1. Principles of Immunobiology in Transplantation
이식면역학 Transplantation immunology
Yon Su Kim, MD.
Department of Internal Medicine
Seoul National University College of Medicine
Yon Su Kim, MD
Department of Internal Medicine
Seoul National University College of Medicine

3. Yu Yu Voronoy, Russia, 1935

5. Harvard Medical School, Dec-23, 1954 Richard Herrick, Ronald Herrick
John Merrill,
Nephrologist
Joseph E. Murray, Plastic Surgeon
Francis Moore, Surgeon
Joseph E. Murray, MD.
The Nobel Prize in Physiology or Medicine 1990
"for their discoveries concerning organ and cell transplantation in the treatment of human disease"

6. 1년 이상 Graft survival을 보인 659명의 Overall survival
서울대학교병원

7. Graft & recipient survival (SNUH 2000-2006)
431 patients
Graft survival
Recipient survival
<50 years : 5YS 91.8%,
≥50 years : 5YS 90.8%
<50 years : 5YS 99.1%
≥50 years : 5YS 92.2%,
Han SS, et al. The Korean Journal of Nephrology 2008;27:

8. Autograft
self-tissue transferred from one body site to another in the same individual
Isograft
tissue transferred between genetically identical individuals, inbred mice, monozygotic twin
Allograft
tissue transferred between genetically different members of the same species (동종이식)
Xenograft
tissue transferred between different species (이종이식)

9. Immunologic Responses

11. Innate immunity Adaptive immunity (rapid response) (slow response)
Nature Reviews Cancer 4, 11-22, 2004

14. Immunologic Propagation

15. Skin GI tract Resp. tract
Bone marrow
APC
Thymus
Lymph node

16. Immunolgic Responses against Allo-antigen

17. T Cells Play A Key Role in Rejection
T deficient
T deficient

18. MHC Class I, II

19. MHC restriction T cells recognize self MHC+peptide, not peptide alone
T cells are tolerant to self MHC, but react with non-self MHC
T cells will only react with one antigen in combination with one MHC molecule
T cell is educated to react with antigen in combination with one out of many MHC molecules

20. APC (dendritic cell, macrophage, B cell
APC (dendritic cell, macrophage, B cell..) maturation, a control point for regulating tolerance and immunity

21. Dendritic Cells as Nature’s Adjuvants
High intracellular MHC II
Endocytosis, high FcR
Low CD80, 86, 40
Actin cables
MATURE DCs
High surface MHC II
Low endocytosis and FcR
High CD80, 86, 40
No actin cables
Jacques B, et al. Nature, 1998, 392:245

22. Th Co-stimulation of T helper cells by professional APC SIGNAL 2 APC
Cognate T-professional APC
co-stimulatory interaction
APC activation
induces B7 costimulatory
molecules on APC
CD28
B7.1/2 Th
APC
Processing
IL-1, IL-12
IFN-
SIGNAL 1
TCR-MHC interaction
Signal 1 & signal 2 (TCR, CD28 signalling)
are required for T cell clonal proliferation
and differentiation to effector cells

23. What is the target for T cell recognition?
- MHC class I difference : CD8 T cells
- MHC class II difference : CD4 T cells

24. Mechanism of T cell activation and proliferation1 2
IL-2
IL-2R
Signal 1+2
Increases IL-2 transcription
and stabilises IL-2 mRNA
High affinity IL-2 Receptor-
 and  chains
Low affinity IL-2 Receptor-
 and  chains
IL-2
IL-2R
Resting T cell

25. Network of immune responses after allogeneic transplantation
DONOR
GvH = GvHD
GvL
HvG =
graft rejection
RECIPIENT

26. Characteristics of alloimmune responses
- Why allografts elicit strong immune responses in vivo ?
High frequency of T cells responding to foreign MHC molecules
1) each allogeneic MHC molecule can be recognized by
multiple T cell clones
2) each different bound peptide in combination with one MHC molecule cross reactive T cell clones
2. Mode of Ag presentation
1) direct
2) indirect
3. Ag experience

27. Characteristic of allogeneic immune responses
1. Modes of alloantigen presentation
Donor APC
Donor MHC
Donor peptide T
APC
Direct
Indirect
Recipient APC
Recipient MHC
Donor peptide T
APC
TCR
Recipient T cells

28. Cascade of Allogeneic Immune Responses
Maturation of Antigen Presenting Cells
Up-regulation of MHC molecules
Up-regulation of co-stimulatory molecules
Activation of T cells
T cell activation
Clonal proliferation
Effector Phase
Cytotoxic T cell mediated lysis
Apoptosis
Delayed type hypersensitivity
Ab dependent cell mediated cytotoxicity

29. Types of rejection
hyperacute rejection
acute rejection
1) Cell mediated rejection
2) Ab mediated rejection
chronic rejection

30. Acute cellular rejection; tubulitis

31. Acute cellular rejection; arteritis

32. Acute humoral rejection

33. Chronic rejection; Interstitial Fibrosis and Tubular Atrophy

34. Biopsy proven acute rejection in SNUH
Episode : ~20%
Han SS et al, The Korean Journal of Nephrology 2008;27:

35. Acute Rejection after Kidney Transplantation
BPAR (% of patients)
p<0.0001
26%
24%
12%
37%
p<0.0001 10 20 30 40 50
12 months post-Tx
BPAR (% of patients)
3 years post-Tx
Low-dose TAC
Low-dose SRL
Standard-dose CsA
Low-dose CsA
Symphony Study, Ekberg H et al AJT, 2009, 9:1876

36. Alloreactive T cell cytotoxicity
perforin/granzyme system; CD8 T cell
Fas/FasL system; CD4 T cell
Alloantibodies
complement cascade; membrane attack complex
ADCC; perforin/granzyme-mediated NK cytotoxicity
Non-T and –B cell effector mechanism
mf activation; DTH (Th1)
eosinophil; eosinophil peroxidase, superoxide (Th2)

37. Classification of immunosuppressive agents
1. Immunophilin binding drugs
a) calcineurin inhibitors; cyclosporine, FK506
b) calcineurin independent; rapamycin
2. Inhibitors of cell division
a) nonselective drugs; azathioprine, cyclophosphamide
b) lymphocyte selective; mycophenolate mofetil
3. Corticosteroids
4. Antibodies
a) polyclonal; anti-lymphocyte globulin
b) monoclonal; anti-CD3 (OKT-3), anti-LFA

38. Sites of action of immunosuppressants
Antigen Presenting Cell
Signal 1
Signal 2
TCR
Calcineurin
Pathway
Cytokine gene
nucleus
Purine
Synthesis
Signal 3
TOR
Cell Cycle
Steroids
Anti-IL-2R
Sirolimus
MMF
ATG
Cyclosporine
& Tacrolimus
Belatacept
OKT3
MHC II B7
IL-2
CD45 CD CD CD28 Interleukin-2 receptor
T Lymphocyte Target lymphocyte

39. Reducing AR ≠ Better long-term graft survival
Long-term graft survival is not optimal yet.
Major survival gains
occurred in 6-12M
Long term survival
unchanged
Survival (%) 20 40 60 80
100 1 2 3 4 5 6 7 8 9 10 11 12
Years
Incidence of early & late AR
Reducing AR ≠ Better long-term graft survival
Herwig-Ulf Meier-Kriesche, et al. American Journal of Transplantation 2004; 4: 378–383

40. Graft Survival by era – ANZDATA Registry
Kaplan-Meier survival estimates, by era 5 10 15 20
0.00
0.25
0.50
0.75
1.00
1965-
1970-
1975-
1980-
1985-
1990-
1995-
2000-
Survival
Better not worse
years

41. Graft Survival by era – ANZDATA Registry
Kaplan-Meier survival estimates, by era
1.00
2000-
0.75
1995-
Worse not better ?
Survival
1990-
0.50
1985-
1980-
0.25
1970-
1975-
1965-
0.00 5 10 15 20
years

42. Clinical Relevance of HLA Donor-Specific Antibodies in Kidney Transplantation
Lefaucheur et al. Am J Transplant. 2008;8:

43. Two signal hypothesis for T-cell activation
Antigen responsiveness
- IL-2 secretion
- T-cell proliferation
- normal immune responsiveness
Antigen unresponsiveness
- no IL-2 secretion
- no T-cell proliferation
- anergy
co-stimulatory
activity
co-stimulatory
activity
TCR
TCR
IL-2 transcription
no IL-2 transcription

44. Blocking of co-stimulation signals
aCD40L Ab
CTLA4-Ig

45. Take home message
Characteristics of allogeneic immune responses
Two different ways of antigen presentation
Significance of co-stimulation signals for T cell activation
Effector mechanisms of rejection
Targets for immunosuppressants