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Mary Ellen Hackett
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Mary Carrington, Ph.D., director of the Basic Sciences Program

For patients with blood cancer such as leukemia, a bone marrow transplant can extend life or even potentially cure the disease. The ideal bone marrow donor is a close relative, such as a brother or sister. If none is available, doctors look for an unrelated donor whose stem cells best match those of the recipient.  

Mary Carrington, Ph.D., director of the Basic Sciences Program
Mary Carrington, Ph.D., director of the Basic Sciences Program

The success of these unrelated donor transplants is sometimes limited by a potentially life-threatening complication called graft-versus-host disease (GVHD), when the donor’s transplanted immune cells attack the recipient’s tissues. 

In recent studies published in Blood and the Journal of Clinical Oncology, the Frederick National Laboratory’s Mary Carrington and colleagues at the Fred Hutchinson Cancer Research Center at the University of Washington in Seattle and around the world report a variation in the HLA genes, where mismatching at these positions between donors and recipients can be tolerated, limiting GVHD and leading to a more successful transplant. 

HLA match determines bone marrow donor suitability 

People have different sets of proteins called human leukocyte-associated (HLA) antigens on the surface of their cells. The set of proteins, called the HLA type, modifies the immune system and is identified by genetic testing. To match a donor and recipient for bone marrow transplant, also called hematopoietic-cell transplant, doctors look at how well the HLA antigens of the donor’s stem cells match those of the recipient’s stem cells. 

HLA genes are polymorphic, meaning they are comprised of multiple combinations of proteins that can vary greatly among people. Each person inherits one HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 gene (or allele) from each of their parents, leading to up to 12 alleles that must be matched. It’s uncommon for two unrelated people to have a perfect HLA match, so determining mismatches that do not lead to GVHD must be defined so the pool of potential donors can be enlarged. Donor selection rests on appropriate matching of a specific series of HLA genes.

The authors of the study sought to gain a better understanding of the features of HLA mismatches that lead to increased transplant-related complications and lower survival vs. those that can be tolerated and not cause GVHD.  

“If we knew which HLA mismatches were acceptable and which were deal breakers, we could select donors with acceptable mismatches, thereby broadening the availability of transplantation as a curative therapy,” said Carrington, director of the Basic Sciences Program at FNL. 

HLA-B is arbiter of degree of donor match  

The authors conducted a retrospective analysis of 10,415 patients who received a transplant between the years 1988 and 2016 from an unrelated donor with one HLA-A, -C, -DRB1 or -DQB1 mismatch and whose HLA and clinical data were contributed by members of the International Histocompatibility Working Group in HCT. Their outcomes for GVHD, relapse, and mortality were compared to a previous group of 1,457 transplant patients with HLA-B mismatches. 

They found that a specific region of the patient’s HLA-B gene that encodes the signal sequence of the molecule (a short amino acid sequence that is eventually clipped off to form the mature HLA-B molecule) determines the ideal degree of HLA mismatches his or her donor should have in order to lower the risks of GVHD, relapse, and death. 

“This discovery may enhance the selection of donors for transplantation and provide important information of risk before transplant, based on the patient’s signal sequence genotype,” Carrington said.