The necessity of matching a donor with a recipient is fundamental for successful transplantation of organs, tissues, or bone marrow. The human body possesses a highly effective defense system that views a transplanted organ as a threat. Compatibility testing is required to minimize the risk that the recipient’s immune system will mount a destructive attack. By carefully selecting a donor whose biological markers closely resemble those of the recipient, medical professionals can significantly reduce the intensity of the immune response.
Recognizing Self vs. Non-Self: The Immune Barrier
The immune system continuously monitors the body to distinguish between its own cells and foreign entities. This distinction is managed by the adaptive immune system, involving specialized white blood cells known as T-cells and B-cells. T-cells patrol the bloodstream, ready to activate a destructive response when they encounter a cell displaying unfamiliar protein markers. If a transplanted organ lacks the recipient’s identifying markers, the T-cells perceive it as “non-self” and initiate an attack.
The resulting immune attack on the transplanted organ is known as rejection. Rejection can manifest as acute rejection, occurring rapidly in the days or weeks following the transplant, or as chronic rejection, a slower process leading to gradual organ failure. Antibodies produced by B-cells also play a significant role by binding directly to the donor cells, marking them for destruction. These antibodies can trigger inflammatory responses that damage the blood vessels within the transplanted tissue.
The Genetic Markers of Compatibility: HLA
The primary molecular structures responsible for distinguishing self from non-self are proteins called Human Leukocyte Antigens (HLA). These antigens are encoded by the Major Histocompatibility Complex (MHC) genes, located on chromosome 6. HLA molecules function as cellular identification tags, displaying protein fragments to patrolling T-cells. This presentation allows the T-cells to check if the cell is healthy and belongs to the body.
The HLA system is divided into two main categories, Class I and Class II, which present antigens to different types of T-cells. HLA Class I molecules (HLA-A, HLA-B, and HLA-C) are found on the surface of virtually all nucleated cells. They present internal protein fragments to cytotoxic CD8+ T-cells, which are responsible for destroying infected or foreign cells.
HLA Class II molecules (HLA-DR, HLA-DQ, and HLA-DP) are typically found only on specialized immune cells, such as B-cells and macrophages. Class II molecules present external protein fragments to helper CD4+ T-cells, which coordinate the broader immune response, including antibody production. The genetic variability of the HLA system is immense, with thousands of different variants, or alleles, for each gene. Since every person inherits one set of these genes from each parent, the chances of two unrelated individuals having a perfect HLA match are extremely low.
The Testing Process: From Blood Type to Molecular Typing
The initial step in assessing donor compatibility involves confirming ABO blood group matching. The ABO blood group system is important because recipients naturally possess pre-formed antibodies, known as isoagglutinins, against the A and B antigens they lack. These antibodies are capable of causing immediate hyperacute rejection if an incompatible organ is used.
While ABO compatibility is a prerequisite for most transplants, precise HLA matching is then pursued using advanced laboratory techniques. Historically, HLA typing relied on serological methods that used antibodies to identify antigens on the cell surface, but these methods lacked precision. Modern histocompatibility labs now employ highly sensitive molecular typing methods to identify the specific HLA alleles at the genetic level.
These molecular methods often utilize Polymerase Chain Reaction (PCR) technology to amplify the DNA sequences of the HLA genes. Techniques like Sequence-Based Typing (SBT) and Sequence-Specific Oligonucleotide Probing (SSOP) accurately determine the exact genetic makeup of the donor and recipient’s HLA markers. This detailed genetic analysis allows for matching at a much higher resolution, identifying specific alleles rather than just broader antigen groups, which helps predict the likelihood of a successful long-term graft outcome.
Final Confirmation: The Crossmatch Test
Even after a high-resolution HLA match is identified, a final, functional test is required to ensure the recipient does not have pre-existing antibodies that will immediately attack the donor’s cells. This definitive test is called the crossmatch. The crossmatch involves taking the recipient’s serum, which contains their circulating antibodies, and mixing it with lymphocytes—white blood cells—from the potential donor.
A positive crossmatch result indicates that the recipient’s antibodies have bound to the donor’s cells, which predicts a high risk of hyperacute rejection. This result typically prevents the transplant from proceeding. Prior to a donor being identified, patients are often screened for sensitization using a Panel Reactive Antibody (PRA) test. The PRA test determines the percentage of the general population to which a patient has pre-formed antibodies, providing an estimate of how difficult it will be to find a compatible donor.
A high PRA value, sometimes over 80%, signifies a highly sensitized patient who has developed antibodies from past events such as blood transfusions, previous transplants, or pregnancy. For these patients, a virtual crossmatch, which uses the recipient’s known anti-HLA antibody profile and compares it to the donor’s HLA type, is often performed first. The final crossmatch confirms compatibility, providing assurance that an immediate, antibody-mediated immune attack is unlikely.