Transplant Types. Basic Concepts of Transplantation Immunology. M. Sue Leffell, PhD. Professor Of Medicine & Director Immunogenetics Laboratory

Transcription

1 Basic Concepts of Transplantation Immunology M. Sue Leffell, PhD Professor Of Medicine & Director Immunogenetics Laboratory Transplant Types Autologous (self to self) Syngeneic (identical twin to twin) Allogeneic (one individual to another within a species) Xenogeneic (across species) 1

2 Allogeneic Immunity Powerful adaptive immune response! Characterized by substantial T & B cell activation and generation of long-lasting immune memory Up to 10% of T cell repertoire may be involved Transplantation has both stimulated and served as a model for immunologic research Major Barriers to Transplantation: Rejection and GVHD Provoked by Alloantigens Encoded by different alleles within a species. Include MHC (HLA), ABO and minor histocompatibility antigens HLA A, B, Cw, DR, DQ, DP 2

3 George Snell Recognition of Histocompatibility Antigens Peter Gorer 1936 Peter Gorer identified a blood group locus encoding antigen II in mice George Snell independently mapped the gene that controlled tumor graft rejection Histocompatibility (H) locus. Their collaboration showed that H and antigen II were the same then named H-2 The Laws of Transplantation Sir Peter Medawar & Colleagues 3

4 Recognition of Human HLA Antigens Jean Dausset Jon van Rood & Rose Payne Walter Bodmer 1952 Jean Dausset observed alloreactive leukoagglutins and discovered MAC (HLA-A2) s Rose Payne determined that pregnancy and transfusions induced leukoagglutinins Jon van Rood identified 4a and 4b (Bw4,w6) Walter Bodmer and Rose Payne described LA, found to be identical to MAC. 1 st IHWS Human Transplantation Becomes Model for Immunologic Studies Organized by D. Bernard Amos at Duke University Microlymphocytotoxicity assay introduced by Paul Terasaki First studies of the impact of HLA compatibility on renal and skin graft survival Jon Ruggero Rose van Rood Ceppellini Payne Felix Rapaport Paul Terasaki Parviz Lalezari 4

5 Microlymphocytotoxicity Advantages of Terasaki s micro-droplet Assay More reproducible Conserved typing sera Permitted sharing of typing sera Facilitated IHWS collaboration and definition of new HLA antigens Family studies during the 2 nd and 3 rd IHWS established that the human MHC had two loci, encoding the LA and 4 antigens 5

6 HLA-Dw Fritz Bach Edmond Yunis Bernard Amos Mixed lymphocyte culture developed by Amos and Bach Yunis showed that Lymphocyte determined (LD) MLC responses were due to a locus distinct from LA and Homozygous typing cells were used to type the new HLA locus, HLA-Dw Recognition of Minor Histocompatibility Antigens 6

7 Allo-Immunogenicity: MHC v.s. mhag Systems Graft Survival (Days) H-1 H-2 H-3 H-10 Mutiple Non-H-2 Murine Histocompatility Systems mhag Minor Histocompatibility Ags HLA Restrict mhag Gene Tissue Distribution HA-1 A2 HA-1 Hematopoietic/ myeloid, lymphoid leukemic cells HA-2 A2 Myosin 1G HB-1 B44 Not Known Hematopoietic/ myeloid, lymphoid leukemic cells B Cell ALL ACC-1 A24 BCL2A1 Hematopoietic/ myeloid, lymphoid leukemic cells ACC-2 B44 BCL2A1 Hematopoietic/ myeloid, lymphoid leukemic cells UGT2B17 A29 UGT2B17 Dendritic, B Cells H-Y B8 UTY Hematopoietic Cells Spierings, E and Goulmy, E. J Clin. Invest. 2005; 115:3398 7

8 Recognition of the Importance of HLA Specific Abs Flemming Kissmeyer-Nielsen Paul I. Terasaki Association of pre-existing HLA specific antibodies and hyperacute renal allograft rejection 1966 F. Kissmeyer-Nielsen 1968 G. M. Williams 1969 Series of cases by Patel and Terasaki CDC crossmatch becomes standard practice CDC antibody screening and definition with cell panels Flow cytometric crossmatches introduced in 1980s MHC Restriction Defined by Zinkernagel & Doherty in 1974 (1996 Nobel Prize). T cells are restricted to recognize foreign peptides bound to self MHC. H-2 compatibility required for lysis of virus infected target cells Restriction element - MHC molecule(s) which binds a given peptide antigen. Alloreactivity is MHC restricted. 8

9 Structural Basis for MHC Restriction Bjorkman PJ, Strominger JL, Wiley DC. Nature,1987;329: Wiley DC, et al. Nature.1996;384: Alloreactivity: Immunological Paradoxes Allogeneic response is fully developed at birth. Frequency of precursor T cells for MHC alloantigens is x > that for nominal Ags. Response to allo-ags is unique: Recognized directly by recipient T cells. Recipient T Cells interact with both self and allo-apc. 9

10 MHC Structure & Function TCRα TCRβ Gras S, et al. Immunol. Cell Biol. 2011;89:388 MHC Polymorphism Affects TCR Interaction with peptide-mhc surface Cumulative allelic differences result in peptide-allogeneic MHC surface (d) that differs greatly from peptide-self-mhc (e). Felix NJ. Allen PM/ Nat Rev Immunol. 2007; 7:

11 TCR & MHC Plasticity TCR CD3 shifting and MHC α2 helix displacement BM3.3 TCR complex with: H2K b - pbm1 (green) H2K b - VSV8 (blue) H2K bm8 - pbm8 (orange) HLA-A2 complex with: Tax peptide (pink) Tel1 peptide (blue) Gras S, et al. Immunol. Cell Biol. 2011;89:388 HLA-A2:Tax Peptide:TCR Wiley DC, et al

12 Shifted Docking - Allorecognition H2K b vs. H2L d H2K b - dev8 H2L d -QL9 2 C TCR Docking Modes: H2K b dev8 Cognate Recognition H2L d QL9 Allo-recognition Gras S, et al. Immunol. Cell Biol. 2011;89:388 Activation of Alloreactive T Cells Molecular Mimicry Bystander activation during infection Molecular mimicry Alloantigen Cross reactivity H-2 alleles: LCMV, Leishmania major, influenza A, vesicular stomatitis virus HLA alleles: EBV, HSV, CMV 12

13 Molecular Mimicry LC13 TCR is specific for EBV EBNA peptide, FLR HLA-B8 HLA-B8 vs. B44 HLA-B*44:05 - mimotope HLA-B*44:05 - allotope HLA-B8 - FLR LC13 TCR Allotope LC13 TCR - FLR Gras S, et al. Immunol. Cell Biol. 2011;89:388 Allo-HLA Cross-Reactivity Viral Specific Memory T Cells 45% of viral specific memory T cells can cross react with HLA Cross-reactivity with both class I and II HLA D Orsogna LJ, et al. Immunogenetics 2012;64:

14 Examples of Viral Ags & HLA Cross-reactivity Virus Viral Ag HLA Restriction Viral Peptide HLA Crossreactivity CMV pp50 A*01:01 VTEHDTLLY A*11:01 VZV IE62 A*02:01 ALWALPHAA B*55:01 H. Influenzae IMP A*02:01 GILGFVFTL B*64:01 HSV-2 VP13/14 A*02:01 FLVDAIVRVA B*44:02/03/07 EBV BRLF1 A*0301 RVRAYTYSK A*02:01 EBV EBNA3A B*08:01 FLRGRAYGL B*44:02,B*55:01 CMV pp65 DRB1*01:01 KYQEFFWDANDIYRI DRB1*09:01 EBV pp65 DRB1*01:01 KYQEFFWDANDIYRI DRB3*01:01 H. Influenzae HA DRB1*04:01 PKYVKQNTLKLAT DRB1*13:01 EBV EBNA2 DRB3*02:02 PRSTVFYNIPPMPLPP SQL DRB1*01:01 EBV EBNA1 DPB1*10:01 NPKFENIAEGLRALLA RS DRB1*01:02 EBV LMP2 DQB1*06:01 TYGPVFMSLGGLLTM VA DRB1*09:01 Adapted from: D Orsogna LJ, Roelen DL, Doxiadis IIN, Claas FHJ. 2010;Transplant Immunol. 4: Other Examples of Molecular Mimicry Smith C, Miles JJ, Khanna R. Am J Transplant.2012;12:

15 Molecular Mimicry &TCR Plasticity Syngeneic LC13 TCR ~ B*08:01 Allogeneic LC13 TCR ~ B*44:05 Syngeneic Allogeneic Syngeneic Allogeneic Syngeneic YAe62 TCR ~ Ia b Allogenic YAe62 TCR ~ K b Smith C, Miles JJ, Khanna R. Am J Transplant.2012;12:15-26 Contributions to Alloreactivity 1. MHC plasticity presentation of multiple peptides 2. TCR plasticity different binding modes 3. Molecular mimicry 4. Indirect and direct recognition Archbold JK, et al. Trends Immunol :

16 Direct Presentation Indirect Presentation Donor APC Donor MHC Donor APC Donor Peptide Recipient APC Recipient MHC T T T Recipient T Cells Types of Direct Presentation Direct Semi-direct Indirect Donor APC Recipient APC Recipient APC Adapted from: Wood KJ, Goto R. Transplantation.2012;93:

17 Induction of Allograft Response: Direct Antigen Presentation Donor MHC class II CD4+ Donor APC TCR CD8+ Donor MHC class I APC: Graft Tissue Cells Passenger leukocytes - Lymphocytes Macrophages Dendritic cells Indirect Allorecognition 17

18 Direct v.s. Indirect Presentation Direct presentation predominates in early stages, inducing acute rejection. Effective direct presentation depends on the presence of donor cl II + APC. Impact of HLA-DR mm > HLA-A, B mm Indirect presentation likely is more important in chronic rejection. Indirect presentation evokes response to minor histocompatibility Ags. Evolving Paradigm: Alloimmunity differs from Infectious Disease Immunity Due to high frequency of alloreactive precursors, the T cell response to allogeneic cells and tissues is largely a memory response Molecular mimicry TCR and MHC plasticity Even 1 st time transplant recipients are essentially, non-naïve. 18

19 Innate Immunity: Transplantation Renal Allograft Sensors of Danger TLRs and NLRs Response to tissue damage and/or microbial products Inflammation Inflammatory mediators Pro-inflammatory cytokines Chemokines Mast Cells, Platelets Early Innate Defense Responses Danger signals Pro-inflammatory cytokines Inflammatory mediators Chemokines Cell recruitment migration Innate Defense Cells -PMN, Mϕ, DC - NK cells -APC 19

20 Activation - Adaptive Immunity Dendritic cells Innate defense responses recruit & shape adaptive responses - Clonal proliferation - Generation of effector & memory cells Lymph nodes Spleen Naïve T, B Cells Generation of Effector Cells Indirect Direct B Cell Self APC CD4+ Donor APC B B T H 2 T H 1 CD8+ Plasma Cells CTL CTL Humoral Rejection Cellular Rejection 20

21 Innate and Adaptive Effector Mechanisms Innate Effectors Defensins Complement Activated MM FCR accessory Cells NK Cells Adaptive Effectors T lymphocytes Th1 vs. Th2 CD8+ CTL B lymphocytes Antibodies Regulation of Immune Responses Innate Cellular Regulation Antibody Regulation CMI Regulation: Central Tolerance Peripheral Tolerance Clonal Downsizing Regulatory T & B Cells 21