Of all the genetic and non genetic factors that can influence stem cell transplant outcome, the most important is HLA matching.
HLA matching is required for all forms of stem cell transplantation other than autologous transplantation. Matching is required at all the classical HLA class I and II loci, HLA-A, B and C, HLA-DRB1, DQB1 and HLA-DPB1 at high resolution allele level. Graft versus Host Disease (GvHD) is a major post transplant complication in stem cell transplantation and can be initiated by as little as a single amino acid mismatch in the peptide binding groove of a HLA antigen. The degree of matching required will be influenced by the nature of the disease and the source of the stem cells. Studies by Petersdorf et. al., and others have shown that the risk of GvHD increases with increasing numbers of mismatches in the Graft versus Host direction (i.e. HLA alleles present in the patient but absent in the donor). Similar studies have also shown that the risk of graft failure increases with increasing numbers of mismatches in the Host versus Graft direction (i.e. HLA alleles present in the donor but absent in the patient). Class II mismatches have been shown to be more relevant in GvHD, with class I mismatches more relevant in graft failure at least in the related setting.
In autologous stem cell transplantation, the donor is the patient, making the HLA alleles the same. Any HLA typing undertaken is therefore not for matching for the transplant but rather for information should an allogeneic donor suddenly be needed or for supportive therapy such as the use of HLA matched platelets.
In the allogeneic setting, HLA matching is required at the high resolution allele level, the ‘best’ matched donor being a syngeneic or genetically identical donor who will be allele matched at all the classical HLA loci. However whilst the absence of HLA mismatches in the syngeneic setting reduce the risk of GvHD, it also reduces the desirable Graft versus Leukaemia (GvL) effect and is therefore associated with an increased incidence of relapse. In the absence of a syngeneic donor, a HLA matched sibling represents the most likely source of a HLA matched donor. A sibling donor has a ¼ chance of being HLA matched. Many Centres will limit their HLA typing to the low to medium resolution HLA typing i.e. 2 digit DNA typing, at HLA-A, B and DR as sufficient to confirm a match between and patient and a sibling donor because of the strong linkage disequilibrium between HLA-B and C as well as between HLA-DR and DQ. This is the minimum required by European Federation for Immunogenetics (EFI) standards in related stem cell transplantation. However limiting typing to these loci may mean that the patient and donor may not be matched at HLA-C and HLA-DQ if one or more parents are homozygous for HLA-A, B, DR as the patient and donor could inherit different haplotypes which could be mismatches at the allele level when high resolution or 4 digit typing is undertaken. There could also be crossover events between HLA-A and HLA-B and between HLA-DR/DQ and HLA-DP (there is a recombination hotspot between DQ and DP) which would remain undetected if typing is not extended to all the classical HLA genes. For this reason, when matching siblings, it is also useful to determine the HLA types of the parents if possible. In addition, where parents share a haplotype, a parent could be matched to the patient and represent a potential source of stem cells. In a related setting, HLA-DP matching is not always taken into account though it may be a consideration if there is a choice of two or more sibling donors matched to the patient at HLA-A, B, C, DR and DQ.
For unrelated allogeneic transplantation with adult Peripheral Blood Stem Cells (PBSC) or Bone Marrow (BM), HLA matching is typically undertaken for HLA-A, B, C, DR and DQ at the high resolution level. The NMDP have recently reported that 8/8 matching, for HLA-A, B, C and DR and excluding HLA-DQB1, has the same outcome as 10/10 matching and is the minimum required for stem cell transplantation. Similar to the related setting, matching for HLA-DP is not necessarily taken into account and a degree of HLA-DP mismatching may be desirable as it is associated with increased GvL and therefore a lower risk of relapse. Petersdorf et al have evaluated the relevance of HLA-DP mismatching in unrelated myeloablative bone marrow and peripheral blood stem cell transplantation and shown that in HLA-A, B, C, DRB1, DQB1 both matched and mismatched transplants, there is a statistically significant association between HLA-DP mismatching and the incidence of grades 2 – 4 aGvHD. This increased risk of aGvHD was seen on both 1 and 2 HLA-DP allele mismatched transplantation. The increased aGvHD they found was associated with a decreased risk of relapse, particularly in transplants matched 10/10 at HLA-A, B, C, DR and DQ, suggesting that mismatching for HLA-DP contributes to the GvL effect.
Transplantation with Cord Blood (CB) derived stem cells leads to a reduced incidence and severity of GvHD due to the relative immaturity of the immune system at birth, allowing for less stringent HLA matching criteria. One or two HLA antigen mismatches (i.e. 4/6 or 5/6 HLA-A, B, DRB1 mismatches) are tolerated. In the double cord blood transplantation setting, the HLA Mismatches between the cord blood units is also taken into account and must kept to a minimum, preferable also no worse than 4/6 or 5/6. In UCB transplantation, cell dose may be the more important factor than HLA matching. HLA matching in UCB transplantation is usually performed at the Broad antigen level for HLA-A and B and at the high resolution allele level for HLA-DR. The use of cord blood has been shown, through analysis of registry data, to be beneficial to patients with rarer HLA types or uncommon HLA haplotypes.
The relative importance of matching at the individual classical HLA loci in stem cell transplant outcome is controversial with many apparently contradicting studies. This may be due to the wide range of disease groups, conditioning regimes and HLA typing techniques used over the years. Some studies have shown that in high risk patients, transplantation with a donor with a single HLA allele mismatch leads to a better outcome than a prolonged search for a fully matched donor. An additive effect appears to exist such that the total number of mismatches may be more important than which specific loci are mismatched, though many transplant teams prefer to avoid mismatches at class II over mismatches at class I. There is however increasing data suggesting that HLA-DR mismatching is no worse than mismatching at any other locus.
Both HLA and non HLA genes play a role in stem cell transplant outcome and therefore influence donor selection. HLA genes are however the main genetic barrier to transplantation and therefore have the most influence on transplant outcome.
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