Though hematopoietic stem cell transplantation (HSCT) from unrelated donors can cure some blood disorders, an HLA-mismatched transplantation can result in graft-versus-host disease (GVHD) which, if severe, can adversely affect outcome. The risk of GVHD is higher when the recipient and donor are HLA-DPB1-mismatched, though the mechanism of GVHD remains unknown.
In a study published in The New England Journal of Medicine, Effie W. Petersdorf, MD, from Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues conducted a genotyping study to examine the GVHD risk associated with the rs9277534 allele, which is related to HLA-DPB1 expression, and how it is linked to the mismatched HLA-DPB1 in the transplant recipient.1
“We now understand the machinery in our genome that governs protein expression actually has biological significance that is important to patients,” Dr. Petersdorf said in a press release from Fred Hutchinson. “We have not considered variation in the regions of genes that are responsible for protein expression; up until now, we have been focused on the specific sequence of the protein itself.”
Dr. Petersdorf and colleagues analyzed transplantations in which only a single DPB1 allele differed in the patient and the donor and the second DPB1 allele was shared. They hypothesized that rs9277534G-linked HLA-DPB1 in a transplant recipient that is not shared by the donor cells (constituting high-expression graft-versus-host mismatch) is more visible to the donor cells than the rs9277534A-linked HLA-DPB1 allele, thus leading to a higher risk of acute GVHD. “If the level of HLA-DPB1 expression provides information about HLA-DPB1 mismatches that are well-tolerated (i.e., associated with favorable outcomes),” the authors wrote, “then rs9277534 can be used prospectively to screen potential unrelated donors before transplantation in order to lower the risk of acute GVHD.”
rs9277534 was genotyped in 3,505 patients to define rs9277534-DPB1 haplotypes, and clinical outcomes were assessed in 2,029 recipients of transplants from unrelated donors who had acute leukemia, chronic myeloid leukemia, or the myelodysplastic syndrome between 1988 and 2008. Of those patients, 1,441 received HLA-A, B, C, DRB1, DQB1-matched transplant from unrelated donors with only one HLA-DPB1 mismatch in the GVD vector of incompatibility (recipient HLA-DPB1 not present in the donor). The remaining 588 recipients received a transplant from an HLA-A, B, C, DRB1, DQB1, DPB1–matched unrelated donor.
The study’s primary endpoint was incidence of acute GVHD, and secondary endpoints included chronic GVHD, relapse, death not preceded by relapse, and death from any cause. All regression models were adjusted for age, source of stem cells, disease severity, T-cell depletion, sex of recipient and donor, cytomegalovirus serostatus, and year of transplantation.
The mean HLA-DPB1 expression was lower with rs9277534A than with rs9277534G. The risk of acute GVHD was higher for recipients with rs9277534G-linked HLA-DPB1 mismatches compared with those with rs9277534A-linked HLA-DPB1 mismatches (hazard ratio [HR]=1.54; 95% CI 1.25-1.89; p<0.001). The risk of death due to causes other than disease recurrence was also higher among recipients with rs9277534G-linked mismatches (high-expression HLA-DPB1) compared with those with rs9277534A-linked mismatches (HR=1.25; 95% CI 1.00-1.57; p=0.05).
Ultimately, the risk of GVHD associated with HLA-DPB1 mismatching was influenced by the HLA-DPB1 rs9277534 expression marker. Among recipients of HLA-DPB1–mismatched transplants from donors with the low-expression allele, recipients with the high-expression allele had a high risk of GVHD. The higher risk of GVHD, however, was balanced by the lower risk of relapse; together, these data led to similar overall mortality (HR 1.03; p=0.70), the authors reported.
“HLA-DPB1 mismatching occurs for more than 80 percent of otherwise HLA-matched transplant recipients and unrelated donors and contributes to substantial morbidity and mortality associated with GVHD,” the authors wrote. After analyzing DNA samples from an additional 146 transplant recipients and their donors who were referred to the Fred Hutchinson Cancer Research Center, “[we showed] that prospective selection of donors with low-expression mismatches is entirely feasible and can be used to substantially reduce the number of transplantations involving high-risk mismatches.”
“The data from Dr. Petersdorf and colleagues underscore the functional importance of HLA-DP in hematopoietic cell transplantation and provide us with a new layer of complexity for donor–recipient matching, which should no longer be based solely on structural considerations but also must account for functional aspects such as levels of protein expression,” wrote Katharina Fleischhauer, MD, from the Institute for Experimental Cellular Therapy at the University Hospital Essen in Germany, in an accompanying editorial.2 “Uncovering the mechanisms that underlie transcriptional and posttranscriptional regulation of HLA expression will be crucial for the design of new matching strategies in the modern era of hematopoietic cell transplantation.”
These findings, which came from a single center, will need to be validated in larger populations, and the current study was not able to identify the specific mechanisms that give rise to GVHD in the context of HLA-DPB1 mismatching.
“Whether mismatching for multiple low-expression HLA alleles carries a lower risk of GVHD than mismatching for many high-expression alleles remains an important question for future studies,” Dr. Petersdorf and colleagues concluded.
- Petersdorf EW, Malkki M, O’Huigin C, et al. High HLA-DP expression and graft-versus-host disease. N Engl J Med. 2015;373:599-609.
- Fleischhauer K. Immunogenetics of HLA-DP—A new view of permissible mismatches. N Engl J Med. 2015;373:669-72.