Download HLA matching, compatibility testing and donor selection

Interpreting HLA typing and matching
Bronwen E Shaw
Introduction
One of the major factors which has contributed to improving the outcomes of Stem Cell
Transplantation is the progress which has been made in the field of HLA. This is evident not only
in the progress made in developing techniques for rapid and accurate tissue typing, but also in
the greatly improved understanding of the HLA system, its function and the impact of HLA
matching on transplant complications.
Unfortunately, in view of the enormous complexity of the HLA system, the nomenclature and
matching is not always easy to understand. In this short summary I hope to outline the
background of the MHC/HLA and provide the reader with a vocabulary for interpreting HLA typing
results. This was originally designed primarily for search co-ordinators and data managers, but I
hope will be helpful, in addition, to others.
An associated powerpoint presentation can be found on the BSBMT website.
What is HLA for?
This primary role of HLA molecules is to presenting peptide to T cells enabling them to recognise
and eliminate ‘foreign’ particles present in an individual, as well as to prevent the recognition of
‘self’ as foreign. The HLA system displays extensive polymorphism most likely due to the need for
the immune system to keep up with and control infectious pathogens (evolutionary pressure). The
HLA region is the most polymorphic (with HLA–B the most polymorphic gene) currently known in
the human genome (http://www.sanger.ac.uk/HGP/Chr6/). In January 2009 there were 3371
named HLA alleles (http://www.ebi.ac.uk/imgt/hla).
If there are so many alleles how do we ever find a match?
Fortunately there are two features in the HLA system which may make finding a match easier as
they allow us to ‘predict’ if a donor will be matched or mismatched from the available information:

Linkage disequilibrium (LD): Alleles occur together with a greater frequency than
would be expected by chance. LD is more frequently observed between loci that are
in close proximity (e.g. between HLA-B and –C and HLA-DRB1 and –DQB1). For
example, over 95% of Caucasoid individuals who have HLA–B*0702 will have HLA–
Cw*0702. In some cases there are more possibilities e.g. those who express B*1801
may express either Cw*0701 (38%), Cw*1203 (38%) or Cw*0501 (34%).

Haplotype: A group of genes inherited together. There are a number of common
haplotypes in different ethnic groups.
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HLA Nomenclature – what does it all mean?
Currently, each HLA allele name has a unique four, six or eight digit number. In practice all alleles
receive at least a four-digit number, and this is required to refer to a tissue type as high
resolution. ‘Longer’ allele names are not needed in routine matching practice at the moment.

The first two digits describe the type, which often corresponds to the serological
antigen e.g. A*24.

The third and fourth digits are used to list the subtypes. Alleles whose numbers differ
in the first four digits must differ in one or more nucleotide substitutions that change
the amino acid sequence of the encoded protein e.g. A*2402 or A*2405.
How do we interpret tissue typing reports?
The way that the tissue typing report will look will be affected by the laboratory technique that has
been used:

Low resolution provides a serological (antigenic) type e.g. A2. It is no longer
appropriate to perform low resolution/serological typing alone for unrelated donors,
but this might be done for siblings. A patient and donor typed to this level are antigen
matched.

Medium resolution typing implies that a DNA based test has been used, but it not
discriminatory enough to tell us the exact allele i.e. it can define specific allele groups
(often as a ‘string’ of possible alleles). For example an HLA-A*0201 allele may be
typed as an A*0201/0205/0209/0240 with the test unable to discriminate further
between these. In other words, the donor could actually have any one of these 4
possible alleles. A patient and donor typed to this level are antigen matched, but
you are unable to tell if they are allele matched. The National Marrow Donor
Program (NMDP) has created allele codes. These codes describe a ‘string’ of
alleles, e.g. a report of DRB1*01AD means that the typing is either DRB1*0101 or
DRB1*0104, but not DRB1*0102 or DRB1*0103
(http://bioinformatics.nmdp.org/HLA/allele_code_lists.html).

High resolution typing methods result in there being no ambiguities e.g. A*0201. A
patient and donor typed to this level are both antigen and allele matched.
Selected references
Bronwen E Shaw. HLA matching, compatibility testing and donor selection. In: Haematopoietic
Stem Cell Transplantation in Clinical Practice. John Barrett & Jennie Treleaven, ed.
London: Churchill Livingstone Elsevier; 2009.
Marsh SGE, Parham P, Barber LD. The HLA FactsBook. London: Academic Press; 2000.
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Petersdorf EW. Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol
2008;20:588-93.
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