Gene Variant Linked to GVHD Risk
NIAID-supported researchers have identified a specific gene variant associated with higher risk of graft-versus-host disease, or GVHD, a common and potentially life-threatening complication following a bone marrow transplant. The findings provide new information to help doctors better match transplant donors and recipients.
Gene Variant Linked to Risk of Graft-Versus-Host Disease
A new study funded in part by NIAID shows that a specific genetic variant is associated with higher risk of graft-versus-host disease (GVHD), a common and potentially life-threatening complication following a bone marrow transplant. The findings, published in the New England Journal of Medicine, offer new information to help health care providers better match transplant donors and recipients.
Making a Match: HLA Typing for Bone Marrow Transplantation
Bone marrow transplantation is a life-saving treatment option for many people with blood diseases such as leukemia, a cancer of the blood cells. Patients with leukemia receive chemotherapy, radiation therapy, or both to kill the cancer cells in their bone marrow. However, these treatments also damage bone marrow stem cells, the precursors of healthy blood and immune cells. To replace these cells, doctors infuse new stem cells from the bone marrow of a healthy, genetically matched donor into the patient.
The better matched the donor and the recipient, the less likely the recipient will reject the transplant or develop GVHD. GVHD occurs when the transplanted donor immune cells—the graft—recognize the recipient, or host, tissues as foreign and mount an immune response against them. Acute GVHD can affect many of the body’s tissues and organs, including the skin, liver, and gastrointestinal tract. Symptoms range in severity from mild to life-threatening and may include an itchy or painful rash, diarrhea, nausea, and jaundice.
Prior to transplantation, recipients and prospective donors are typed for human leukocyte antigens (HLA), cell-surface proteins that help the immune system distinguish “self” (a patient’s own cells) from “non-self” (foreign pathogens or donor cells). Typically, doctors attempt to match donors and patients for five major HLA types: HLA-A,-B,-C,-DRB1, and -DQB1. Each person has two variants of each gene, called “alleles”—one inherited from the mother and one from the father. The number of HLA alleles in the population is quite large, and it is rare to find an exact match between two unrelated people. Partial mismatches are common, particularly for recipients in minority racial and ethnic groups, who have a relatively small pool of donors matching their precise HLA type.
Identifying “Permissible Mismatches”
Not all HLA mismatches are equal. Some lead to high risk of GVHD, while others have a lesser impact and may be considered “permissible.” NIAID-funded researcher Effie W. Petersdorf, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, Washington, studies how to optimize matching of patients with unrelated donors to minimize GVHD.
In her current study, Dr. Petersdorf and colleagues focused on a sixth HLA type called HLA-DPB1. More than 80 percent of otherwise matched transplants are mismatched at HLA-DPB1. The researchers identified a genetic variation associated with how much HLA-DPB1 is present, or “expressed,” on the cell surface. People with the high-expression variant have many copies of HLA-DPB1 on the surfaces of their cells, while people with the low-expression variant have fewer copies.
Relationship between HLA-DPB1 variants and GVHD risk. In the study, one HLA-DPB1 allele was matched for donor and recipient, while the second varied. Recipients with a high-expression allele were more likely to experience GVHD, especially when they received a transplant from a donor with a mismatched low-expression allele.
Studying the Impact of HLA-DPB1 Expression on GVHD Risk
The investigators analyzed data from more than 2,000 leukemia patients who had received bone marrow transplants from unrelated donors matched at HLA-A,-B,-C,-DRB1, and -DQB1. The majority (1,441 recipients) had a mismatch in one of the two HLA-DPB1 alleles, while the remaining 588 received transplants from HLA-DPB1-matched donors.
The researchers found that risk of GVHD was heightened when the recipient had a high-expression HLA-DPB1 allele. They suggest that this may be because the large number of HLA-DPB1 copies on the recipient’s cells presents a highly visible target for the transplanted donor immune cells. The risk was increased when a recipient with a high-expression allele received a transplant from an HLA-DPB1-mismatched donor with a low-expression allele.
For recipients with a low-expression allele, HLA-DPB1 matching was less important, and these recipients had a lower overall risk of GVHD. The researchers propose that because cells in these recipients express fewer copies of HLA-DPB1 on their surfaces, the transplanted donor immune cells do not react as strongly.
Applying the Findings to Clinical Practice
The study findings suggest that HLA-DPB1 matching may help reduce GVHD risk, particularly for recipients who carry a high-expression allele. “Our data provide new information on the role of HLA-DPB1 expression in transplantation-associated risks that can be used to guide the selection of donors for future transplant recipients in order to minimize the risk of acute GVHD,” the study authors conclude.
Petersdorf EW, Malkki M, O’hUigin C, Carrington M, Gooley T, Haagenson MD, Horowitz MM, Spellman SR, Wang T, Stevenson P. High HLA-DP expression and graft-versus-host disease. New England Journal of Medicine (2015).
Fleischhauer K. Immunogenetics of HLA-DP — a new view of permissible mismatches. New England Journal of Medicine (2015).Gene Variant Linked to Risk of Graft-Versus-Host Disease