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The Importance of an Additional Gene in Matching Bone Marrow Transplants

Thousands of people are diagnosed each year with blood diseases, some of which may be deadly, such as leukemia, a form of cancer. The only cure for many people with leukemia is a bone marrow transplant from a genetically matched donor. Bone marrow contains blood stem cells that are the source of the body’s blood and immune systems. The better matched the bone marrow, the greater the chance that the body will accept the transplant and the less likely the recipient will develop a common complication of bone marrow transplantation known as graft-versus-host disease (GVHD) in which the immune cells from the donor react to the recipient’s cells and tissues. Unfortunately, finding genetically matched donors is very difficult.

Improved Criteria for Matching Donor and Recipient Tissue Type

Substantial progress has been made in defining the criteria for matching the donor and recipient tissue type for a successful bone marrow transplant. Modern tissue typing methods allow matching of the precise DNA sequence of human leukocyte antigen (HLA) genes (alleles) that play a major role in the immune system. When a transplant recipient and donor share the same HLA alleles, the recipient is less likely to develop severe GVHD.

A fully matched bone marrow donor is an individual genetically matched for five specific alleles: HLA-A,-B,-C,-DRB1, and -DQB1. A study supported by NIAID and recently reported in the journal Blood shows that knowing the matching status of an additional, sixth allele at HLA-DPB1 provides doctors additional information that will allow them to more accurately assess the risks and benefits of the bone marrow transplant procedure.

Study Analyzes 5,929 Bone Marrow Patient-Donor Pairs

Led by NIAID grantee Effie Petersdorf, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, and conducted by Bronwen Shaw, M.D., of the Anthony Noland Research Institute, London, on behalf of the International Histocompatibility Working Group (IHWG), the study retrospectively analyzed 5,929 bone marrow patient-donor pairs from around the world. The researchers looked at data collected from transplants that occurred between 1985 and 2003. They established the degree of matching at the traditional five alleles as well as at the sixth allele, DPB1, and found 470 donor-recipient pairs that matched at all six genetic loci. They also looked at the frequency of acute GVHD, the number of deaths, and the incidence of leukemia relapse.

Overall, recipients mismatched at DPB1 had a 38 percent higher risk of developing acute GVHD but a 43 percent lower risk of relapse than those matched at the same allele.

To Match or Not-to-Match at the Sixth Allele

“It’s a significant finding,” says NIAID’s Transplantation Basic Sciences program officer, Francesca Macchiarini, Ph.D. “Consider a patient with a history of recurrent leukemia who has reached the bone marrow transplant stage. This new information may help the clinician decide whether it is better to transplant bone marrow that is matched or one that is mismatched at DPB1, depending on the severity of the recipient’s condition and his or her chances of leukemia relapse.”

It is easier to find donors matched for the five classical loci, HLA-A, B, C, DR and DQ, without including DPB1. The new analyses may provide clinicians a tool to determine which higher-risk patients might benefit most from HLA-DP matching. “When you are a transplant recipient, you want to take advantage of all the odds in your favor, and the clinician wants to do that too,” notes Dr. Macchiarini.

Scientists still do not know the precise mechanism that leads to lower relapse when the donor and recipient are HLA-DPB1 mismatched. The authors suspect, however, that the donor’s immune cells recognize the recipient’s leukemic cells expressing a different HLA-DPB1 as foreign and kill them, through a phenomenon known as the graft-versus-tumor, or graft-versus-leukemia, effect.

Overall, says Dr. Macchiarini, this large-scale study and the data gleaned from it will help improve the outcomes for patients undergoing bone marrow transplantation for leukemia.

Reference

Shaw B et al. The importance of HLA-DPB1 in unrelated donor haematopoietic cell transplantation. Blood DOI: 10.1182/blood-2007-06-095265 (2007).

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Last Updated March 06, 2009