1. Transplantation Immunology1 Transplantation: Chapter 17 You are not responsible for: Immunosuppressive therapies Clinical aspects of specific organ transplants Transplants Organ in 2005 Cornea 47,000 Kidney 16,477 Liver 6444 Heart 2127 Lung 1408 Pancreas 570 Self-Test Questions: Intro: all A.I: 1 – 5, 7, 8 A.II: 2 – 4 B: 2, 3, 5 C: 1 D: 4 E: 2

2. Transplantation Immunology2 What are different types of tissue transplants? Sources -- Living donor; & self -- Cadaver -- Animal Autologous graft -- e.g., skin, artery transplants -- not rejected Isograft -- e.g., any organ -- not rejected Allograft -- kidney, liver, heart transplants -- rejected; unless Im privileged Xenograft -- rejected, unless non-antigenic -- e.g., heart valves

3. Transplantation Immunology3 What are types of rejection? 1. Host-vs-Graft Hyperacute rejection -- rapid: minutes to hours -- humoral; existing Abs; complement -- blood type -- xenografts Acute rejection -- humoral or cell mediated -- days/weeks Chronic rejection -- months / years -- despite immunosuppressive therapy Long term not much improved -- Kidney: half-life only 8-10 years 2. Graft-vs-Host ( discussed later) Recipient Abs against donor MHC Recipient CTLs attack donor cells Recipient Abs, attack donor cells 5 Year survival rate (2009) Kidney: 69.3% Heart: 74.9% Liver: 73.8% Lung: 54.4%

4. Transplantation Immunology4 What are the mechanisms of Immune rejection Direct vs Indirect allo-recognition Effector cells Rejection mechanisms

5. Transplantation Immunology5 What causes ‘Direct’ allo-recognition? Primary mechanism of rejection (10x greater than indirect) Recipient T-cells are activated by: Graft-MHC + Graft peptides Why would T-cells bind to peptides in non-self MHC? Graft-MHC + peptide can resemble … Self-MHC + foreign peptide May contribute mostly toward acute rejection MHC + peptide

6. Transplantation Immunology6 What causes ‘Indirect’ allo-recognition? Recipient T-cells are activated by recipient MHC + graft (MHC) peptides Analogous to normal T-cell response to pathogens (or vaccines) Recipient DCs migrate into graft and phagocytose Ags -- fewer T-cells respond (most AG being ‘self’) but among these will also be… -- MHC peptides -- Minor Histocompatibility Antigens May contribute mostly toward chronic rejection -- graft DCs soon removed from body

7. Transplantation Immunology7 When does Graft vs Host Disease (GvHD) occur? -- bone marrow -- some solid organ Immune cells of graft react against recipient tissues -- Allo-reactive antibodies -- Cell-mediated attack Occurs in 75%+ of bone marrow transplants But has beneficial effect against leukemic and cancerous cells

8. Transplantation Immunology8 What are the primary anti- rejection therapies? 1. Corticosteroids, e.g., prednisone 2. Anti-proliferatives, e.g., azothrioprine 3. T-cell signaling/activation disruptors a) chemotherapeutic agents -- IL-2 inhibitors; e.g., cyclosporine-A, rapamycin b) humanized Mabs -- anti-CD3 -- anti-IL2r (e.g., basiliximab) -- anti-CD20, a B-cell AG) (e.g., rituximab) c) fusion molecules -- B7 antagonist (blocks B7/CD28 interaction) -- e.g., Belatacept; CTL-4 + IgG FC Cyclosprine-A

9. Transplantation Immunology9 Organ perfusion prior to transplant can minimize direct acute rejection -- why? -- also improves organ performance What are some experimental anti-rejection therapies? 1. Bone marrow HSC transplants -- transplant HSC from done to recipient 2. Thymic manipulation -- inject donor AG into recipient thymus 3. Treg cell induction -- in vitro or in vivo 4. and others…

10. Transplantation Immunology10 How is tissue-matching performed? -- minimizes HLA incompatibility 1. Alloantibody Screening -- Abs against specific HLA 2. HLA (tissue) matching a) Serological -- use HLA specific mABs b) DNA analysis -- look for HLA-allele specific sequences Not all HLA tested for… Why? HLA typing at NY Blood Center Serology HLA Class I (A,B,C) HLA Class I HLA-B27 DNA analysis PCR- broad allele class resolution HLA Class I (A,B,C) DNA sequencing allele level resolution, HLA Class I (A,B,C) by HLA-Class II (DRB1) HLA-Class II (DQB1) http://www.nybloodcenter.org/HLA- Typing.do?sid0=92&page_id=185

11. Transplantation Immunology11 Not all HLA genes are equally important Why? In Kidney -- Little MHC-II expressed 6 HLA antigens examined: -- HLA-A, HLA-B, and HLA-DR e.g., HLA-A1 & A2, B7 & B8, DR2 & DR3 Liver -- little MHC-I or -II expressed -- usually only ABO matched What about… Cornea: No matching …Why? Heart: No matching …Why? Increased HLA matching yields only minor improvements in kidney survival