1. HLA: matching and donor selection
Dr Bronwen Shaw
Consultant in haematopoietic cell transplantation
Royal Marsden Hospital
Anthony Nolan Trust

2. Overview Why does HLA matter in transplantation? HLA Some examples
Where is it found?
What does it do?
Tissue typing?
What does the nomenclature mean and how do we classify ‘matching’ and ‘mismatching’?
Polymorphism
Some examples

3. Survival for CML Unrelated HCT: JMDP Tally Effect
HCT Component Data
Survival for CML Unrelated HCT: JMDP Tally Effect

4. What is HLA? What is it for?
Human Leukocyte Antigen
Discovered: in mice (1937), humans (1954)
Function: to present peptides to T cells, thus allowing elimination of foreign particles and recognition of self (so in transplants this has to be modulated)

6. 4 Mb
3 Mb
2 Mb
1 Mb
0 Mb
HLA-A
HLA-C
HLA-B
HLA-DR
HLA-DQ
HLA-DP

7. The HLA Family A1 A2
Cw7
Cw5 B8
B44

8. The HLA Family A1 A2 A3
A26
Cw7
Cw5
Cw7
Cw8 B8
B44 B7
B14

9. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 Cw7

10. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26

11. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26

12. The HLA Family B44 A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B7 B14 A1 A3 A1 A26

13. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26

14. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26

15. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26

16. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26

17. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 Cw7

18. MHC Sequencing Consortium, 1999
One of the most gene-dense regions of the genome
224 genes identified within the 3.6 Mb
40% of the genes have functions within the immune response
HLA is the most polymorphic region in the human genome

20. Map of the human MHC on chromosome 6

21. - found on all nucleated cells
HLA Class I
- found on all nucleated cells
Polymorphism located in exons 2 & 3 1 L
exon
protein
domain 5 TM 8
3'UT 6 7
CYT 2 3 4 a a a

22. Class I HLA-A

23. - restricted to cells of the immune system
HLA Class II
- restricted to cells of the immune system
Polymorphism located in exon 2 1 L
exon
protein
domain 5
3'UT
-chain gene 2 3 4
TM/CYT 6
b-chain gene a1 a 1 
TM CYT

24. Class II HLA-DR

25. HLA and Tissue Typing
Cell

26. Serology-low resolution
HLA and Tissue Typing
Serology-low resolution
e.g. A2
Cell

27. HLA and Tissue Typing Cell Medium resolution ‘string’
e.g. A*0201/0205/0209/0240
SSP, SSOP
High resolution (definitive)
e.g. A*
SBT
Cell

28. HLA Nomenclature Gene names Antigen names Allele names
HLA-A or HLA-DRB1
Antigen names
A2 or DR1
Allele names
A* or DRB1*

29. HLA Allele Nomenclature
Locus
Asterisk
Allele family
(serological
where
possible)
Amino
acid
difference
Non-coding
(silent)
polymorphism
Intron,
3’ or 5’
polymorphism
N = null
L = low
S = Sec.
A = Abr.

30. Level of resolution Low level of resolution A*02 Antigen matched
Medium level (string) A*0201/0205/0209/0240
High level A*020101
Antigen matched
Allele matched
Type is ONE OF these four: Antigen matched
BUT do not know if allele matched

31. Ambiguity
Using medium level resolution typing it is possible to exclude some but not all alleles from a group, hence the National Marrow Donor Program (NMDP) codes.
B*1501 or B*1502 = B*15AB
B*1501/1502/1505/1515/1521/1545/1556/1570 = B*15FGR
This is important for donor selection i.e. you may be able to tell if a donor is definitely MISMATCHED but not matched

32. Numbers of HLA antigens and alleles 1968 - 2004
120 New HLA Class I alleles per year
50 New HLA Class II alleles per year

33. Number of HLA Alleles June 2004/2006/2007 (http://www. ebi. ac
HLA- A HLA- B HLA-C
325 (24) (49) (9)
489/ / /335
DRB DQA1 DQB1 DPA1 DPB1
458 (20) (7)
545
(DRB1 463/542) / /127
MICA TAP
Figures in parenthesis indicate the number of serologically defined antigens at each locus.

34. Linkage Disequilibrium/ Haplotypes
LD: Alleles occur together with a greater frequency than would be expected by chance
B/C strong, DR/DQ strong, A less strong, DP weak
e.g. B* % will be Cw*0701
But B*1801 either Cw*0501, *0701
e.g DRB1* will be DQB1*0602
But DRB1*0401 either Cw*0301, *0302
Haplotype: A group of genes inherited together
e.g. A*0101,B*0801,Cw*0701,DRB1*0301,DQB1*0201

35. Examples for search coordinators and data managers

36. Example 1: VUD search Patient: Finding a donor:
A*0101, B*0801, DRB1*0301
Finding a donor:
Common haplotype - therefore likely
Usually in strong LD - therefore ‘predictable’
Even at low resolution (A1, B8, DR3) good chance of being matched

37. Example 1: Data entry Patient: Donor: A*0101, B*0801, DRB1*0301
A1, B8, DRB1 03: Antigenic match for A, B, DRB1
No data can be entered for C, DQB1, DPB1
No data can be entered for allele level matching
A*0101, B*0801, DRB1*0301: Allelic and antigenic match for A, B, DRB1

38. Example 2: VUD search Patient: Finding a donor:
A*0201, B*1801, DRB1*0401
Finding a donor:
Less strong LD - therefore ‘ NOT predictable’ i.e. equal chance of C being *0701, *0501, *1203; DQB1 50/50 chance of *0301, *0302
At low resolution (A2, B18, DRB4) unable to predict this will match

39. Example 2: VUD search (cont)
Donor A*02

40. Example 2: VUD search (cont)

41. Example 2: VUD search (cont)

42. Example 2: VUD search (cont)

43. Example 2: VUD search (cont)

44. Example 2: VUD search (cont)

45. Example 2: VUD search (cont)

46. Example 2: Data entry Patient: Donor: A*0201, B*1801, DRB1*0401
A2, B18, DRB1 04: Antigenic match for A, B, DRB1
No data can be entered for C, DQB1, DPB1
No data can be entered for allele level matching
A*0201, B*1801, DRB1*0401: Allelic and antigenic match for A, B, DRB1
A*0201/05, B*1801, DRB1*0401: Allelic and antigenic match for B, DRB1
Antigenic match for A BUT cannot say that this is an allelic match

47. Example 2: Data entry Patient: Donor: A*0201, B*1801, DRB1*0401
A2, B18, DRB1 04: Antigenic match for A, B, DRB1
No data can be entered for C, DQB1, DPB1
No data can be entered for allele level matching
A*0201, B*1801, DRB1*0401: Allelic and antigenic match for A, B, DRB1
A*0201/05, B*1801, DRB1*0401: Allelic and antigenic match for B, DRB1
Antigenic match for HLA-A BUT cannot say that this is an allelic match

48. Example 3: search and data
patient
donor
search
data
A*0201/9207/9209
Probable match (rare)
Select donor
Antigen match
(probable allelic)
B*3503
B*4403
Match
Antigenic and allelic match
Cw*0401/24
Cw*1601
Cw*0401/20/24
DRB1*0701,
DRB1*1501/18
DQB1*0202
DQB1*0602
Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

49. Example 3: search and data
patient
donor
search
data
A*0201/9207/9209
Probable match (rare)
Select donor
Antigen match
(probable allelic)
B*3503
B*4403
Match
Antigenic and allelic match
Cw*0401/24
Cw*1601
Cw*0401/20/24
DRB1*0701,
DRB1*1501/18
DQB1*0202
DQB1*0602
Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

50. Example 3: search and data
patient
donor
search
data
A*0201/9207/9209
Probable match (rare)
Select donor
Antigen match
(probable allelic)
B*3503
B*4403
Match
Antigenic and allelic match
Cw*0401/24
Cw*1601
Cw*0401/20/24
DRB1*0701,
DRB1*1501/18
DQB1*0202
DQB1*0602
Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

51. Example 4: search and data
patient
donor
search
data
A* /06
A* /16-22/24-31/33/36-41
A* /06/07
A* /16-22/24-31/33/36-42/44/45
Probable match - but not certain
Antigen match
Cannot report allelic status
B*0801/05/07/10
B*4402/05/11/14
B*0801/05/07/10/12
Cw*0701/05/06/08/14
Cw*0401/03/04/05/06/07
Cw*
Probable match (one antigen)- but not certain
Definite mismatch
Antigen match x1
Cannot report allelic status Antigen and allelic mm x1
DRB1*1301/40
DRB1*1401
DRB1*1301
DQB1*0603/14
DQB1*050301
Rare alleles: ???????????

52. Useful websites Anthony Nolan Trust: www.anthonynolan.org.uk
NMDP allele codes:
World Marrow Donor association:
Bone marrow donor worldwide:
HLA database: