Canterbury DHB

Context

The HLA system

The major histocompatibility complex (MHC) is located at 6p21.3 and contains the human leucocyte antigen (HLA) region which spans 3.6Mb, including 200 genes.

The class I region encodes the “classical” class I antigens, A, B and C, which are expressed on all cells in the body except erythrocytes. Class I antigens comprise a polymorphic alpha chain and a non-polymorphic beta chain (coded on chromosome 15) forming a dimer.

The class II regions encodes HLA-DQ, -DP and –DR which are expressed on B cells, dendritic cells and monocytes. Class II antigens can also be expressed on other cells during inflammation. The class II antigen is made up of alpha and beta chains which are encoded at HLA-DRA (invariable) and –DRB (extremely polymorphic). DQ and DP antigens have polymorphic alpha and beta chains.

Individuals can possess two HLA-DR molecules using the same alpha chain and one beta chain from the first DRB1 locus and the other from the second DR locus, e.g. DRB3, DRB4 DRB5 etc.

Several other genes encoded within the class II region assist in processing and presentation of the antigen.

The class III region does not contain any HLA genes but does encode proteins which play an important role in the immune system, e.g. heat shock protein, tumour necrosis factor and complement.

Searching for a matched unrelated donor

Many registries use software to estimate the likelihood of finding a suitable donor. Based on factors below the probability of finding a 10/10 donor is high (>95%) in 30%, intermediate (approx 50%) in 30% and low (<5%) in 40%. For patients with a 10/10 match around 40% will also have an HLA-DPB1 match.

In order to maximise the cost-effective of searching several groups have developed algorithms for obtaining a MUD in an acceptable time period, e.g. a 9-10/10 donor could be found for 72% of patients within 14 weeks [Querol, Haematologica 2009]. A recent Austrian study reported that a 9-10/10 match could be found for 78% (88% in Europeans) in 1.84 months [Rosenmayr, Trans Med Hemotherapy 2012].

Significance of single HLA-mismatches

For some time a 10/10 match was considered ideal, but based on the proven negative impact of mismatches at the HLA-A, B, C and DR loci and several recent studies which have questioned the importance of matching at DQB1 (Shaw, Arguello et al. 2010) the current gold standard is an 8/8 match.

However, some HLA mismatches have been shown to be permissive using in vitro T-lymphocyte assays and the relevance of mismatches must be interpreted in light of other donor/patient factors. Urgency of transplant, T-cell depletion and RIC may all influence the impact of HLA mis-matches.

The effect of single mis-matches is not seen in high risk or advanced stage disease and is most evident in low risk, early stage disease (Lee, Klein et al. 2007, Petersdorf, Gooley et al. 2007). The Anthony Nolan Trust data showed that in patients with early stage disease OS at 5 years was significantly better in 12/12 compared to 10/10 donors (63% v 41%) (Shaw, Arguello et al. 2010).

The NZBS has produced a brief account of the HLA system with particular reference to transplantation.

About this Canterbury DHB document (8876):

Document Owner:

Andrew Butler (see Who's Who)

Issue Date:

December 2016

Next Review:

December 2018

Keywords:

Note: Only the electronic version is controlled. Once printed, this is no longer a controlled document. Disclaimer

Topic Code: 8876