Bone Marrow Transplantation (BMT) is a life-saving procedure that offers a potential cure for various blood cancers and certain immune system disorders. The process involves replacing a patient’s diseased blood-forming cells with healthy stem cells from a donor. The success of this treatment hinges on finding a donor whose tissue type is compatible with the recipient, a process known as human leukocyte antigen (HLA) matching. An optimal match is crucial because it directly influences whether the new immune system will be accepted and determines the risk of severe complications.
The Biological Role of HLA Markers
Human Leukocyte Antigens (HLA) are proteins found on the surface of nearly all cells, acting as markers for the immune system. These markers are encoded by the most variable gene cluster in the human genome. Their primary function is to present antigens to T-cells, allowing the immune system to distinguish between the body’s own cells and foreign invaders.
The HLA system is categorized into two main classes. Class I molecules (HLA-A, HLA-B, and HLA-C) are expressed on most nucleated cells and present internal antigens to CD8+ cytotoxic T-cells. Class II molecules (HLA-DR, HLA-DQ, and HLA-DP) are found on specialized immune cells, presenting external antigens to CD4+ helper T-cells.
The high degree of variability (polymorphism) in the HLA genes means thousands of different combinations exist. Since a person inherits one set of genes (a haplotype) from each parent, the chance of two unrelated individuals sharing an identical tissue type is exceptionally low. This genetic diversity makes the search for a compatible donor challenging, as minor differences can trigger a powerful immune response.
Defining the Standard for Matching
The standard for unrelated donor transplantation involves high-resolution typing at five specific HLA loci: HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1. Since an individual possesses two alleles for each locus, this standard aims for a “10/10” match, meaning all ten alleles across these five genes are identical.
Precision typing uses high-resolution molecular methods to identify the exact genetic sequence of the alleles. While a 10/10 match offers the best outcome, searches often begin with an 8/8 match (HLA-A, -B, -C, and -DRB1 loci only). A single mismatch (9/10 or 7/8 match) may be acceptable but increases the risk of complications.
The impact of a mismatch varies depending on the specific HLA locus involved. Mismatches at HLA-A, -B, -C, or -DRB1 are considered more detrimental than a mismatch at HLA-DQB1. Clinical practice uses “permissible mismatches,” where certain single-allele differences are less likely to provoke a severe immune reaction, broadening the donor pool.
Clinical Consequences of Mismatching
Inadequate HLA matching leads to two primary risks: Graft-versus-Host Disease (GvHD) and graft rejection. Minimizing the number of HLA mismatches is essential for improving patient safety and long-term survival.
GvHD occurs when the donor’s T-cells recognize the recipient’s body tissues as foreign and launch an attack. Its severity correlates with the degree of mismatch. Acute GvHD typically manifests within the first 100 days post-transplant, frequently affecting the skin, liver, and gastrointestinal tract.
Chronic GvHD can develop anytime after the transplant, presenting symptoms that mimic autoimmune disorders. The risk of both forms of GvHD increases significantly with more HLA mismatches, leading to higher mortality rates. Conversely, graft rejection occurs when the recipient’s residual immune system attacks the transplanted donor cells, preventing the new stem cells from establishing themselves in the bone marrow.
Alternative Strategies When a Perfect Match Is Not Available
When a fully matched unrelated donor cannot be found, physicians turn to alternative donor sources. These strategies use donors with less stringent HLA compatibility, made possible by advances in immunosuppressive therapies. The Haploidentical Transplant is a prominent alternative, involving a half-matched donor, typically a parent or child.
Haploidentical donors share exactly half of their HLA markers with the recipient, representing a significant mismatch. This approach relies on high-dose post-transplant cyclophosphamide (PTCy), administered after the stem cell infusion. PTCy selectively eliminates the highly reactive donor T-cells that cause GvHD while sparing the stem cells necessary for engraftment. This technique has made haploidentical transplants a rapidly available option with outcomes comparable to fully matched transplants in some settings.
Another established option is the Cord Blood Transplant, which uses stem cells collected from an umbilical cord after birth. Cord blood stem cells are biologically immature and less prone to causing severe GvHD, allowing for less stringent HLA matching criteria. A cord blood unit with a match of 4/6 or 5/6 is often considered acceptable for transplantation.