1STEM CELLTRANSPLANTATIONAND HISTOCOMPATIBILITYDr. Ann Van de Velde, Haematologist
From HLA typing to immunogenetic profiling2                Drawing Apparatus - Copyright: Robert Howsare
Goal3    Investigate structural differences between HLA    alleles    Find the best donor/recipient match for    hematop...
The Haematopoietic System4
A good match (1/2)5       Our immune system attacks things it doesn’t        recognize, including cells and tissues.    ...
A good match (2/2)6       To determine whether the donor is a good        immunological match with the recipient, a tissu...
7
8
46 XY – 46 XX9
The beginnings10
DNA11           Although 99.9% of human           DNA sequences are the           same in every person,           enough o...
Beyond the Double Helix12        Human Genome Project (HGP) 2004        There are approximately 23,000 genes in human   ...
What is HLA?13        Human Leukocyte Antigens        The proteins encoded by HLAs are those on the         outer part o...
HLA antigens14        =>antibody production        ABO: natural antibodies        HLA: not-natural antibodies:         ...
Origins – Jean Dausset (F)     Nobel Prize in Physiology and Medicine in 198015        1954: anti-leucocyte agglutinating...
Histocompatibility16        HLA typing        Screening and identification of HLA antibodies        Polymorphism of HLA...
DNA profiling (°10/09/1984, UK)     = DNA testing = DNA typing = genetic fingerprinting17        not = full genome sequen...
Variations of VNTR allele lengths18     in 6 individuals
HLA19     2 Classs: I and II        Each class of HLA is represented by more than one         locus (polygeny).        c...
Homologous chromosomes (diploid)20
Homologous chromosomes (diploid)21
Chromosome 622                    The HLA complex is located within the                    6p21.3 region on the short arm ...
23
24
Haplotypes25
Alleles     different forms of a gene/genetic locus26
Allelic variation at a gene locus27             WHO Nomenclature Committee for Factors             of the HLA System      ...
Haplotypes28        All loci are expressed co-dominantly, that is to say         both the set of alleles inherited from o...
Homozygous and heterozygous29
30
MHC class I31         locus                #     Major Antigens         HLA A               1,884         HLA B           ...
MHC class II32                                                                                  Theor.     HLA     -A1    ...
Nomenclature applied to HLA33        serological (antibody based) recognition          e.g.,   HLA-B27 or, shortened, B2...
34
Αλληλους / Allelos / "each other”35
GVH en GVL (1/2)36        The most impressive impact of novel DNA typing         methods concerns matching for allogeneic...
GVH and GVL (2/2)37      Allogeneic stem cell transplantations have the     therapeutic effect of eliminating leukemia ce...
Now the HLA-matched donor is ready38     to have her stem cells collected
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HLA Matching

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London, UK and Antwerp, B

July 2012

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  • The same and yet different tunes, its final result takes some time but in the end there is that one coming together line, overcoming all difficulties and differencies; reminds me of HLA matching in highly polymorphic species (humans)
  • An allele is one of two or more forms of a gene or a genetic locus (generally a group of genes). The form "allel" is also used, an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation. However, many variations at the genetic level result in little or no observable variation. Diploid organisms have one copy of each gene (and therefore one allele) on each chromosome. If both alleles are the same, they are homozygotes. If the alleles are different, they are heterozygotes.
  • A population typically includes multiple alleles at each locus among various individuals. Allelic variation at a locus is measurable as the number of alleles (polymorphism) present, or the proportion of heterozygotes in the population
  • Number of variant alleles at class II loci (DM, DO, DP, DQ, and DR)
  • Most designations begin with HLA- and the locus name, then * and some (even) number of digits specifying the allele. The first two digits specify a group of alleles. Older typing methodologies often could not completely distinguish alleles and so stopped at this level. The third through fourth digits specify a synonymous allele. Digits five through six denote any synonymous mutations within the coding frame of the gene. The seventh and eighth digits distinguish mutations outside the coding region. Letters such as L, N, Q, or S may follow an allele's designation to specify an expression level or other non-genomic data known about it. Thus, a completely described allele may be up to 9 digits long, not including the HLA-prefix and locus notation.
  • 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.
    23. 23. 23
    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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