Transplantation Immunology

January 29, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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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:

1- Lack of suitable APCs In some tissues



2- Different expression of HLA molecules

Privileged sites: e.g.cornea No significant IR Lack of lymphatic drainage

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

- The generated alloreactive CTLS

attack graft cells bearing MHC I and destroy them by direct cytotoxicity CD4 Tcells

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

C M I

HUMORAL IgG or IgM

Foreign GRAFT cell

MQ

NK

1- Opsonization destruction

3- ADCC

2- Complement mediated lysis

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

Destroy graft cells

TC

CD4 Lymphokines activating Infl.& MQ

Endothelial injury

YYYY

Delayed type hypersensitivity

Alloantigen in Vessel wall



 

After months or years No treatment Prevention: proper matching

CYTOKINES

Proliferation of smooth Muscle cells

Gradual lumen narrowing

ischemia, Interstial fibrosis Loss of function

Histocompatibility testing Recipient preparation Post-operative immunosuppressive therapy

1- ABO typing 2- 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:

Powerful anti-inflammatory drugs (corticosteroid)

prednisone

Cytotoxic drugs

-Azathioprine -Cyclophosphamide

Fungal & bacterial derivatives

-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

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

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