Bone marrow transplantation (BMT) is a life-saving procedure that replaces damaged or diseased bone marrow with healthy blood-forming stem cells. This procedure treats various blood cancers, immune system disorders, and genetic diseases that affect blood production. For the new stem cells to successfully engraft and begin producing healthy blood cells, the donor and recipient must be genetically compatible. Determining this compatibility is the most complex step in the transplant process, as a poor match can lead to severe, life-threatening complications.
The Biological Basis of Compatibility
The immune system uses specific markers on the surface of cells to determine if they belong to the body or are foreign invaders. These markers are known as Human Leukocyte Antigens (HLA), which are proteins found on most cells, especially white blood cells. The HLA system is incredibly diverse, meaning countless variations exist across the population.
HLA genes are inherited from both parents, and the combination of these genes forms a person’s unique HLA type. Researchers have categorized these antigens into two main classes: Class I and Class II. Class I antigens, specifically HLA-A, HLA-B, and HLA-C, are present on almost all nucleated cells and help the immune system recognize foreign materials.
Class II antigens, which include HLA-DR, HLA-DQ, and HLA-DP, are primarily found on specialized immune cells, where they play a role in activating other immune cells. Because a person inherits one set of these genes from each parent, a donor and recipient must match across the critical loci in both classes for a transplant to be successful.
Understanding HLA Typing and Scoring
The process of determining the genetic compatibility between a patient and a potential donor is called HLA typing. This laboratory analysis involves using advanced molecular techniques, like high-resolution DNA sequencing, to identify the precise versions, or alleles, of the HLA genes carried by both individuals. Early methods provided only low-resolution typing, but modern high-resolution typing is necessary to identify subtle differences that can still trigger an immune response.
Compatibility is scored based on the degree of matching across the most influential HLA loci: A, B, C, and DRB1, and sometimes DQB1 and DPB1. The current gold standard for an unrelated donor is a “10/10 match,” which signifies perfect compatibility across the five loci that are generally considered the most critical (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1, with two alleles for each). When HLA-DPB1 is also included, the ideal match is a “12/12 match,” but this level of perfection is rare.
A single mismatch, such as a 9/10 score, can significantly increase the risks of post-transplant complications, making the degree of matching a direct predictor of transplant success. The lab analysis must be precise because even minor differences in the HLA proteins can be recognized as foreign. The matching score helps doctors weigh the risks and benefits of proceeding with a specific donor.
Identifying Potential Donor Sources
When a patient requires a bone marrow transplant, the search for a suitable donor follows a specific hierarchy, beginning with the closest relatives. The first option is a matched sibling, as siblings have a 25% chance of inheriting the exact same HLA genes from both parents, making them the most likely source of a perfect match. If an HLA-identical sibling is not available, the search moves to other family members, though the chances of a full match are much lower.
If no suitable related donor is found, the search is then expanded to national and international registries of volunteer unrelated donors. These vast databases contain the HLA types of millions of people worldwide, significantly increasing the probability of finding a high-resolution match. This search can be time-consuming, sometimes taking months to identify and confirm the best possible candidate.
For patients who cannot wait or for whom a fully matched donor remains elusive, alternative sources are available. One option is a haploidentical transplant, which uses a donor who is only a half-match, typically a parent or a child, since they share 50% of their HLA markers. Another alternative is umbilical cord blood, which is collected at birth and stored, offering cells that are generally more tolerant of HLA mismatches and leading to a lower risk of certain complications.
Why Mismatches Lead to Complications
The entire purpose of the rigorous matching process is to prevent the immune-mediated complications that arise from incompatibility. When a donor and recipient are not sufficiently matched, the donor’s immune cells can recognize the recipient’s body as foreign, leading to a condition called Graft-versus-Host Disease (GVHD). In GVHD, the transplanted immune cells attack the patient’s tissues, often targeting the skin, liver, and gastrointestinal tract.
Conversely, the recipient’s remaining immune system can recognize the donor cells as foreign and launch an attack, resulting in graft rejection. This complication prevents the transplanted cells from establishing themselves in the bone marrow, leading to a failure to produce new blood cells. Both GVHD and graft rejection can be fatal, underscoring why minimizing HLA disparity is important. Even a single HLA mismatch can substantially increase the severity and incidence of both acute and chronic GVHD.