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Transplantation Immunology Current Status

Transplantation Immunology Current Status. Volker Daniel, MD Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, Im Neuenheimer Feld 305 D-69120 Heidelberg Germany Volker.Daniel@med.uni-heidelberg.de. Transplantation Immunology.

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Transplantation Immunology Current Status

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  1. Transplantation Immunology Current Status Volker Daniel, MD Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, Im Neuenheimer Feld 305 D-69120 Heidelberg Germany Volker.Daniel@med.uni-heidelberg.de

  2. Transplantation Immunology • TPL (numbers, overview, history) • HLA • Preoperative tests (prophylaxis of rejection) • Mechanisms of rejection (solid organs) • Immunosuppression • Tolerance (induction) • Clinical complications (infection, cancer) • Bone marrow and stem cell transplantation • Xenotransplantation • Artifical organs

  3. Transplantation Immunology • TPL (general aspects, numbers, overview, history) • HLA • Preoperative tests (prophylaxis of rejection) • Mechanisms of rejection (solid organs) • Immunosuppression • Tolerance (induction) • Clinical complications (infection, cancer) • Bone marrow and stem cell transplantation • Xenotransplantation • Artifical organs

  4. Organ FailureAlternative Treatment Strategies Mechanical organ replacement • Dialysis, bioartificial liver, cardiovascular device Artificial organs • Tissue engineering, therapeutical cloning Organs of other species • Xenotransplantation

  5. Benefit of Transplantation • nearly unrestricted quality of life • rehabilitated in profession and social relationships

  6. Expenses

  7. Pioneers of Transplantation • Joseph Murray (kidney, 1954) • James D. Hardy (lung, 1963) • Richard Lillehei (pancreas, 1966) • Christian Barnard (heart, 1967) • Thomas E. Starzl (liver, 1967) • Jean Dausset (HLA, 1958) • Jon van Rood (Eurotransplant, 1967)

  8. International Transplant Records Clinical Transplants 2001; 279-318

  9. Postmortale Organspenden (Stand: 02/06) www.dso.de

  10. www.ctstransplant.org

  11. Transplantation Immunology • TPL (general aspects, numbers, overview, history) • HLA • Preoperative tests (prophylaxis of rejection) • Mechanisms of rejection (solid organs) • Immunosuppression • Tolerance (induction) • Clinical complications (infection, cancer) • Bone marrow and stem cell transplantation • Xenotransplantation • Artifical organs

  12. Genetic organization of the MHC in humans and the mouse

  13. HLA class II

  14. Expression of MHC Antigens

  15. Association between HLA and susceptibility to autoimmune disease

  16. Population studies show association of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype

  17. Family studies show strong linkage of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype

  18. Transplantation Immunology • TPL (general aspects, numbers, overview, history) • HLA • Preoperative tests (prophylaxis of rejection) • Mechanisms of rejection (solid organs) • Immunosuppression • Tolerance (induction) • Clinical complications (infection, cancer) • Bone marrow and stem cell transplantation • Xenotransplantation • Artifical organs

  19. Microlymphocytotoxicity Assay Separation of lymphocytes using densitiy gradient centrifugation Separation of lymphocytes in T and B cells using Dynabeads Dotting lymphocytes on Terasaki microtrays predotted with HLA antisera, Incubation period of 30 min Addition of rabbit serum (complement), Incubation period of 60 min Addition of acridinorange and ethidiumbromide, Incubation period of 15 min Fluorescence microscopy

  20. Mikrolymphocytotoxicity test Positive Negative

  21. Molecular-Based Techniques for HLA Typing • RFLP (Restriction Fragment Length Polymorphism) • PCR-SSO (PCR - Sequence Specific Oligonucleotide Hybridization) - Dot Blot (Standard Procedure) = amplified DNA is dotted - RDB (Reverse Dot Blot = oligos are dotted) • PCR-SSP (ARMS) (PCR - Sequence Specific Primers) • SBT (Sequence Based Typing) • PCR-RFLP u.a.

  22. HLA-Typing; Degrees of Resolution

  23. Polymorphism of HLA June 2006 http://www.ebi.ac.uk/imgt/hla/stats.html

  24. Full List of HLA-A, -B, and -DR alleles (2 digits) assigned as of April 2003 http://www.anthonynolan.com/HIG/nomenc.html

  25. Full List of HLA-B alleles assigned as of April 2003

  26. New HLA Antigens und Alleles

  27. Meyer M, Czachurski D, Tran TH, Opelz G, Mytilineos J. A new PCR-SSP typing method for six single-nucleotide polymorphisms impairing the blood-clotting cascade as well as T-cell stimulation.Tissue Antigens. 2005 Dec;66(6):650-5. Czachurski D, Scollo A, Skambraks A, Perichon AM, Scherer S, Tran TH, Opelz G, Grappiolo I, Mytilineos J. Description and characterization of two new HLA alleles, B*4051 and DRB1*1364, identified by sequence-based typing.Tissue Antigens. 2005 Aug;66(2):151-5. Czachurski D, Scherer S, Gehrke S, Laux G, Opelz G, Mytilineos J. Identification of two new HLA alleles: B*3546* and B*5611*. How reliable are the published HLA-B intron 2 sequences?Tissue Antigens. 2004 Oct;64(4):500-5. Czachurski D, Opelz G, Mytilineos J. A new HLA-DRB allele (DRB1*15014) identified in a Caucasian individual.Hum Immunol. 2003 Feb;64(2):310-3. Czachurski D, Rausch M, Scherer S, Opelz G, Mytilineos J. Characterization of a new HLA-A allele, A*0256, identified in a Caucasian individual.Tissue Antigens. 2002 Aug;60(2):180-3.

  28. Lancet. 2005 Apr 30-May 6;365(9470):1570-6. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies.Opelz G; Collaborative Transplant Study.

  29. Figure 2. 10-year follow-up of kidney grafts from HLA-identical sibling donors

  30. Transplantation. 2002 Apr 27;73(8):1269-73. Kidney graft failure and presensitization against HLA class I and class II antigens.Susal C, Opelz G.

  31. Figure 1. Influence of ELISA-detected pretransplant IgG-anti-HLA class I and class II antibodies on cadaver kidney graft survival. Recipients possessing both anti-HLA class I and class II antibodies (I+/II+) had a significantly lower graft survival rate than antibody-negative recipients (I-/II-) (log-rank P <0.0001). Anti-HLA class I-positive/class II-negative (I+/II-) and anti-HLA class I-negative/class II-positive recipients (I-/II+) showed surprisingly good graft success rates.

  32. N Engl J Med. 1994 Mar 24;330(12):816-9. The influence of HLA compatibility on graft survival after hearttransplantation. The Collaborative Transplant Study.Opelz G, Wujciak T.

  33. Figure 1. Actuarial Survival Rates of First Heart Transplants According to the Number of HLA-A, B, or DR Mismatches. The numbers of mismatched antigens and the numbers of grafts studied are indicated for each curve.

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