basics of transplantation

1. TRANSPLANTATION
BIOLOGY

2. Nomenclature
• Graft
• Flap
• Autograft
• Allograft
• Isograft
• Xenograft
• Orthotopic transplantation
• Heterotopic transplantation
• Vascularised Composite Allograft

3. History
1st transplant – kidney – Joseph E Murray – 1955
1st hand transplant – Jean Michel Dubernard – France – 1998
1st full face transplant – 2010 – Spain
2011 – Bohdan Pomahac – BW hospital, Boston, USA

4. Survival depends on ???
Goal of transplantation???

5. TRANSPLANTATION IMMUNOLOGY
IMMUNOSUPPRESSIVE DRUGS
FUTURE OF TRANSPLANTATION

6. MAJOR HISTOCOMPATIBILITY COMPLEX
• Short arm of chromosome 6
• Human Leukocyte Antigen (humans)
• Swine Leukocyte Antigen (swine)
• H-2 (mice)
• RT1 (rats)
• Inherited in a codominant fashion
CLASS I
• HLA – A,B,C
• All nucleated cells
• CD8+ T cells

7. MHC
Class II
• HLA- DR, DP, DQ
• Vascular endothelium, APC (macrophages,
lymphocytes, dendritic cells)
• CD4 Th cells

8. OTHER TRANSPLANT ANTIGENS
ABO blood group proteins – brisk antibody mediated
Minor histocompatibility antigens – very slow cell mediated
Skin specific antigens – cell mediated

9. MACROPHAGES
• Phagocytosis
• Antigen presentation
• Both class I and class II MHC
• Secrete cytokines

10. NK CELLS
• non-T, non-B lymphocyte
• Does not require MHC molecules or antigen presentation
• Incorporates lipophilic protein into cell membrane >
increased permeability> cell lysis
• Secretes interferon γ, interferon α

11. B LYMPHOCYTE
• Etymology – Bursa of Fabricius, chicken
• Produced in fetal liver and bonemarrow
• After maturation move to spleen and LN
• Express both MHC I and II
• Produce immunoglobulin
• Ig M, G, D, E, A
• Opsonization and complement activation

12. T LYMPHOCYTES
• Etymology – thymus
• Cell mediated immunity
• Express both MHC I & II
• Helper T (Th) (CD3, CD4)
• Cytotoxic T (CD3, CD8)
• Suppressor T (Ts) (CD3, CD8)
• T cell Receptor (TCR)

13. MHC RESTRICTION
T CELL
TCR
ANTIGEN
M
H
C
APC
CD 4 - MHC
CLASS II
CD 8 - MHC
CLASS I

14. CD4
ACTIVATION APC
IL 1
CD 4 IL 2
CD 8
CD 4
IL4 IL5

15. ANTIGEN RECOGNITION AND GRAFT
REJECTION
• Indirect representation
• Direct representation
• More vigorous response

16. Hyperacute rejection
• immediately
• preformed antibodies
• standard screening enough

17. Acute Rejection
• days to weeks
• T cell mediated
• fever, graft tenderness, edema, loss of function
• vasculitis – humoral response

18. Chronic rejection
• months to years
• progressive loss of tissue architecture and fibrosis
• slowed by immunosuppression

19. IMMUNOLOGICAL SCREENING
• Blood group typing
• HLA typing
• Cross matching
• Antibody screening

20. IMMUNO SUPPRESSION
• Induction
• Maintenance
• Rescue

21. CORTICOSTEROIDS
• Maintenance and rescue agent
• Not used alone
• Block IL 1 and TNFa by APC, interferon y by T
cells, migration and lysosomal enzyme release by
neutrophils

22. ANTI PROLIFERATIVE AGENTS
AZATHIOPRINE
• 1st immunosuppressive drug
• Maintenance drug
• Not solitary drug
• Along with calcineurin inhibitors and steroids
• Blocks proliferative response of T and B cells
MYCOPHENOLATE MOFETIL
• Maintenance and rescue
• Replaced Azathioprine
• Not solitary

23. CALCINEURIN INHIBITORS
CYCLOSPORINE
• Maintenance
• T cell specific immunosuppressants
• Inhibits production of IL2
• Promotes production of TGF-B
• Nephrotoxic, neurotoxic, hypertensive
TACROLIMUS
• Maintenance
• 100 times more potent
• Same ADR
• Topical preparation – hand and face transplant immunosupp protocol

24. MACROLIDE
RAPAMYCIN
• Replaced Tacrolimus
• Interrupts T cell activation pathway even in presence of IL2
• Hypertriglyceridemia, marrow suppression
• Interrupts wound healing, administered after peritransplant period

25. ANTITHYMOCYTE GLOBULIN
• Inoculation of heterologous species with human lymphocytes
• Plasma collected
• IgG fraction purification
• Induction, rescue agents
• Thrombocytopenia, Anemia, Leukopenia

26. OKT3
• Murine monoclonal antibody
• Against CD3
• Induction, rescue agent
• Systemic cytokine response – hypotension, pulmonary
edema, cardiac myodepression, aseptic meningitis
• Viral reactivation

27. ANTI IL2
(DACLIZUMAB, BASILIXIMAB)
• Against CD25, high affinity chain of IL2 receptor
• Maintenance, induction agent
• Reduces acute rejection episodes
• Not solitary drug
ALEMTUZUMAB
• Anti-CD52 antibody
• Depletes Tcells, reduced effect on B cells, NK cells
• Induction agent with Tacrolimus and MMF

29. IMMUNOLOGIC TOLERANCE
1. CLONAL DELETION
2. ANERGY
3. SUPPRESSION

30. CLONAL DELETION
• Tcells specific for antigen are eliminated.
• Central deletion
• Peripheral deletion
• Positive and negative selection in T cell maturation
Advances –
• Strain specific neonatal rodents – donor cells – accepted skin allografts
• Total body irradiation + donor marrow infusion = chimerism
• Develop immune system tolerant to both antigens
• Intrathymic injection of donor cells

31. ANERGY
• T cell activation requires costimulatory signal
• CD28/B7 CD40L/CD40 signal pathways
• Rodent models – interruption of pathway > tolerance
• Primate model > no tolerance
• Modifications of technique under study

32. SUPPRESSION
• CD4+CD25+ cells
• Treg cells
• Increased incidence in tolerant pts
• Less incidence in rejection cases
• Technique to produce Treg cells could increase tolerance