1. Transplantation Immunology
Nehal Draz

3. 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

5. 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

6. 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

7. The Major Histocompatibility (MHC)
HLA

8. Refers to genes encoding
MHC
Refers to genes encoding
HLA proteins
MHC molecules
Refers to the protein HLA

9. 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

10. 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

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

12. 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

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

14. 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

15. 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

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

17. 1- Hyperacute rejection
Within minutes
Circulating preformed anti ABO or anti-HLA antibodies
Activation of compl. and clotting pathways
No treatment
Prevention: proper matching

18. 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

19. 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

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

21. 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

22. 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

23. 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

24. 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

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

26. 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

27. 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

28. 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

29. 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

30. 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

31. Thank you!!