بسم الله بسم الله الرحمن الرحيمالرحمن الرحيم

Faculty of medicine. Alexandria

university. Department of

pathology. Graft Graft rejectionrejection

0bjectives:11..IntroductionIntroduction..

22..Types of transplantationTypes of transplantation..

33..Graft rejectionGraft rejection..

44..Causes of graft rejectionCauses of graft rejection..

55..Mechanism of graft rejectionMechanism of graft rejection..

66 . .Types of graft rejectionTypes of graft rejection..

77..Treatment of graft rejectionTreatment of graft rejection..

Types of transplantation :

Autologous graft = auto graftAutologous graft = auto graft..

Synegenic graft = syngraftSynegenic graft = syngraft..

Allogeneic graft = allograftAllogeneic graft = allograft..

Xenogenic graft = xenogaftXenogenic graft = xenogaft..

TransplantationTransplantation: : Transferring cells, tissues, or organs

from one site to another

Graft rejectionGraft rejection::

Occurs when aOccurs when a transplanted organ or tissue organ or tissue fails to be accepted by the body of the fails to be accepted by the body of the transplant recipienttransplant recipient..

Pleomorphism of MHC genes

Different MHC Ags within species& individuals

Causes of graft Causes of graft rejectionrejection::

T Lymphocytes recognize transplanted organ as foreign& release cytokines that lyse cells.

Graft failure

Mechanism of graft rejection:1.T Cell Mediated (Cellular rejection)

Direct pathway. Indirect pathway.

2.Antibody Mediated Reactions

(Humoral rejection)

Mechanism of Mechanism of graft rejectiongraft rejection::

::11..T Cell Mediated (Cellular rejection)T Cell Mediated (Cellular rejection)

CD4CD4

+ +CD8 cellsCD8 cells

Lysis of grafted tissue.

cytokinecytokine

mononuclear cells

inflammation

Types of T cell mediated reactionTypes of T cell mediated reaction : : 1. Direct Pathway:1. Direct Pathway:

T cells of recipient recognize allogenic MHC molecule on T cells of recipient recognize allogenic MHC molecule on the surface of an APC in donor.the surface of an APC in donor.

interstitial dendritic cells of donor organs are the best interstitial dendritic cells of donor organs are the best immunogenic.(why?)immunogenic.(why?)

CD4+ and CD8+ T cells of recipient encounter antigens in CD4+ and CD8+ T cells of recipient encounter antigens in lymph nodeslymph nodes

CD4+ proliferate, release cytokines& trigger delayed CD4+ proliferate, release cytokines& trigger delayed hypersensitivity reaction. hypersensitivity reaction.

Cytokines vascularity &induceinflammation.Cytokines vascularity &induceinflammation. mature CTLs are generated and lyse grafted tissue .mature CTLs are generated and lyse grafted tissue .

recipient T lymphocytes recognize antigens after being presented by own antigen-presenting cells.same as presentation of microbial antigens.

22 . .Indirect pathwayIndirect pathway::

2.Antibody Mediated Reactions2.Antibody Mediated Reactions : : (Humoral rejection)(Humoral rejection)

1. In Hyperacute reaction:1. In Hyperacute reaction: previous exposure to the donor antigens.previous exposure to the donor antigens. As in:As in:

previous rejected kidney transplant.previous rejected kidney transplant.

Multiparous women.Multiparous women.

Previous blood transfusion.Previous blood transfusion.

2. In chronic rejection:2. In chronic rejection: not previously exposed to the donor antigen.not previously exposed to the donor antigen. Abs cause damage by complement, ADCC &Ag Ab complexAbs cause damage by complement, ADCC &Ag Ab complex

Types of graft Types of graft rejectionrejection::a) Hyper acute = immediatea) Hyper acute = immediate..

b) Acute = cellularb) Acute = cellular..

c) Chronic = fibrosisc) Chronic = fibrosis..

Hyper acute Hyper acute rejectionrejection:: ReactionReaction due to due to : :

complement + preexisting antibodies as complement + preexisting antibodies as (ABO) (humoral)(ABO) (humoral) TimeTime::

occurs within minutes to hoursoccurs within minutes to hours..ComplicationComplication::

Rapid thrombosis, no vascularizationRapid thrombosis, no vascularization.. InfarctsInfarcts..

Acute systemic inflammationAcute systemic inflammation. . PrognosisPrognosis::

Organ is removedOrgan is removed..

Steps involvedSteps involved : :

Morphology of hyper acuteMorphology of hyper acuteIn hyper acutely rejecting kidney In hyper acutely rejecting kidney GrosslyGrossly: :

cyanotic, mottled, flaccid and may excrete few drops of bloody cyanotic, mottled, flaccid and may excrete few drops of bloody urineurine

Microscopically:Microscopically:

Acute necrotizing vasculitis.Acute necrotizing vasculitis.

Neutrophil accumulation.Neutrophil accumulation.

Platelet aggregation.Platelet aggregation.

Complements activation &endothelial damage.Complements activation &endothelial damage.

Acute inflammation &vascular thrombosis.Acute inflammation &vascular thrombosis.

Hyper acute rejectionHyper acute rejection::

Acute rejectionAcute rejection::ReactionReaction : :

cellular: Primary activation of T cellscellular: Primary activation of T cells..& & humoralhumoral..

TimeTime:: weeks after transplantationweeks after transplantation....

ComplicationComplication::

organ failure (mainly in vascularized organs)organ failure (mainly in vascularized organs) recurrent episodes chronic rejectionrecurrent episodes chronic rejection..

PrognosisPrognosis:: treatabletreatable..

Acute rejectionAcute rejection

Diagnosis:Diagnosis: signs& symptoms.signs& symptoms. Lab diagnosis& tissue biopsy Lab diagnosis& tissue biopsy..

Morphology of acute rejection:Morphology of acute rejection:

There is There is acute cellular rejectionacute cellular rejection

11 . .T lymphocyte infiltrationT lymphocyte infiltration..

22 . .injury of the tissueinjury of the tissue..

33 . .injury of organ bood vesselsinjury of organ bood vessels

Chronic rejectionChronic rejection:: Reaction: cellularReaction: cellular

chronic immune responsechronic immune response..

fibrosis of internal blood vesselsfibrosis of internal blood vessels..

( ( allograft vasculopathyallograft vasculopathy))

TimeTime : :

along yearsalong years..

ComplicationComplication::

loss of function graduallyloss of function gradually..

PrognosisPrognosis::

need anew transplant usually after a decadeneed anew transplant usually after a decade

Morphology of chronic rejectionMorphology of chronic rejection:: Loss of function in transplanted organsLoss of function in transplanted organs termed termed chronic allograft vasculopathy Grossly Grossly

vascular changes: of dense intimal fibrosis in vascular changes: of dense intimal fibrosis in the cortical arteries& renal ischemiathe cortical arteries& renal ischemia

glomerular loss and tubular atrophyglomerular loss and tubular atrophy

shrinkage of renal parenchyma.shrinkage of renal parenchyma. Microscopically:Microscopically:

vascular lesionsvascular lesions

mononuclear cell infiltratesmononuclear cell infiltrates

Chronic kidney rejectionChronic kidney rejection

TreatmentTreatment::a) Hyperacute rejection:

only by removal of the organ immediately

b) Chronic rejection: irreversible & cannot be prevented.

only treatment is a new transplant after

10 years.

c) Acute rejectionc) Acute rejection:: 11..high dose corticosteroidshigh dose corticosteroids..

22..repeatedrepeated . .

33..tripple therapytripple therapy . .

Not enough

Not enough

Triple therapyTriple therapy::11..Corticosteroids e.g Cyclosporin ACorticosteroids e.g Cyclosporin A..

22..Calcineurin inhibitorCalcineurin inhibitor..

33..Antiproliferative agentAntiproliferative agent. .

plusplus::

antibodies against blood vesselsantibodies against blood vessels..

& & blood transfusion remove antibodies blood transfusion remove antibodies against the transplant against the transplant..

Graft associated immune Graft associated immune suppressionsuppression::

11..corticosteroidscorticosteroids:: lyse mature T cellslyse mature T cells..

+ +DnaseDnase

cytokine synthesiscytokine synthesis

IL1, IL6& TNFIL1, IL6& TNF

11..Metabolic toxinsMetabolic toxins::

lymphocyte growthlymphocyte growth..

asas::

AzathioprineAzathioprine

CyclophosphamideCyclophosphamide

CyclosporinCyclosporin

CalcineurinCalcineurin

22..IrradiationIrradiation::

44..Induce tolerenceInduce tolerence:: by multiple blood transfusionby multiple blood transfusion..

55..AntibodiesAntibodies:: against T cell surface proteinsagainst T cell surface proteins..

monoclonal Ab against CD3monoclonal Ab against CD3.. antibodies against b cellsantibodies against b cells..

Can also remove Ab by plasmapheresisCan also remove Ab by plasmapheresis

Thank you..…