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HLA Matching

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London, UK and Antwerp, B

July 2012

Published in: Health & Medicine, Technology
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HLA Matching

  1. 1. 1STEM CELLTRANSPLANTATIONAND HISTOCOMPATIBILITYDr. Ann Van de Velde, Haematologist
  2. 2. From HLA typing to immunogenetic profiling2 Drawing Apparatus - Copyright: Robert Howsare
  3. 3. Goal3 Investigate structural differences between HLA alleles Find the best donor/recipient match for hematopoietic stem cell transplation
  4. 4. The Haematopoietic System4
  5. 5. A good match (1/2)5  Our immune system attacks things it doesn’t recognize, including cells and tissues.  Stem cell transplants can be rejected by the recipients immune system.  Therefore, the transplanted stem cells must match the recipient closely enough that they wont be recognized as intruders.
  6. 6. A good match (2/2)6  To determine whether the donor is a good immunological match with the recipient, a tissue typing test is performed using blood samples from both individuals.  This test identifies certain proteins, called HLA antigens, which reside on the surfaces of specific immune cells.  If the donor and the recipient have identical HLA antigens, they are a good match.
  7. 7. 7
  8. 8. 8
  9. 9. 46 XY – 46 XX9
  10. 10. The beginnings10
  11. 11. DNA11 Although 99.9% of human DNA sequences are the same in every person, enough of the DNA is different to distinguish one individual from another, unless they are monozygotic twins.
  12. 12. Beyond the Double Helix12  Human Genome Project (HGP) 2004  There are approximately 23,000 genes in human beings  Understanding how these genes express themselves will provide clues to how diseases are caused.
  13. 13. What is HLA?13  Human Leukocyte Antigens  The proteins encoded by HLAs are those on the outer part of body cells that are unique to that person.  Plays a key role in immune response  More polymorphic than red blood groups  ABO system: 4 possible combinations (A, B, AB, O)  HLA system: > 1 million combinations
  14. 14. HLA antigens14  =>antibody production  ABO: natural antibodies  HLA: not-natural antibodies: as a result of an immunologic challenge of a foreign material containing non-self HLAs via  Pregnancy  Blood transfusion  Transplantation
  15. 15. Origins – Jean Dausset (F) Nobel Prize in Physiology and Medicine in 198015  1954: anti-leucocyte agglutinating substance  1958: isoantibody specific to leucocytes  1965: all leucocyte antigens = part of complex  1968: renamed HLA  1980: Nobel Prize  => made it feasible to publish the first genetic map and, later on, the first physical map of the human genome.
  16. 16. Histocompatibility16  HLA typing  Screening and identification of HLA antibodies  Polymorphism of HLA represents a major barrier to hematopoietic stem cell (HSC) transplantation.
  17. 17. DNA profiling (°10/09/1984, UK) = DNA testing = DNA typing = genetic fingerprinting17  not = full genome sequencing  repetitive ("repeat") sequences that are highly variable  variable number tandem repeats (VNTRs)  short tandem repeats (STRs)  Siblings:  VNTR loci are very similar  Unrelated individuals:  VNTR loci are very different
  18. 18. Variations of VNTR allele lengths18 in 6 individuals
  19. 19. HLA19 2 Classs: I and II  Each class of HLA is represented by more than one locus (polygeny).  class I loci are HLA-A,-B and –C  class II loci HLA-DR, -DQ and -DP.  All the HLA genes map within a single region of the chromosome (hence the term Complex).
  20. 20. Homologous chromosomes (diploid)20
  21. 21. Homologous chromosomes (diploid)21
  22. 22. Chromosome 622 The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system.
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  24. 24. 24
  25. 25. Haplotypes25
  26. 26. Alleles different forms of a gene/genetic locus26
  27. 27. Allelic variation at a gene locus27 WHO Nomenclature Committee for Factors of the HLA System > 7000 alleles
  28. 28. Haplotypes28  All loci are expressed co-dominantly, that is to say both the set of alleles inherited from ones father and the set inherited from ones mother are expressed on each cell.  The set of linked alleles found on the same chromosome is called a haplotype.
  29. 29. Homozygous and heterozygous29
  30. 30. 30
  31. 31. MHC class I31 locus # Major Antigens HLA A 1,884 HLA B 2,490 HLA C 1,384 Minor Antigens HLA E 11 HLA F 22 HLA G 49
  32. 32. MHC class II32 Theor. HLA -A1 -B1 -B3 to -B5 1 possible combination locus # # # s DM- 7 13 91 DO- 12 13 156 DP- 34 155 5,270 DQ- 47 165 7,755 DR- 7 1,094 92 8,302 DRB3, DRB4, DRB5 have variable presence in humans 1
  33. 33. Nomenclature applied to HLA33  serological (antibody based) recognition  e.g., HLA-B27 or, shortened, B27  "HLA" in conjunction with a letter * and four-or- more-digit number  e.g., HLA-B*08:01, A*68:01, A*24:02:01N N=Null)
  34. 34. 34
  35. 35. Αλληλους / Allelos / "each other”35
  36. 36. GVH en GVL (1/2)36  The most impressive impact of novel DNA typing methods concerns matching for allogeneic HSC transplantation because subtle serologically silent sequence differences between allelic subtypes are recognized by alloreactive T-cells with serious consequences for graft outcome.
  37. 37. GVH and GVL (2/2)37  Allogeneic stem cell transplantations have the therapeutic effect of eliminating leukemia cells, with the danger of developing graft versus host disease. When donor and patient are HLA-identical, these effects are due to minor histocompatibility antigens, which are expressed from polymorphic genes. Identifing which genes and which peptides cause the GvL effect, without the development of GvHD.
  38. 38. Now the HLA-matched donor is ready38 to have her stem cells collected

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