The success of an organ or stem cell transplant depends on the body’s ability to accept the foreign tissue, a process regulated by the immune system. This acceptance centers on the Human Leukocyte Antigen (HLA) system, a set of unique molecular identity markers found on nearly every cell. An HLA mismatch occurs when a donor’s markers do not align with a recipient’s, causing the recipient’s immune system to perceive the transplanted tissue as a foreign invader. This recognition triggers a powerful immune response intended to destroy the perceived threat, making HLA compatibility a defining factor in transplant outcomes.
Understanding Human Leukocyte Antigens
Human Leukocyte Antigens are proteins encoded by the Major Histocompatibility Complex (MHC), the most variable gene cluster in the human genome. These proteins serve a surveillance function, presenting small fragments of other proteins, called antigens, on the cell surface to patrolling immune cells. Immune T-cells constantly check these presented antigens to determine if the cell belongs to the body or if it is foreign, such as a virus or transplanted organ.
The HLA system has two primary classes. HLA Class I molecules (HLA-A, HLA-B, and HLA-C) are expressed on nearly all nucleated cells. Their function is to present internal peptides to cytotoxic T-cells, the immune system’s killer cells. HLA Class II molecules (HLA-DR, HLA-DQ, and HLA-DP) are found mainly on specialized immune cells like B-cells, macrophages, and dendritic cells. These molecules present external antigens to helper T-cells, which orchestrate the broader immune response. The immense genetic variability within the HLA system means finding a perfect match between two unrelated individuals is rare, complicating transplantation.
Measuring Incompatibility: HLA Typing
HLA typing is the laboratory process used to identify the specific genetic versions, or alleles, of the HLA genes present in the donor and recipient. Clinicians focus on six primary loci: HLA-A, HLA-B, HLA-C (Class I), and HLA-DR, HLA-DQ, HLA-DP (Class II). Particular emphasis is placed on A, B, C, and DRB1 due to their strong influence on transplant success. Since a person inherits one set of genes from each parent, 12 alleles are typically analyzed for a comprehensive match assessment.
The testing result is summarized in a match score, which quantifies the degree of incompatibility. For instance, in the context of bone marrow transplantation, a full match is often described as 12/12, meaning both alleles at all six loci are identical. A perfect match is most likely between full siblings, who have roughly a 25% chance of complete identity. The greater the number of mismatched HLA markers, the higher the likelihood the recipient’s immune system will mount a strong reaction against the transplanted tissue. This quantifiable risk guides donor selection and determines the intensity of subsequent anti-rejection therapies.
The Impact of Mismatch in Transplants
An HLA mismatch creates a direct immunological barrier, triggering two distinct reactions depending on the transplant type.
Solid Organ Transplants: Rejection
In solid organ transplants (e.g., kidney or heart), the primary danger is rejection, where the recipient’s immune system attacks the foreign tissue. Acute rejection occurs quickly after the transplant and involves a vigorous T-cell response to the donor’s foreign HLA molecules. Rejection can also manifest as chronic rejection, a slower, long-term process involving antibody production that causes progressive damage and scarring, eventually leading to organ failure. Each additional mismatch in the most immunogenic loci (HLA-A, -B, and -DR) increases the intensity of this host-versus-graft reaction.
Hematopoietic Stem Cell Transplants: Graft-versus-Host Disease (GVHD)
In hematopoietic stem cell transplantation (HSCT), the mismatch poses the severe threat of Graft-versus-Host Disease (GVHD). In this scenario, the immune cells within the donor’s graft recognize the recipient’s entire body as foreign and launch an attack. The donor’s T-cells see the recipient’s HLA markers as non-self, leading to systemic damage, often affecting the skin, liver, and gastrointestinal tract. A mismatch in the graft-versus-host direction significantly increases the risk of severe acute and chronic GVHD, which remains a leading cause of complication and mortality after HSCT.
Clinical Strategies for Risk Management
Clinicians counteract the immunological risk of HLA mismatch using pre-transplant screening and post-transplant medication. Crossmatching is performed immediately before the transplant to determine if the recipient has pre-formed antibodies against the donor’s HLA markers. A positive crossmatch, indicating pre-existing donor-specific antibodies, usually bars the transplant due to the high risk of immediate, catastrophic rejection.
A fundamental strategy is the lifelong administration of immunosuppressive drugs. These medications dampen the recipient’s immune response, preventing T-cells from attacking the transplanted organ. Transplants involving a higher degree of HLA mismatch may require more intensive induction and maintenance immunosuppression protocols. For highly sensitized patients (those with many anti-HLA antibodies from prior events), desensitization protocols may be used before the transplant to temporarily reduce antibody levels and make a mismatched transplant feasible.