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HLA biomarker may predict GVHD risk following HSCT
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The HLA-DPB1 rs9277534 expression marker influenced the risk for graft-versus-host disease associated with HLA-DPB1 mismatching, according to study results published in The New England Journal of Medicine.
Patients who undergo hematopoietic stem cell transplantation from HLA-DPB1–mismatched donors with a high expression of rs9277534 faced a greater risk for developing GVHD, the researchers reported.
“HSCT from unrelated donors can cure blood disorders; however, GVHD remains a major impediment to successful outcomes,” Effie W. Petersdorf, MD, professor of medical oncology at University of Washington School of Medicine and member of the clinical research division at Fred Hutchinson Cancer Research Center in Seattle, and colleagues wrote. “GVHD can occur after HLA-matched transplantation when the donor cells recognize polymorphic peptides (“minor histocompatibility antigens”) presented by the recipient’s HLA. In HLA-mismatched transplantation, direct recognition of the recipient’s mismatched HLA by the donor’s cells provides a potent stimulus for graft-versus-host allorecognition; recognition of the donor’s mismatched HLA by the recipient’s immune system leads to rejection.”
The HLA-DPB1 regulatory region variant rs9277534 is associated with HLA-DBP1 expression. Petersdorf and colleagues conducted their study to determine whether GVHD risk correlated with the rs9277534 allele linked to mismatched HLA-DPB1 in the transplant recipient.
In order to define rs9277534-DPB1 haplotypes, the researchers genotyped rs9277534 samples from 3,505 individuals. They also determined the linkage of rs9277534 alleles among patients who underwent HLA-matched unrelated HSCT (n = 1,441).
In the final analysis, the researchers compared the risk for GVHD among HSCT recipients with a mismatched HLA-DPB1 allele linked to rs9277534G (high expression) and rs9277534A (low expression).
The researchers observed lower mean HLA-DPB1 expression with rs9277534A compared with rs9277534G (14.62 vs. 24.95; mean difference in expression = –10.33; 95% CI, –14.95 to –5.7).
HSCT recipients with rs9277534G-linked HLA-DPB1 mismatches faced an increased risk for grade 2, grade 3 or grade 4 acute GVHD (HR = 1.32; 95% CI, 1.13-1.55), as well as increased risk for grade 3 or grade 4 disease (HR = 1.34; 95% CI, 1.08-1.68). However, patients with a high expression allele demonstrated a lower risk for relapse (HR = .8; 95% CI, 0.64-0.99).
Among recipients of transplants from donors with rs9277534-linked HLA-DPB1, recipients with rs9277534G-linked HLA-DPB1 mismatches experienced a higher risk for acute GVHD than recipients with rs9277534A-linked HLA-DPB1 mismatches (HR = 1.54; 95% CI, 1.25-1.89). These recipients also faced an increased risk for death from causes other than disease recurrence (HR = 1.25; 95% CI, 1-1.57).
Among 753 recipients who died from causes other than disease recurrence, 31.6% had infections, 29.3% had organ toxicity or organ failure, 19.8% had GVHD and 19.3% died of other causes.
“The importance of levels of HLA-DP and HLA-C expression in influencing the strength of alloimmune responses in transplant recipients has direct implications for transplants mismatched at multiple HLA loci,” Petersdorf and colleagues concluded. “Synergistic effects of multilocus HLA mismatching on transplantation outcomes have been well observed. Whether mismatching for multiple low expression HLA alleles carries a lower risk for GVHD than mismatching in many high expression alleles remains an important question for future studies.” – by Cameron Kelsall
Disclosure: Petersdorf reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Daniel R. Couriel, MD, MS
Hematopoietic stem cell transplantation (HSCT) from unrelated donors is a curative treatment modality for a broad spectrum of hematologic malignancies. Unfortunately, its success is still hindered by both acute and chronic graft-versus-host disease (GVHD).HLA mismatches between donor and recipient are tightly linked to both acute GVHD and transplant outcomes, as they can generate a powerful allogeneic response from the donor against the recipient. The introduction of polymerase chain reaction- and DNA-based, high-resolution typing revealed that HLA-DPB1 was mismatched in about 85% of unrelated transplants, and that undetected HLA-DPB1 mismatching was associated with severe GVHD.
In their recent publication in The New England Journal of Medicine, Petersdorf and colleagues show an association between highly expressed variants of HLA-DP and acute GVHD, emphasizing the importance of functional, in addition to structural, differences in the interpretation of HLA matching and permissible mismatches.
HLA-DP molecules are expressed on the surface of activated T cells, dendritic cells and B cells, and have been shown to play an important role in autoimmunity, clearance of viral and tumor antigens, and transplantation. In particular, the structure of DPB1 includes 5 coding exons and a sixth one in the 3’ untranslated region. This region contains specific single nucleotide variations that can differ from one individual to another, known as single-nucleotide polymorphisms (SNPs). There are two particular SNP adenosine-guanine variants (rs9277534A/G and rs2281389A/G). Petersdorf and colleagues demonstrate that rs9277534 controls the level of expression of HLA-DP through mechanisms that are still unclear. In this setting, the rs9277534G variant is associated with higher DPB1 levels than rs9277534A. Further, the group demonstrated patterns of linkage disequilibrium (ie, nonrandom association of genes in different loci due to inheritance in blocks) between rs9277534 and rs2281389. In particular, the rs9277534A (low expression) variant is exclusively associated to rs2281389, and to specific DPB1 alleles that occur with a combined frequency of about 70% in persons of white European descent.
In this study, Petersdorf and colleagues analyze the association of individual DPB1-rs9277534-rs2281389 mismatches and the risk for acute GVHD in unrelated donor–recipient pairs that differ in only one DPB1 allele. In this analysis, recipients with an rs9277534G variant leading to high expression of the DPB1 mismatched allele had a significantly higher risk for acute GVHD than those with rs9277534A, the lower-expression variant. The higher risk for acute GVHD and resulting nonrelapse mortality were associated with a lower risk for relapse, leading to similar OS between groups. Of note, the association between rs9277534G and acute GVHD was also observed in cases in which DPB1 was matched. Finally, when the donor’s mismatched DPB1 allele was not encoded by the rs9277534G (high expression) variant, rs9277534G in the recipient was not associated with a higher incidence of GVHD, supporting the notion of immunologic tolerance due to high expression of DPB1 in the donor cells.
In summary, this study elegantly defines permissible mismatches based on levels of antigen expression, which add a level of complexity and innovation to the way we interpret HLA matching in unrelated HSCT.
References:
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Fernandez-Vina MA, et al. Blood. 2013;doi:10.1182/blood-2013-02-481945.
Fleischhauer K. N Engl J Med. 2015;doi:10.1056/NEJMe1505539.
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Petersdorf EW, et al. Br J Haematol. 2001;doi:10.1046/j.1365-2141.2001.02655.x.
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