Organ transplantation is a life-saving medical procedure, but the recipient’s body immediately mounts a defense against the new organ. This process, known as organ rejection, is a sign that the immune system is functioning correctly. The defense system identifies the transplanted tissue as foreign material, similar to an invading bacterium or virus. The body’s natural response is to mobilize its cellular and molecular forces to neutralize this perceived threat. The mechanism behind this recognition involves specific molecular markers that define every cell.
The Body’s Identity Tags
The fundamental reason for transplant rejection lies in the body’s method of cellular identification, which uses markers called the Major Histocompatibility Complex (MHC). In humans, these are known as Human Leukocyte Antigens (HLA), a diverse group of proteins found on the surface of most cells. HLA molecules function as identity tags, signaling to the immune system whether a cell is “self” or “non-self.”
These identity tags are divided into two main classes. Class I HLA molecules are expressed on nearly all nucleated cells and present internal protein fragments, allowing the immune system to monitor for threats like viral infections. Class II HLA molecules are typically found only on specialized immune cells, such as B-cells and dendritic cells, and they present fragments of external proteins.
When an organ is transplanted, it carries the donor’s unique HLA signature, which is genetically inherited and almost certainly different from the recipient’s. The genetic variability of HLA is immense, making a perfect match between unrelated individuals extremely rare. This disparity means the donor organ’s cells are instantly flagged as foreign, triggering an alarm. The degree of HLA mismatch directly correlates with the strength of the immune response and the likelihood of rejection.
The Immune System’s Attack Sequence
Once foreign HLA markers are detected, the immune system orchestrates a targeted attack primarily involving specialized T-lymphocytes, or T-cells. Recognition occurs through two distinct pathways.
Direct Pathway
The direct pathway involves the recipient’s T-cells recognizing the intact donor HLA molecules displayed on the surface of the transplanted organ’s cells, often carried by donor dendritic cells. This recognition leads to a potent and rapid activation of cytotoxic T-cells, the immune system’s primary assassins. These killer T-cells interact with the foreign cells and release toxic substances like perforin and granzymes to induce programmed cell death (apoptosis) in the graft tissue. This mechanism is especially prominent immediately following transplantation.
Indirect Pathway
The indirect pathway occurs when the recipient’s own antigen-presenting cells engulf shed donor HLA molecules. These cells process the foreign HLA into small fragments, which are then presented on the recipient’s own Class II HLA molecules. This presentation activates helper T-cells, which stimulate B-cells to produce donor-specific antibodies. These antibodies cause damage by binding to the transplanted organ’s blood vessels, leading to inflammation and injury. The indirect pathway is a more prolonged response that contributes significantly to the long-term deterioration of the graft.
Different Timelines of Rejection
Organ rejection can manifest at different times, each corresponding to a different underlying mechanism.
Hyperacute Rejection
This is the fastest and most dramatic form, occurring within minutes to hours after the organ’s blood supply is connected. It happens when the recipient has pre-existing antibodies, often due to prior blood transfusions, pregnancies, or previous transplants. These antibodies immediately recognize and attack antigens on the donor organ’s blood vessel lining. This rapid reaction triggers clotting and thrombosis within the organ, causing immediate and irreversible graft failure.
Acute Rejection
Acute rejection is the most common type, typically occurring days to several weeks or months after the procedure. This form is largely mediated by newly activated T-cells targeting the foreign HLA through the direct recognition pathway. Symptoms can range from mild to severe, but with modern immunosuppressive drugs, these episodes are often reversible.
Chronic Rejection
Chronic rejection is a slow, progressive decline in organ function that takes months to years to develop. This complex process involves a combination of cellular and antibody-mediated injury, often driven by the indirect pathway. Chronic rejection leads to scarring and fibrosis in the transplanted organ’s tissues and blood vessels, which slowly restricts blood flow and function. This represents the leading cause of long-term graft loss.
Strategies to Overcome Rejection
Medical science employs two main strategies to minimize the risk of organ rejection and improve long-term graft survival.
Tissue Matching
Tissue matching involves testing the donor and recipient for compatibility, focusing on the most influential HLA markers: HLA-A, HLA-B, and HLA-DR. A higher degree of match reduces the initial immune response and allows for better outcomes. Cross-matching is also performed before the transplant to ensure the recipient does not possess pre-formed antibodies against the donor’s cells, which would cause hyperacute rejection.
Immunosuppressive Therapy
The second strategy is immunosuppressive therapy, a regimen of drugs designed to dampen the recipient’s immune system. These medications target the key cellular players in the rejection sequence, primarily T-cells and B-cells. Calcineurin inhibitors, for example, block a specific signaling pathway within T-cells, preventing their activation and proliferation. Anti-proliferative agents prevent the rapid multiplication of T-cells and B-cells, slowing the immune attack. While these drugs significantly reduce rejection risk, they must be taken for the lifetime of the transplanted organ and increase the recipient’s susceptibility to infections.