cells engage T cells

Antigen handlingResponse to theenvironment

The Immunologic SynapseMHC-peptide

Respondingto the T cell

Initial T cell binding


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Hyperacute Rejection

Characterized by thrombotic occlusionof the graftBegins within minutes or hours after

anastamosisPre-existing antibodies in the hostcirculation bind to donor endothelial

antigensActivates Complement CascadeXenograft Response


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Hyperacute Rejection

1. Preformed Ab,

2. Complement activation,3. neutrophil margination,4. inflammation,

5. Thrombosis formation


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Acute Rejection

Vascular and parenchymal injurymediated by T cells and antibodies thatusually begin after the first week of transplantation if there is noimmunosuppressant therapyIncidence is high (30%) for the first 90days


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Acute Rejection

1. T-cell, macrophage and Abmediated,

2. myocyte and endothelial damage,


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Chronic Rejection

Occurs in most solid organ transplantsHeartKidneyLungLiver

Characterized by fibrosis and vascular abnormalities with loss of graftfunction over a prolonged period.


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Chronic Rejection

1. Macrophage T cell mediated2. Concentric medial hyperplasia3. Chronic DTH reaction


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Tissue and OrganTransplantation

Today it is possible to transplant many differentorgans and tissues including:

Most common transplantation is blood

transfusion.Bone Marrow transplantationOrgans : Heart, kidneys, pancreas, lungs,liver and intestines.Tissues : include bones, corneas, skin, heartvalues, veins, cartilage and other connectivetissues.


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Most Common Transplantation-Blood Transfusion-

Transfuse Not transfused


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Bone Marrow TransplantationUsed for Leukemia, Anemia and immunodeficiency,especially severe combined immunodeficiency (SCID).

About 10 9 cells per kilogram of host body weight, isinjected intravenously into the recipients.

Recipient of a bone marrow transplant isimmunologically suppressed before grafting.Eg. Leukemia patients are often treated with cyclo-

phosphamide and total body irradiation to kill allcancerous cells.Because the donor bone marrow containsimmunocompetent cells, the graft may reject the host,

causing graft versus host disease (GVHD).


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Heart Transplantation :First heart transplant in South Africaby Dr. Christian Barnard in 1964.

One year survival rate is >80%.HLA matching is desirable but notoften possible, because of thelimited supply of heart and theurgency of the procedure.


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Lung Transplantation : First attempt in 1963 by Hardy and Co -workers.First successful transplantation byToronto group in 1983.In conjunction with heart transplantation,to treat diseases such as cystic fibrosisand emphysema or acute damage tolungs.First ear survival rate is about 60%.


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Xenogeneic Transplantation

A major barrier to xenogeneictransplantation is the presence of naturalantibodies that cause hyperacuterejection.


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Immunosuppressive Agents

Immunosuppression can be brought aboutby different ways :-

Total Lymphoid IrradiationImmunosuppressive drugs


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Immunosuppressive Drugs

Three main immunosuppressant drugsCyclosporins act by inhibiting T-cellactivation, thus preventing T-cells fromattacking the transplanted organ.Azathioprines disrupt the synthesis of DNA and RNA and cell division.Corticosteroids such as prednisolonesuppress the inflammation associatedwith transplant rejection.


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Immunosuppressive Therapy

Monoclonal antibodiesTo suppress the activity of

subpopulation of T-cells.To block co-stimulatory signals.

Ab to the CD3 molecule of TCR (Tcell receptor) complex results in arapid depletion of mature T-cells fromthe circulation.


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Antibody to CD4 shown to prolong graftsurvival.

Ab specific for implicated cytokine canprolong the survival of graft.

Facts


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FactsMore than 50,000 people, waiting for compatibledonor. For ethical and practical reasons, speciesclosely related to human such as Chimpanzee havenot been widely used.Xenogeneic transplantation may be major issue of

research xenograft technology including geneticallymodified animal may become a new source of organsupply.Side effects of immunosuppressive agent use for graftneed a change of specificity in action and avoidinggeneral immune suppression.Techniques such as transgenic animal production and

wide range of research in this field hope to result in


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Why is fetus not rejected by the mother?

A/B C/D

A/C, A/D, B/C, B/D


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Why is fetus not rejected?

Placenta acts as a barrier or filter.It filters anti-MHC Abs.

Trophoblast---outermost layer of fetaltissue---is in direct contact with maternalblood.

Trophoblast expresses weak or no MHC .


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Why is fetus not rejected?

progesterone---hormone---immunosuppressive.Placenta expresses FasL.Spontaneous abortions are some timestriggered by maternal immune responseagainst fetus.


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UPDATE


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Transplantation Immunology-Cc Nsg

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