Human Leukocyte Antigens (HLA) are proteins found on the surface of most cells, acting as unique identification tags for the immune system. These markers allow the body’s defenses to distinguish between “self” cells and foreign invaders, such as viruses, bacteria, or donor cells. A close HLA match between donor and recipient is paramount for transplant success, especially in procedures involving blood-forming cells like stem cell or bone marrow transplants, as it determines the patient’s ability to accept the new cells.
The Immune Role of Human Leukocyte Antigens
HLA molecules are the human version of the Major Histocompatibility Complex. Their fundamental function is to present small protein fragments, called peptides, to immune cells, which allows the immune system to monitor cellular health. If a cell is infected by a virus, the HLA displays viral peptides, signaling the immune system to destroy that cell.
The HLA genes are located on chromosome 6 and are highly polymorphic, meaning thousands of variations exist within the human population. While this extensive variability is beneficial for species defense against diverse pathogens, it creates a significant challenge in transplantation. Every person inherits one set of these genes from each parent, resulting in a unique combination of markers.
The HLA system is divided into two main groups: Class I and Class II antigens. Class I antigens (HLA-A, HLA-B, and HLA-C) are found on nearly all nucleated cells. Their primary role is to alert immune cells, specifically CD8+ T cells, to internal threats like viral infections or cancerous changes.
Class II antigens (HLA-DR, HLA-DQ, and HLA-DP) are limited to specific immune cells like B cells, macrophages, and dendritic cells. These cells use Class II markers to present foreign peptides to CD4+ helper T cells, which coordinate the overall immune response. A difference in Class I or Class II markers signals a foreign presence to the recipient’s immune system, which is the root cause of transplant rejection.
Determining Compatibility and Finding a Donor
Because HLA markers are inherited, finding a compatible donor begins with family members. A person has a 25% chance of being a perfect HLA match with a sibling who shares both parents. Parents and children are always a half-match (haploidentical) because half of the markers are inherited from each parent.
When a fully matched family member is unavailable (approximately 70% of patients), the search expands to national and international donor registries. To find a match, both the patient and potential donors undergo HLA typing, a process that determines their specific set of HLA markers. Modern typing methods use advanced molecular techniques to identify these markers in detail.
Transplant specialists prioritize matching the most significant markers: HLA-A, HLA-B, HLA-C, and HLA-DRB1 (eight key markers). A “full match” is commonly defined as matching 8 out of 8 markers, or sometimes 10 out of 10 when HLA-DQ and HLA-DP are included. Even a single mismatch can increase the risk of complications, particularly in stem cell transplants.
Because of HLA polymorphism, finding a perfect match in the unrelated donor pool is difficult and often depends on shared ancestry. Individuals from the same ethnic background have a higher likelihood of sharing HLA types. If a full match is unavailable, a haploidentical donor (such as a parent or child) may be considered, requiring specialized techniques and intense immunosuppression to manage the half-match.
The Outcomes of HLA-Matched Transplants
Even with the best HLA match, the immune system may still recognize transplanted cells as foreign, leading to potential complications. The two primary risks associated with HLA differences are Graft Rejection and Graft-versus-Host Disease (GvHD). Both outcomes result from the immune system reacting to non-self HLA markers on the donor or recipient cells.
In Graft Rejection, the recipient’s existing immune cells recognize the donor’s cells as foreign and attack them, potentially leading to transplant failure. This reaction is similar to how the body fights a bacterial infection. The better the HLA match, the lower the chance the recipient’s immune system will mount this destructive response.
Conversely, Graft-versus-Host Disease (GvHD) occurs when the transplanted immune cells (the “graft”) recognize the recipient’s body (the “host”) as foreign and attack the recipient’s tissues. GvHD is primarily seen in stem cell and bone marrow transplants, where the donor provides a new immune system. The donor T-cells perceive the recipient’s HLA markers as foreign, leading to an attack that commonly targets the skin, liver, and gut.
To manage the risk of rejection and GvHD, patients receive immunosuppressive drugs following the transplant. These medications suppress the immune system’s activity, preventing T-cells from attacking foreign HLA markers. While advanced matching techniques have improved success rates, post-transplant monitoring and immunosuppression remain necessary to balance graft acceptance against the risk of infection.