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

Yu Yu Voronoy, Russia, 1935

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"

1년 이상 Graft survival을 보인 659명의 Overall survival 서울대학교병원 1990-2005

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;27:576-583

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)

Immunologic Responses

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

Immunologic Propagation

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

Immunolgic Responses against Allo-antigen

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

MHC Class I, II

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

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

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

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

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

Mechanism of T cell activation and proliferation 1 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

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

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

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

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

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

Acute cellular rejection; tubulitis

Acute cellular rejection; arteritis

Acute humoral rejection

Chronic rejection; Interstitial Fibrosis and Tubular Atrophy

Biopsy proven acute rejection in SNUH Episode : ~20% Han SS et al, The Korean Journal of Nephrology 2008;27:576-583

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

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)

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

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 CD4 CD3 CD28 Interleukin-2 receptor T Lymphocyte Target lymphocyte

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

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

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

Clinical Relevance of HLA Donor-Specific Antibodies in Kidney Transplantation Lefaucheur et al. Am J Transplant. 2008;8:324-331

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

Blocking of co-stimulation signals aCD40L Ab CTLA4-Ig

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