hla: matching and donor selection dr bronwen shaw consultant in haematopoietic cell transplantation...

HLA: matching and donor selection

Dr Bronwen ShawConsultant in haematopoietic cell transplantation

Royal Marsden Hospital

Anthony Nolan Trust

Overview

• Why does HLA matter in transplantation?

• HLA• 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

Survival for CML Unrelated HCT: JMDP Tally EffectHCT Component DataHCT Component Data

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)

4 Mb

3 Mb

2 Mb

1 Mb

0 Mb

HLA-A

HLA-C

HLA-B

HLA-DR

HLA-DQ

HLA-DP

The HLA Family

A1 A2

Cw7 Cw5

B8 B44

The HLA Family

A1 A2

Cw7 Cw5

B8 B44

A3 A26

Cw7 Cw8

B7 B14

The HLA Family

A1

Cw7

B8

A1 A2

Cw7 Cw5

B8 B44

A3 A26

Cw7 Cw8

B7 B14

A3

Cw7

B7

The HLA Family

A1

Cw7

B8

A1 A2

Cw7 Cw5

B8 B44

A3 A26

Cw7 Cw8

B7 B14

A1 A26

Cw7 Cw8

B8 B14

A3

Cw7

B7

The HLA Family

A1

Cw7

B8

A1 A2

Cw7 Cw5

B8 B44

A3 A26

Cw7 Cw8

B7 B14

A1 A26

Cw7 Cw8

B8 B14

A2

Cw5

B44

A3

Cw7

B7

A3

Cw7

B7

The HLA Family

A1

Cw7

B8

A1 A2

Cw7 Cw5

B8B44A3 A26

Cw7 Cw8

B7 B14

A1 A26

Cw7 Cw8

B8 B14

A2

Cw5

B44

A3

Cw7

B7

A3

Cw7

B7

A2

Cw5

B44

A26

Cw8

B14

The HLA Family

A1

Cw7

B8

A1 A2

Cw7 Cw5

B8 B44

A3 A26

Cw7 Cw8

B7 B14

A1 A26

Cw7 Cw8

B8 B14

A2

Cw5

B44

A3

Cw7

B7

A3

Cw7

B7

A2

Cw5

B44

A26

Cw8

B14

A1

Cw7

B8

A3

Cw7

B7

The HLA Family

A1

Cw7

B8

A1 A2

Cw7 Cw5

B8 B44

A3 A26

Cw7 Cw8

B7 B14

A1 A26

Cw7 Cw8

B8 B14

A2

Cw5

B44

A3

Cw7

B7

A3

Cw7

B7

A2

Cw5

B44

A26

Cw8

B14

The HLA Family

A1

Cw7

B8

A1 A2

Cw7 Cw5

B8 B44

A3 A26

Cw7 Cw8

B7 B14

A1 A26

Cw7 Cw8

B8 B14

A2

Cw5

B44

A3

Cw7

B7

A3

Cw7

B7

A2

Cw5

B44

A26

Cw8

B14

A1

Cw7

B8

A3

Cw7

B7

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

P5-15

{

}

HLA-

FHC

GIV-11

{

}

MICE {

}

HCGIX

-5 {

}

P5-14

{

}HC

GIV-1

0 {

}HL

A-75

{

}P5

-13 {

}

HCGIV

-9 {

}

HLA-

90 {

}

RPL7

B {

}HC

GII-8

{

}P5

-12 {

}

HCGIV

-8 {

}

P5-11

{

}HL

A-G

HCGV

III-2 {

}

MICF {

}

3.8-1

.4 {

}P5

-10 {

}

P5-9

{

}HL

A-54

{

}P5

-7 {

}

HLA-

16 {

}

HCGII

-73.8

-1.3 {

}

P5-6

{

}HC

GIV-6

P5-5

{

}HL

A-70

HLA-

21 {

}

HCGIV

-5 {

}

P5-4

{

}HL

A-A

P5-3

{

}HC

GIV-4

{

}HL

A-80

{

}HC

GII-6

{

}MIC

D {

}HC

GIX-4

3.8-1

.2 {

}P5

-2 {

}

HCGIV

-3 {

}

HLA-

59 {

}

HCGV

III-1HC

GVII

HTEX

4

3.8-1

.5 {

}

HCGIV

-7 {

}

HCGV

RFB3

0HC

GIZN

FB7

ZNF1

73

GT25

7HL

A-30

{

}HC

GII-5

{

}HC

GII-4

{

}MIC

C {

}HC

GII-3

{

}

HLA-

92 {

}

CAT7

5X

Tel

Cen

Classical Class I (1.8 Mb)

BTL-I

IHL

A-DR

AHL

A-DR

B3HL

A-DR

B2 {

}

HLA-

DRB1

HLA-

DQA1

HLA-

DQB1

GLN-

tRNA {

}

COX3

-L {

}

HLA-

DQB3

{

}HL

A-DQ

A2 {

}

HLA-

DQB2

{

}HL

A-DO

BTA

P2LM

P7TA

P1RIN

G9 {

}

LMP2

RING8

{

}IPP

2 {

}RIN

G14 {

}

HLA-

Z1 {

}

HLA-

DMB

RING1

3 {

}HL

A-DM

ARIN

G3HL

A-DO

AHL

A-DP

A1RP

L32-L

{

}HL

A-DP

B1HL

A-DP

A2 {

}

COL11

A2 {

}

HLA-

DPB2

{

}HL

A-DP

A3 {

}

COL11

A2RX

RBRIN

G5RIN

G2RIN

G1ZN

F-L {

}

TAT-S

F1-L

{

}HS

ACM2

LRP

S18

B3GA

LT4BIN

G5 {

}

HLA-

DRB9

{

}

Classical Class II (0.8 Mb)

Extended Class II (0.3 Mb)

BAT1

NFKB

IL1AT

P6G

LTA TNFa

LST1

1C7

AIF1

BAT2

BAT3

ApoM

G4 BAT4

CSK2

BG5

bG5

cBA

T5G6

fG6

eG6

dG6

cG6

bDD

AHCL

IC1

MSH5

NG23

G7c

Val-T

RSsn

RNP

HSPA

1LHS

PA1A

HSPA

1BG8 NE

UNG

22G9

aNG

36G1

0C2 BF RD SK

I2WDO

M3L

STK1

9C4

BP4

50-C

21B

TNXB

CREB

L1NG

7

LTB NG5

NG3

PPT2

LPAA

TG1

6

G18

NOTC

H4

RAGE

PBX2

Class III (0.7 Mb)

TC4

HSR1

HLA-

E

CAT5

6AB

C50

PROA

-hom {

}

DBP2

RPL7

A {

}KIA

A017

0TU

BBFL

OTILL

INIER

3DD

R1P5

2

TCF1

9PO

U5F1

NOB4

{

}HC

GII-2

{

}HC

GIX-3

{

}

HLA-

CHC

GIV-2

{

}KIA

AOO5

5 {

}RP

L3-ho

m {

}HC

GII-1

{

}HL

A-B

HCGIV

-1 {

}

DHFR

P {

}HL

A-17

{

}P5

-8 {

}

NOB2

{

}NO

B3 {

}

NOB1

{

}HC

GIX-2

{

}MIC

AHL

A-X {

}

P5-1

3.8-1

.1HC

GIX-1

{

}MIC

B

FB19

NOB5

{

}

B30.2

-L {

}

TSBP

HNRP

A1 {

}

BING4

HKE2

RGL2

TAPB

PBIN

G1DA

XXBIN

G3 {

}

rPL35

A-L {

}

rPL12

-L {

}

APT-2

DR8

6DR1

65

74 8DR53

DR51

C4A, C4B,C4B, C4BC4A,C4B, C4BC4A,C4B

DR52

C4AQO, C4B1

Extended Class I (4 Mb)

HFE

RFP

hs6M

1-8 {

}

hs6M

1-15

hs6M

1-26 {

}

hsSA

RA {

}

hs6M

1-1hs

6M1-4

hs6M

1-3hs

6M1-2

{

}hs

6M1-6

hs6M

1-5 {

}

hs6M

1-7 {

}

hs6M

1-25 {

}

hs6M

1-24 {

}

hs6M

1-23 {

}

hs6M

1-22 {

}

hs6M

1-21

hs6M

1-20

hs6M

1-19 {

}

hs6M

1-18

hs6M

1-17

hs6M

1-16

FAT1

0 {

}Ma

s-GP

CR-L

{

}Ma

s-GP

CR-L

rPS17

{

}Ma

sPO {

}

hs6M

1-14 {

}

FAT1

0hs

6M1-1

3 {

}rPL

13 {

}

hs6M

1-12

GABB

R1SM

T3B

{}

MOG

ZNF5

7-L

DDX6

-L {

}

HSET

H2AF

AL1

H2BF

A1H1

FTH4

F2i

H1F2

H3FC

H2BF

QiH2

AFOL

iH3

F2H4

F2H1

F1Ro

Ret

SLC1

7A2

H2BF

KH2

AFK {

}

H3FH

H2BF

JH3

FIH4

n1H4

n2H1

F3H2

A {

}H3

FDH2

AFOL

iiH2

BFAii

H4FJ

RPS1

0 {

}H2

BFG

H2AF

GH3

n1H1

{

}BT

N3A3

BTN2

A3BT

N3A1

BTN2

A2BT

N3A2

BTN2

A1bG

LU-L

{

}SM

A3-L

MP-L

{

}GA

PDH-

L {

}

H2AF

ALii

H2BF

AiiiH4

F2ii

H3 {

}

H2AF

AH2

BFQii

hs6V

1-2 {

}

rPL1

0 {

}

ZNF-

184-L

{

}

hs6V

1-1 {

}

POM1

21-L

PRSS

16ZN

F184

hnRN

PA1-L

{

}

HB15

{

}rPL

2 {

}

C11H

1.2-L

{

}

rPL24

{

}H4

FFP {

}

H2BF

CH2

AFC

H3F1

KH4

F2iii

H4F2

iv

H4_n

ovel

H1_n

ovel

H2B_

nove

lH2

A_no

vel

H1_n

ovel

H2B_

nove

lH_

nove

l {

}H2

B_no

vel

H4_n

ovel

HBFE

H2AF

EH2

AFD

H2BF

DH2

BFID

H2AF

IH1

F5H3

FFH4

FKH3

FJH2

AFN

HSBF

N-L

hs6M

1-10

KIAA0

036

hs6M

1-30 {

}

hs6M

1-31 {

}

hs6M

1-29 {

}

hs6M

1-35 {

}

ZNF1

65SR

E-ZB

F {

}PR

D51 {

}

ZF47

LPR

D51

TOB4

{

}ZN

L43-L

{

}ZN

F47-L

ZNF2

0-L {

}

ZNF9

1-LSR

E-ZB

Phs

6M1-9

{

}GP

X5 {

}

GPX5

ZFP3

8-LNO

P56-L

BBC1

{

}

CYTO

KERA

TINZN

F91L

hs6M

1-28

hs6M

1-27

TRE

{}

STG

CDSN

SEEK

1SP

R1HC

R

hs6M

1-33 {

}

hs6M

1-32

hs6M

1-34 {

}

BTN

HISTONEs HISTONEsBTNs ZNFsORs ORs

hs6V

1-3 {

}

hs6V

1-4 {

}

hs6V

1-5 {

}

SLC1

7A1

SLC1

7A3

SLC1

7A2

VR1s

Map of the human MHC on chromosome 6

1

L

exon

proteindomain

5

TM

8

3'UT

6 7

CYT

2 3 4

Polymorphism located in exons 2 & 3

HLA Class I- found on all nucleated cells

Class I HLA-A

1

L

exon

proteindomain

5

3'UT

-chain gene

2 3 4

TM/CYT

1

L

exon

proteindomain

6

3'UT

-chain gene

3 42 5

TM CYT

Polymorphism located in exon 2

HLA Class II - restricted to cells of the immune system

Class II HLA-DR

HLA and Tissue Typing

Cell


CellSerology-low resolution

e.g. A2


Cell

Medium resolution ‘string’e.g. A*0201/0205/0209/0240

SSP, SSOP

High resolution (definitive)e.g. A*02010101

SBT

HLA Nomenclature

• Gene names HLA-A or HLA-DRB1

• Antigen names A2 or DR1

• Allele names A*020101 or DRB1*01010101

HLA Allele Nomenclature

HLA - A * 24 02 01 01

Locus Asterisk Allele family(serological

where possible)

Aminoacid

difference

Non-coding(silent)

polymorphism

Intron, 3’ or 5’

polymorphism

N = nullL = low

S = Sec.A = Abr.

HLA - A * 24 02 01 02 L

Low level of resolution A*02

Medium level (string) A*0201/0205/0209/0240

High level A*020101

Level of resolution

Antigen matched

Allele matched

Type is ONE OF these four: Antigen matched BUT do not know if allele matched

• 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

Ambiguity

Numbers of HLA antigens and alleles 1968 - 2004

120 New HLA Class I alleles per year

50 New HLA Class II alleles per year

Number of HLA Alleles June 2004/2006/2007

(http://www.ebi.ac.uk/imgt/hla/stats.html)

HLA- A HLA- B HLA-C

325 (24) 592 (49) 175 (9)489/617 830/960 210/335

DRB DQA1 DQB1 DPA1 DPB1

458 (20) 28 57 (7) 22 103545 (DRB1 463/542) 34 78/87 23

125/127

MICA TAP

56 11

Figures in parenthesis indicate the number of serologically defined antigens at each locus.

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*0801 - 99% will be Cw*0701– But B*1801 either Cw*0501, *0701

– e.g DRB1*1501 - 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

Examples for search coordinators and data managers

Example 1: VUD search

• Patient:– 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

Example 1: Data entry• Patient:

– A*0101, B*0801, DRB1*0301

• Donor:– 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

• No data can be entered for C, DQB1, DPB1

Example 2: VUD search

• Patient:– 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

Example 2: VUD search (cont)

• Donor A*02

Example 2: VUD search (cont)

• A*02


– A*0201, B*1801, DRB1*0401

• Donor:– 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*0201/05, B*1801, DRB1*0401: Allelic and antigenic match for B, DRB1

• Antigenic match for A BUT cannot say that this is an allelic match


– A*0201, B*1801, DRB1*0401

• Donor:– 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*0201/05, 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

Example 3: search and data

patient donor search dataA*0201/9207/9209 A*0201/9207/9209 Probable match (rare)

Select donor

Antigen match

(probable allelic)

B*3503

B*4403

B*3503

B*4403

Match

Select donor

Antigenic and allelic match

Cw*0401/24

Cw*1601

Cw*0401/20/24

Cw*1601

Probable match (rare)

Select donor

Antigen match

(probable allelic)

DRB1*0701,

DRB1*1501/18

DRB1*0701,

DRB1*1501/18

Probable match (rare)

Select donor

Antigen match

(probable allelic)

DQB1*0202

DQB1*0602

DQB1*0202

DQB1*0602

Match

Select donor

Antigenic and allelic match

Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

Example 4: search and data

patient donor search dataA*0101-03/06

A*0201-14/16-22/24-31/33/36-41

A*0101-03/06/07

A*0201-14/16-22/24-31/33/36-42/44/45

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

B*4402/05/11/14


Antigen match

Cannot report allelic status

Cw*0701/05/06/08/14

Cw*0401/03/04/05/06/07

Cw*0701/05/06/08/14

Cw*0501-04

Probable match (one antigen)- but not certainDefinite mismatch

Antigen match x1

Cannot report allelic status Antigen and allelic mm x1

DRB1*1301/40

DRB1*1401

DRB1*1301

DRB1*1401


Antigen match x1


DQB1*0603/14

DQB1*050301

DQB1*0603/14

DQB1*050301


Antigen match x1


Rare alleles: ???????????

Useful websites

• Anthony Nolan Trust:

www.anthonynolan.org.uk

• NMDP allele codes: http://bioinformatics.nmdp.org/HLA/Allele_Codes/Allele_Code_Lists/index.html

• World Marrow Donor association:

www.worldmarrow.org

• Bone marrow donor worldwide:

www.bmdw.org

• HLA database:

http://www.ebi.ac.uk/imgt/hla/

hla: matching and donor selection dr bronwen shaw consultant in haematopoietic cell transplantation...

Documents

hla matter

hla bhla

yearnumber of hla alleles

hlaahla class

immune response hla

hla allele nomenclaturehla

year50 new hla class

hladrb1antigen names