HLA matching in hematopoietic cell transplantation

Progress in hematopoietic cell transplantation has been greatly facilitated by our increasing knowledge of the HLA system, as well as by improved therapies for achieving sustained engraftment, preventing graft-versus-host disease, and protecting the patient from infection. Disparity for HLA genes can cause graft rejection and graft-versus-host disease and decrease survival in patients receiving grafts from both related and unrelated donors. The presence of patient alloantibodies against donor antigens demonstrated by a positive crossmatch is a strong risk factor for graft rejection. The availability of matched donors for patients lacking a genotypically HLA-matched sibling has been greatly improved by the establishment of international registries of HLA-typed volunteer donors. The development of accurate and reproducible high-resolution DNA-based typing methods has significantly improved the prospects for identifying unrelated donors who are well matched with the patient for HLA. The use of these methods to optimize donor selection will improve both donor identification and the success of unrelated donor transplants.     

The role of HLA matching in transplantation

All viable human tissues transplanted from one individual to another are at risk of rejection. The extent of risk depends on the donor HLA-host T cell receptor disparity. Such disparity is now known to involve genetic products coded by both HLA and non-HLA genes. T cell responses to mismatches on transplants are graded: the greater the mismatch the greater the number of clones of T cells responding. Consequently, the more severe the rejection process. Global statistics support this view in that cumulative mismatches at HLA are associated with poorer graft survival. However such studies also suggest that mismatches at different HLA loci vary in potency. The strength of mismatch seems to increase from HLA-A, the weakest, through HLA-B to HLA-DR, the most potent. Analysis of clinical results suggests that the risk associated with HLA mismatches in kidney transplantation dwindles after the first five months post-transplant. Although graft losses tend to occur sporadically thereafter, no major risk associated with HLA mismatches can be discerned. Whether this dwindling impact of HLA mismatches with time post-transplant is a general phenomenon applicable to all transplants, or whether it suggests some form of adaptation of host to graft in kidney transplant recipients alone is a subject for further exploration. Tissues vary widely in their susceptibility to rejection through HLA mismatches.(ABSTRACT TRUNCATED AT 250 WORDS)     

Optimal HLA matching in hematopoietic cell transplantation

Only 30% of patients in need of a hematopoietic cell transplant will have an HLA identical sibling to serve as the donor. Advances in the field of immunogenetics together with the growth of donor registries and cord blood banks worldwide have provided many of these patients the opportunity for a life saving transplant. Current data demonstrate the importance of matching the unrelated donor for HLA alleles and antigens. When a matched volunteer donor is not available, use of mismatched donors may be considered. New concepts in the selection of mismatched donors include consideration for the locus, the number of mismatches, differences between alleles and antigens, the location and nature of amino acid mismatches that define class I epitopes, and the presence of haplotype mismatching. When cord blood transplantation is an option, both cell dose and HLA matching are important variables. Optimizing the overall outcome of hematopoietic cell transplantation requires an appreciation for the relative importance of HLA factors with respect to other non-genetic factors that also influence transplant outcome.     

Effect of HLA matching in renal transplantation]

Evaluation of HLA-matching is useful in determining graft function and survival in a recipient in cadaveric renal transplantation. The effects of HLA on graft function, which serum creatinine indicative of, and graft survival were examined in both living and cadaveric transplantation in 280 Japanese renal transplants performed at Osaka University and Osaka Prefectural Hospital between October, 1982 and December, 1991 (cadaver 68, living 212). HLA-DR mismatch had a strong effect in living transplants, whereas no disparity was found in cadaver transplants with HLA-DR mismatch. HLA-B, DR mismatch had more effect than HLA-DR in cadaver transplants, and the same effect as HLA-DR in living transplants. HLA-AB affected graft function. It can be used to predict the effect of long-term graft survival. The HLA-haplotype match had the strongest association with graft survival and function in both cases of living and cadaver transplants. HLA-haplotypes of a cadaveric donor and a recipient were presumed by means of the linkage disequilibrium. These findings showed that HLA-matching, especially of haplotype, is an essential factor in relatively low risk renal transplant survival and function. 1-haplotype-matched transplantation, determined by the family study or presumed by the linkage disequilibrium is recommended if not 2-haplotype matched.     

Current status of HLA matching in renal transplantation

Summary The impact of HLA compatibility on the success rate of kidney transplants was studied in over 80,000 recipients of primary transplants. The transplants were done from 1982 to 1991 at over 300 transplant centers in 43 countries. The results show that matching the HLA chromosomes in related donor transplants has a striking influence. It is also important that matching for individual HLA antigens in cadaver transplants provides a highly significant improvement in graft survival (P<0.0001). After 5 years, matched grafts have a survival rate approximately 20% higher than completely mismatched grafts. The matching effect is particularly strong in presensitized and second graft recipients. There is now direct evidence that even if it is necessary to transport well-matched kidneys a long way, they have a significantly higher success rate than locally transplanted poorly matched kidneys. New data based on molecular technology show that the precise identification of HLA-DR antigens by DNA typing further improves the success rate of HLA-matched transplants.Abbreviations MM mismatched antigens - RFLP restriction fragment length polymorphism     

The role of HLA matching in hematopoietic cell transplantation

Hematopoietic cell transplantation (HCT) can be a life-saving therapy for patients with genetic and acquired hematologic diseases. Despite major advances in supportive care during HCT, immunological complications of the alloimmune response, including graft rejection and graft-versus-host disease (GVHD), remain major impediments to successful clinical outcomes. Although graft rejection mediated by host immune cells and GVHD mediated by donor immune cells can be prevented or mediated by immune suppression therapy, genetic HLA matching remains essential for successful strategies designed to minimize the risks of transplantation. The most favorable HCT results are seen in patients with a genotypically HLA-identical sibling donor, but the limited availability of matched related donors has severely restricted the clinical application of this therapy. Fortunately, the establishment of large unrelated volunteer donor registries now provides the opportunity to identify HLA matches for many patients who lack a family donor. The criteria for unrelated donor matching, however, are poorly defined. Until recently, an analysis of matching beyond HLA-identical siblings has been limited by typing technology. The introduction within the past few years of new methods for high resolution typing and definition of HLA alleles has had a profound impact on our ability to identify and interpret the multiple nucleotide sequence polymorphisms that encode HLA antigens. Preliminary studies clearly demonstrate the importance of precise matching at the allele level for successful transplantation. There remain, however, important unanswered questions about the relative importance of different HLA loci in matching strategies, as well as incomplete information about permissible limits of mismatching in different patient populations.     

The economic implications of HLA matching in cadaveric renal transplantation.

BACKGROUND: The potential economic effects of the allocation of cadaveric kidneys on the basis of tissue-matching criteria is controversial. We analyzed the economic costs associated with the transplantation of cadaveric kidneys with various numbers of HLA mismatches and examined the potential economic benefits of a local, as compared with a national, system designed to minimize HLA mismatches between donor and recipient in first cadaveric renal transplantations. METHODS: All data were supplied by the U.S. Renal Data System. Data on all payments made by Medicare from 1991 through 1997 for the care of recipients of a first cadaveric renal transplant were analyzed according to the number of HLA-A, B, and DR mismatches between donor and recipient and the duration of cold ischemia before transplantation. RESULTS: Average Medicare payments for renal transplant recipients in the three years after transplantation increased from 60,436 dollars per patient for fully HLA-matched kidneys (those with no HLA-A, B, or DR mismatches) to 80,807 dollars for kidneys with six HLA mismatches between donor and recipient, a difference of 34 percent (P<0.001). By three years after transplantation, the average Medicare payments were 64,119 dollars for transplantations of kidneys with less than 12 hours of cold ischemia time and 74,997 dollars for those with more than 36 hours (P<0.001). In simulations, the assignment of cadaveric kidneys to recipients by a method that minimized HLA mismatching within a local geographic area (i.e., within one of the approximately 50 organ-procurement organizations, which cover widely varying geographic areas) produced the largest cost savings (4,290 dollars per patient over a period of three years) and the largest improvements in the graft-survival rate (2.3 percent) when the potential costs of longer cold ischemia time were considered. CONCLUSIONS: Transplantation of better-matched cadaveric kidneys could have substantial economic advantages. In our simulations, HLA-based allocation of kidneys at the local level produced the largest estimated cost savings, when the duration of cold ischemia was taken into account. No additional savings were estimated to result from a national allocation program, because the additional costs of longer cold ischemia time were greater than the advantages of optimizing HLA matching.     

Clinical usefulness of HLAMatchmaker in HLA epitope matching for organ transplantation

HLAMatchmaker is a computer algorithm that determines HLA compatibility at the structural level. Donor-recipient histocompatibility is assessed with polymorphic amino acid configurations that represent structurally defined elements of HLA epitopes originally assigned as triplets and more recently as eplets. For many patients, HLAMatchmaker can identify mismatched HLA antigens that can be considered compatible at the structural level. Structurally based HLA matching reduces humoral allosensitization and correlates with good transplant outcome. Moreover, HLAMatchmaker is useful in the analysis of serum antibody reactivity and benefits the strategy of identifying acceptable mismatches for highly sensitized patients.     

BSHI Guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) “Guideline for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic progenitor cell transplantation” was undertaken by a BSHI appointed writing committee. Literature searches were performed, and the data extracted were presented as recommendations according to the GRADE nomenclature.     

Reduced graft rejection with good HLA-A and B matching in high-risk corneal transplantation

We examined the effect of matching for HLA-A and B antigens on the success of corneal transplantation in a single-center, prospective, masked study that began in March 1979. The study involved 97 consecutive recipients at high risk because of prior corneal graft rejection or serious vascularization of the native cornea. Donor corneas were selected on the basis of ABO-blood-group compatibility, a negative lymphocyte crossmatch, and optimal HLA-A and B matching; all clinical personnel were "masked" to the degree of HLA matching during the study. Among 38 patients receiving corneas with a good HLA match (two or more antigens), only 8 (21 percent) had graft rejection, as compared with 29 of 59 (49 percent) with a poor match (no or one antigen) (P less than 0.010). The mean (+/- SE) difference in rejection-free graft survival increased with time: 88.4 +/- 5.5 percent versus 73.5 +/- 5.9 percent at six months, and 80.1 +/- 7.5 percent versus 38.5 +/- 7.9 percent at two years. Cox multiple regression analysis, which included the HLA-A and B match and nine other potential confounding variables and risk factors also identified a significant (P less than 0.009) relative risk (4.6) of rejection reactions as well as irreversible graft rejection (P less than 0.016; relative risk, 11.2) with poor HLA-A and B matching. Our findings indicate that good HLA-A and B matching yields a significant long-term benefit in reducing the number of episodes of graft rejection and subsequent failure in high-risk recipients of corneal transplants.     

The role of HLA matching in renal transplantation: experience from one center

The influence of serology-based HLA matching on the risk of acute rejection episodes and of graft loss was analyzed in a material of 678 living donor (LD) and 997 cadaveric donor (CD) renal transplantations performed in our center in the period 1989-97. In LD transplantation, recipients of HLA-identical sibling grafts had the lowest rejection risk and the best graft survival, with a half-life estimate of 30 years. One-HLA-haplotype mismatched grafts did better than two-haplotype mismatched related or unrelated donor grafts. Matching for HLA-DR significantly reduced the rejection risk of one-haplotype mismatched grafts. In CD first transplants, HLA-DR matched grafts had a lower incidence of rejection and better survival than HLA-DR mismatched grafts. Expected half-life for HLA-DR matched grafts was 12 years compared to less than 7 years for HLA-DR mismatched grafts. The effects of matching for HLA-A and -B did not reach statistical significance. In CD regrafts, a two-antigen mismatch for HLA-A or -DR led to a significantly poorer graft survival, but the panel-reactive antibody (PRA) status of the recipient was the most influential factor. In CD renal transplantation, we conclude that organ allocation based on matching for HLA-DR 1-14 is effective and not too difficult to obtain even in centers with a short patient waiting list.     

Implementation of molecular matching in transplantation requires further characterization of both immunogenicity and antigenicity of individual HLA epitopes

Over the past decade, high HLA epitope mismatch scores have been associated with inferior transplant outcomes using several tools, of which HLAMatchmaker is most well-known. This software uses theoretically defined polymorphic amino acid configurations, called eplets, for HLA compatibility analysis. Although consideration of eplet mismatch loads has potential for immunological risk stratification of transplant patients, the use of eplet matching in organ allocation algorithms is hindered by lacking knowledge of the immunogenicity of individual eplets, and the possibility that single mismatched amino acids, rather than complete eplets, are responsible for HLA antibody induction.There are several approaches to define eplet immunogenicity, such as antibody verification of individual eplets, and data-driven approaches using large datasets that correlate specific eplet mismatches to donor specific antibody formation or inferior transplant outcomes. Data-driven approaches can also be used to define whether single amino acid mismatches may be more informative than eplet mismatches for predicting HLA antibody induction.When using epitope knowledge for the assignment of unacceptable antigens, it important to realize that alleles sharing an eplet to which antibodies have formed are not automatically all unacceptable since multiple contact sites determine the binding strength and thus biological function and pathogenicity of an antibody, which may differ between reactive alleles.While the future looks bright for using HLA epitopes in clinical decision making, major steps need to be taken to make this a clinical reality.