Transplantation Immunology Nehal Draz

Graft Types I- Based on foreigness 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

II- According to origin 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

III- According to immunogenecity Bone marrow is the most immunogenic Liver is the least immunogenic depending on: Privileged sites: e.g.cornea No significant IR 1- Lack of suitable APCs In some tissues 2- Different expression of HLA molecules Lack of lymphatic drainage

The Major Histocompatibility (MHC) HLA

Refers to genes encoding 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

Functions of MHC 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

IR to transplants I- Sensitization phase Recipient Tcells can recognize donor allo Ags in the graft by 2 different ways:

A. Direct allorecognition 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

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

C M I II- Effector phase Secrete cytokines enhancing graft damage: CD8 Tcells - The generated alloreactive CTLS attack graft cells bearing MHC I and destroy them by direct cytotoxicity C M I 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

HUMORAL Y destruction IgG or IgM MQ NK 3- ADCC 1- Opsonization Foreign GRAFT cell IgG or IgM MQ destruction NK 3- ADCC 1- Opsonization 2- Complement mediated lysis effector phase. cont

Mechanisms of Graft Rejection 1- Hyperacute rejection 2- acute rejection 3- Chronic rejection

1- Hyperacute rejection Within minutes Circulating preformed anti ABO or anti-HLA antibodies Activation of compl. and clotting pathways No treatment Prevention: proper matching

Lymphokines activating 2- Acute rejection Within days or weeks Treatment: immunosuppression Prevention: proper matching TC Destroy graft cells CD4 Lymphokines activating Infl.& MQ YYYY Endothelial injury

Proliferation of smooth 3- Chronic rejection Delayed type hypersensitivity Alloantigen in Vessel wall CYTOKINES Proliferation of smooth Muscle cells After months or years No treatment Prevention: proper matching Gradual lumen narrowing ischemia, Interstial fibrosis Loss of function

Prevention of graft rejection Histocompatibility testing Recipient preparation Post-operative immunosuppressive therapy

I- Histocompatibility testing 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

II- Recipient preparation Complete history taking & full clinical examination Treatment of hypertension if present Treatment of infections if present Prophylactic antibiotics Pre-transplantation immunosuppressive therapy

III- Post-operative 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

Common immunosuppressive drugs 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

Complications of post- operative immunosuppression Infections Malignancies: especially lymphomas & carcinoma of the skin Anaphylaxis or serum sickness Graft verus host disease (GVHD)

Bone Marrow Transplantation (BMT) 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

Special problems associated with BMT 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: Rashes Diarrhea Pneumonitis Liver dysfunction Wasting Death GVHD Graft Versus Host Disease

Strategies for preventing graft rejection & GVHD following BMT 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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