Nehal Draz

1- Autograft: from one area to another, same inbividual, NO IR

2- Syngraft (Isograft; Syngeneic): genetically identical individuals, NO IR, Histocompatible

3- Allograft (commonest) two genetically dissimilar individuals, same species, Histoincompatible & rejection

4- Xenograft: donor & recipient from different species Histoincompatible & rejection

Living graft: from a living donor,e.g. liver segment, kidney, BM

Cadaveric graft: from a recently dead individual,e.g. heart, cornea, liver, kidney

Bone marrow is the most immunogenic

Liver is the least immunogenic depending on:

Privileged sites: e.g.cornea No significant IR

Lack of lymphatic drainage

2- Different expression of HLA molecules

1- Lack of suitable APCsIn some tissues

HLA

MHC

Refers to genes encoding HLA proteins

MHC molecules

Refers to the protein HLA

Allelic polymorphism: The MHC genes represents the most

polymorhic genetic system Multiple different allels of the same

gene exist in the human population Different allels of the same gene can

give Ags with slightly distinct sequences

e.g. A gene has 151 allels

1- control IR by MHC restriction

2- targets of IR resulting in cytotoxity in graft rejection

3- Certain MHC allels are associated with some diseases e.g. multiple sclerosis &DR2

Recipient Tcells can recognize donor allo Ags in the graft by 2 different ways:

Recipient Tcells recognize donor;s Ags on donor's MHC molecules on the graft APCs

Donor APCs leave the graft & migrate to the regional lymph nodes

There they activate recipient’s Tcells

The activated Tcells are carried back to the graft which they attack directly

Uptake of donor MHC molecules by the recipient own APCs and presentation to self Tcells on self MHC molecules

CD8 Tcells

CD8 Tcells

CD4 Tcells

CD4 Tcells

- The generated alloreactive CTLS attack graft cells bearing MHC I and destroy them by direct cytotoxicity

Secrete cytokines enhancing graft damage:- IL-2: stimulate CTLs- IFNγ: increase allogenic MHC class I &II on graft cells- IL4, 5, 6 stimulate Ab production by Bcells

CM I

IgG or IgMForeign GRAFT cell

Y1- Opsonization

2- Complement mediated lysis

3- ADCCdestructionMQ NK

HUMORAL

effector phase. cont

1- Hyperacute rejection

2- acute rejection

3- Chronic rejection

Within minutes Circulating preformed

anti ABO or anti-HLA antibodies

Activation of compl. and clotting pathways

No treatment

Prevention: proper matching

Within days or weeks

Treatment: immunosuppression

Prevention: proper matching

TC

CD4

YYYY

Destroy graft cells

Lymphokines activating Infl.& MQ

Endothelial injury

After months or years

No treatment Prevention:

proper matching

Alloantigen in Vessel wall

Proliferation of smoothMuscle cells

Gradual lumen narrowing

ischemia,Interstial fibrosisLoss of function

Delayed type hypersensitivity

CYTOKINES

Histocompatibility testingHistocompatibility testing

Post-operative immunosuppressive therapyPost-operative immunosuppressive therapy

Recipient preparationRecipient preparation

1- ABO typing2- HLA testing: determination of HLA

phenotype for donor & recipient which can be done by:

a) microlymphocytotoxicity test b) HLA molecular typing: PCR c) white cell cross matching: mixed

lymphocytotoxicity test

3- detection of preformed Abs against donor cells in the serum of the recipient

Complete history taking & full clinical examination

Treatment of hypertension if present Treatment of infections if present Prophylactic antibiotics Pre-transplantation

immunosuppressive therapy

The drugs used to suppress the immune system can be divided into 3 categories:

Cytotoxic drugsCytotoxic drugs

Powerful anti-inflammatory drugs (corticosteroid)Powerful anti-inflammatory drugs (corticosteroid)

Fungal & bacterial derivativesFungal & bacterial derivatives

prednisone

-Azathioprine-Cyclophosphamide

-Cyclosporine A-FK506-Rapamycin

Drug Mechanism of action

Cyclosporine & FK 506 Block Tcell cytokine production

Rapamycin Inhibits IL-2 signaling which inhibits lymphocyte proliferation

Corticosteroids Reduce inflammation by inhibiting MQ cytokine secretion

Anti IL-2 receptor Inhibit T cell proliferation by inhibiting IL-2 binding

Anti-CD40 ligand Inhibit cellular activation by blocking co-stimulation

Monoclonal Ab against Tcell surface markers

Depletion of Tcells

Infections

Malignancies: especially lymphomas & carcinoma of the skin

Anaphylaxis or serum sickness

Graft verus host disease (GVHD)

A successful therapy for tumors derived from marrow precursors such as leukemia & lymphomas

It may be also successful in treatment of some primary immunedefficiency disease such as severe forms of thalassemias

In leukemia therapy, the source of leukemia must be first destroyed by aggressive cytotoxic chemotherapy. The patient is thus severely immunocompromised

Bone marrow cells are highly immunogenic& can elicit a strong IR

Therefore, very careful donor/recipient HLA matching is critical

If mature donor Tcells are transplanted with the marrow cells, these mature Tcells recognize the tissues of the recipient as foreign causingsevere inflammatory disease called:

GVHD

Graft Versus Host Disease

-Rashes-Diarrhea-Pneumonitis-Liver dysfunction-Wasting-Death

-Rashes-Diarrhea-Pneumonitis-Liver dysfunction-Wasting-Death

1- The most crucial factor is donor selection &MHC compatibility: an identical twin is the ideal donor

2- From poorly matched grafts, T lymphocytes can be removed using monoclonal Abs. to avoid induction of an immune response by the immune competent (mature) donor Tcells against the tissues of the immunocompromised recipient & hence GVHD

3-Malignant cells should be eliminated from the recipient blood to avoid recurrence of the underlying malignancy which necessitated the BMT in the first place

4- Methotrexate, cyclosporin & prednisone are often used to control GVHD