Donor-Specific Antibodies (DSAs) are specialized proteins within the body’s immune system. In organ transplantation, these antibodies specifically target components of the donor organ. Their presence can significantly influence how well a transplanted organ functions and its long-term viability within the recipient.
What Are Donor-Specific Antibodies?
Antibodies are proteins produced by the immune system to recognize and bind to foreign substances. In transplantation, these antibodies become “donor-specific” when they target human leukocyte antigens (HLAs) found on the donor organ’s cells. HLAs are unique genetic markers that help the immune system distinguish between “self” and “non-self.” When a recipient receives an organ with different HLAs, their immune system may recognize these as foreign, triggering an antibody response.
These donor-specific antibodies can develop in a recipient through several pathways before transplantation. Common exposures include previous pregnancies, where the mother’s immune system encounters fetal HLAs inherited from the father, or prior blood transfusions, which introduce foreign cellular components. Individuals who have undergone a previous organ transplant may have already developed antibodies against HLAs from that prior donor. Antibodies present before transplantation are termed “pre-formed DSAs,” while those that develop after the transplant, in response to the new organ, are known as “de novo DSAs.”
How DSAs Impact Transplant Outcomes
Donor-specific antibodies can negatively affect a transplanted organ through various immune mechanisms, leading to different forms of rejection. One severe and immediate type is hyperacute rejection, which occurs within minutes to hours after transplantation. This rare event happens when pre-formed DSAs in the recipient’s bloodstream immediately recognize and attack the donor organ’s blood vessels, causing rapid clotting and organ failure.
DSAs also contribute to acute antibody-mediated rejection (AMR), which appears weeks to months following transplantation. In this scenario, DSAs bind to the donor organ’s endothelial cells, which line the blood vessels, activating the complement system. This activation can lead to inflammation, damage to the vessel walls, and impaired organ function. Even without complement activation, DSAs can cause damage through antibody-dependent cell-mediated cytotoxicity (ADCC), where other immune cells are recruited to destroy the antibody-bound donor cells.
Over the long term, DSAs are associated with chronic antibody-mediated rejection, a process that causes gradual and irreversible damage to the transplanted organ. This prolonged attack can lead to scarring and fibrosis within the organ, reducing its ability to function effectively. For instance, in kidney transplants, chronic AMR can result in transplant glomerulopathy, an injury to the filtering units of the kidney. In heart transplants, DSAs can contribute to cardiac allograft vasculopathy, a condition where the heart’s blood vessels narrow, diminishing the longevity of the transplanted heart.
Identifying and Monitoring DSAs
Medical professionals use specific diagnostic tools to detect and measure donor-specific antibodies in transplant recipients. One widely used method is the solid phase assay, particularly the Luminex single antigen bead (SAB) assay. This test uses microscopic beads, each coated with a specific HLA antigen, to identify and quantify the HLAs a patient’s antibodies target. The strength of the antibody binding is measured, which helps assess the potential risk.
Crossmatch tests are also employed to determine if a recipient’s antibodies directly react with a potential donor’s cells. The flow cytometry crossmatch is a more sensitive version of this test, where recipient serum is mixed with donor lymphocytes, and any antibody binding is detected using fluorescent markers. A positive crossmatch indicates a high risk of immediate rejection if that specific donor organ were used. Routine monitoring of DSA levels, both before transplantation and periodically afterward, helps clinicians assess immunological risk, guide treatment decisions, and intervene early if signs of rejection emerge.
Strategies for Managing DSAs
Managing donor-specific antibodies involves a range of clinical strategies, implemented both before and after transplantation, to reduce their harmful impact. Prior to transplantation, desensitization therapies aim to lower existing DSA levels, making a transplant possible for highly sensitized patients who might otherwise not find a compatible donor. Common desensitization approaches include plasmapheresis, a procedure that removes antibodies from the blood, and intravenous immunoglobulin (IVIg), which can neutralize existing antibodies and modulate the immune system.
Other agents, such as rituximab, an anti-CD20 antibody that targets antibody-producing B cells, are also used in desensitization protocols. Emerging therapies, including proteasome inhibitors like carfilzomib that reduce plasma cells (antibody factories), and anti-CD38 monoclonal antibodies such as daratumumab, are being explored for their ability to reduce DSA levels. Interleukin-6 (IL-6) inhibitors like tocilizumab also help reduce immunodominant DSA scores.
After transplantation, if antibody-mediated rejection is diagnosed, intensified immunosuppression is initiated to suppress the immune response and prevent further organ damage. Treatments for diagnosed antibody-mediated rejection involve a combination of plasmapheresis and IVIg to remove or neutralize circulating DSAs. Corticosteroids are also administered to reduce inflammation. Patients with DSAs require ongoing immunosuppression and long-term surveillance to maintain graft function and prevent late rejection.