Role of HLA Matching in Solid Organ Transplant Survival

The primary role of the HLA molecules is to present pathogen derived peptides to T cells thereby eliciting a T cell mediated adaptive immune response. The T cell recognises both the HLA molecule and the peptide it presents, distinguishing self derived peptides from foreign peptides. It is this ability to restrict the T cell response, distinguishing self from foreign and permitting an immune response to be mounted against the foreign that makes the HLA antigens the main immunological barrier to transplantation, necessitating HLA matching.

 

In 1954, the first successful living-related donor kidney transplant was performed by a team in Boston, USA. The procedure involved a kidney transplant between young identical twins whose HLA were matched at all 6 classical loci. The organ survived for many years. Many studies have since shown a strong correlation between the level of HLA matching at the Broad level for HLA-A, B and DR and graft survival. In the UK in the 1990’s, it was shown that the best outcome was achieved with kidneys that had no mismatches at HLA-A, HLA-B, and HLA-DR loci (000 mismatches). The next most favourable outcome was achieved with one mismatch at either A or B loci or one mismatch at both the A and B , but no mismatch at the DR locus (100, 010, or 110 mismatches).

 

A recent UNOS study had suggested that the influence of HLA matching in kidney transplantation in the Calcineurin Inhibitor era was reduced, especially with improvements in surgical techniques. However a European CTS study (Opelz et al) which reviewed transplants over two decades from 1985 to 2004 contradicts this. The European study found a statistically significant association between graft survival and the number of mismatches and the number of rejection episodes.

 

In the UK an updated HLA matching algorithm was implemented in 2006. The previous matching scheme was potentially iniquitous to patients from ethnic minorities, with potentially rarer HLA types, who are under represented on the donor panels. A system of ‘defaulting’ of rare HLA antigens to common equivalents was introduced. e.g. HLA-A80 in a patient was defaulted to HLA-A1 and HLA-DR103 was defaulted to HLA-DR1, making it much more likely that such patients will be transplanted.

 

The current UK scheme comprises 5 tiers as far as HLA matching is concerned:

  1. Tiers A comprises 000 matched highly sensitised paediatric patients and 000 matched HLA-DR homozygous paediatric patients
  2. Tier B consists of all other 000 matched paediatric patients
  3. Tier C consists of 000 matched highly sensitised adult patients and 000 matched HLA-DR homozygous adult patients
  4. Tier D consists of all other 000 matched adult patients and all well matched paediatric patients (100, 010, and 110 HLA-A, B and DR mismatches)
  5. Tier E consists of all other patients

 

 

A point system is then used to prioritise within each tier based on factors including waiting times.

 

The emphasis that the scheme places on prioritising 000 matched paediatrics highlights the impact of mismatching of HLA antigens on the development of alloantibodies and therefore the ability to re-transplant in later years should the graft fail. The data the current UK algorithm is based on four identified levels (graded levels 1 – 4) of HLA matching which were found in a review of transplant outcomes based on the UK 1998 algorithm, to correlate well with increasing risk of transplant failure. Level 1 comprises 000 HLA-A, B and DR mismatches, Level 2 comprises 0 HLA-DR and 0 or 1 HLA-B mismatch, Level 3 comprises 0 HLA-DR and 2 HLA-B mismatches or 1 HLA-DR and 1 HLA-B mismatch and Level 4 comprises 1 HLA-DR and 2 HLA-B mismatches or 2 HLA-DR mismatches. The UK data showed that HLA-A mismatches had no effect on transplant outcome.

 

The impact of matching for HLA-C, DQ and DP in kidney transplantation has been reviewed in a small number of studies. One study has suggested a potential influence of HLA-C mismatching on the number of acute rejection episodes in the presence of 1 additional HLA-B mismatch. The role of HLA-DQ mismatching in the presence of a HLA-DR match has received relatively little study in recent years. One study in the 1980’s and another in the 1990’s found no significant correlation between HLA-DQ mismatching and graft outcome in the presence of a HLA-DR match. In the UK, the 2010 BSHI/BTS guidelines require that laboratories are capable of identifying antibodies to HLA-DP so that donors who should be crossmatch negative can be identified even though HLA-DP typing of deceased donors prior to a matching run is not currently required. It is however being consulted on and encourage On Call. HLA-DP matching is not thought to play a significant role in first transplants even in the presence in preformed donor specific antibodies. A small number of studies have however shown a potential role for HLA-DP matching in re-transplants patients. Matching for specific HLA-DP epitopes may be more relevant than HLA-DP antigen matching. Several studies have shown that HLA-DP antibodies in the sera of sensitized patients are specific for epitopes shared by many different HLA-DP antigens rather than being unique to specific HLA-DP antigens.

 

HLA matching for kidney transplantation is generally at the Broad antigen level and not at the allele level. One study has shown a correlation between allele level mismatched in HLA-DRB1 and the number of rejection episodes though the study found no correlation with long term survival. Certainly the ability to identify allele specific antibodies using the current generation of solid phase HLA antibody detection techniques presents the ability to list allele specific antibodies as unacceptable mismatches. In addition, a number of studies have shown that the use of structural epitope matching techniques such as HLAMatchmaker is predictive of positive crossmatches. Duquesnoy has shown that in 0 HLA-DR matched, HLA-A and/or HLA-B mismatched transplants, the number of epitope mismatches correlates significantly with 5 year graft survival.

 

The impact of HLA matching in kidney transplantation continues to evolve in the desensitisation era with the presence of preformed donor specific alloantibodies no longer the absolute contraindication to transplantation that it once was. The UK BSHI/BTS guidelines require that laboratories are capable of identifying HLA antibodies to HLA-A, B, C, DR, DQ and DP so that donors who should be negative can be identified for crossmatching. However desensitisation protocols may permit transplantation even in the presence of donor specific antibodies for any of these HLA loci.

 

Not all solid organ transplantations require the level of HLA matching that is the norm in kidney transplantation though most require HLA antibody definition. Pancreatic transplantation is one exception which does require the same level of HLA matching as kidney transplantation. With cardiothoracic transplantation, HLA matching is not necessarily undertaken but antibody definition is required and if present then a prospective crossmatch or retrospective crossmatch within 48 hours is required.

 

HLA matching prior to liver transplantation is not required and prospective crossmatching is not indicated. Some centres do carry out HLA antibody identification to aid in setting immunosuppression levels. HLA matching is not necessarily undertaken for small bowel and intestinal transplantation.

 

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