Allele expression levels may hold the key to graft-versus-host disease levels

1. After transplant, graft-versus-host disease (GVHD) was more likely when the recipient had a high-expression allele and the donor had a low-expression allele.

2. Further studies investigating the effects of mismatching multiple low-expression HLA alleles compared to multiple high-expression alleles are needed.

Evidence Rating Level: 2 (Good)           

Study Rundown: GVHD is a major obstacle in the successful hematopietic-cell transplantation of unrelated donors for the cure of blood disorders. GVHD can occur when HLA-matched donor cells recognize the recipient’s HLA cells. The rs2281389 variant has been associated with acute GVHD though it is not a direct mediator of it. This variant is strongly associated with rs9277534 allele in the HLA-DPB1 regulatory region, which has been shown to be associated with life-threatening GVHD. This close relationship may mark the connection for the risk of GVHD.

This study evaluated the risk associated with GVHD and rs9277534G-linked HLA-DPB1 mismatches compared to rs9277534A-linked mismatches. A total of 3505 persons were genotyped for rs9277534. Clinical outcomes were evaluated in 2029 transplant recipients for leukemia, chronic myeloid leukemia or myelodysplastic syndrome from unrelated donors. The study showed that rs9277534A-linked HLA-DPB1 alleles were expressed at a lower level compared to the rs9277534G-linked alleles. Furthermore, compared with recipients who had rs9277534A-linked mismatches, transplant recipients with rs9277534G-linked HLA-DPB1 mismatches had higher risks of grade 2,3, or 4 acute GVHD and of grade 3 or 4 disease but showed a lower risk of relapse. The overall mortality between the two groups remained the same. Results show that rs9277534G recipients from rs9277534A-linked donors had higher risks of grade 2,3, or 4 acute GVHD and of grade 3 or 4 disease than rs9277534A recipients. The study demonstrates that HLA-DPB1 mismatch on its own is not enough to cause GVHD and that genotyping for alleles such as rs9277534 may reduce the number of transplantation involving high-risk mismatches.

Click to read the study, published today in NEJM

Relevant Reading: Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study

In-Depth [retrospective cohort]: The study population included genetic results from 2029 individuals. The primary end point for this study was acute GVHD (assessed as grade 2,3, or 4 and as grade 3 or 4). Secondary end point were chronic GVHD, relapse, death not preceded by relapse, and death from any cause. In this study sample, the rs9277534A-linked HLA-DPB1 alleles were expressed at lower levels than rs9277534G-linked alleles (mean difference in expression, -10.33; 95% [CI], -14.95 to -5.70; p<0.001). Recipients of the rs9277534G-linked HLA-DPB1 mismatches were at higher risk of grade 2,3, or 4 acute GVHD (HR = 1.32; 95% [CI], 1.13-1.55; p<0.001) and of grade 3 or 4 disease (HR = 1.34; 95% [CI], 1.08-1.68; p=0.009) as compared to those of rs9277534A-linked mismatches. Recipients with rs9277534G-linked mismatches had a lower risk of relapse compared to rs9277534A-linked recipients (HR = 0.80; 95%CI, 0.64 – 0.99; p=0.04). Recipients with rs9277534G from donors with rs9277534A had higher risks of grade 2,3,or4 acute GVHD (HR = 1.54; 95% [CI], 1.25-1.89; p<0.001) and grade 3 or 4 disease (HR = 1.50; 95% [CI], 1.12-2.01; p=0.007) than recipients with rs9277534A and the same donor type. The overall mortality between the two groups was the same.

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