The success of an organ transplant relies on replacing a failing organ while preventing the recipient’s immune system from destroying the new tissue. When a transplanted organ is introduced, the body recognizes differences between the donor’s and recipient’s cells, triggering rejection.
Antibody-mediated rejection (AMR) is a specific type of rejection where the recipient’s immune system uses specialized proteins called antibodies to attack the graft. This differs from T-cell mediated rejection, which involves direct attack by immune cells. AMR is a significant complication that can lead to graft injury, dysfunction, and eventual loss of the transplanted organ.
The Mechanism of Donor Specific Antibodies
The core of antibody-mediated rejection involves the recipient recognizing the donor’s Human Leukocyte Antigens (HLA) on the transplanted organ’s cells. HLA molecules are unique identification tags found on the surface of most cells. When the recipient’s immune system encounters these differing HLA markers, it perceives them as foreign, initiating a defense response.
This recognition leads to the production of Donor Specific Antibodies (DSAs) by the recipient’s B-cells and plasma cells. DSAs are tailored to bind to the donor’s HLA molecules on the transplanted organ’s endothelium (blood vessel lining). Sensitization—the production of DSAs—can occur before the transplant due to prior blood transfusions, pregnancy, or previous transplants.
Once a DSA binds to the HLA, it triggers the activation of the complement system, a group of proteins that works in a chain reaction to eliminate targets. This reaction deposits complement fragments, which directly injure endothelial cells, causing inflammation and clotting in the microvasculature.
The antibodies also recruit innate immune cells, such as Natural Killer (NK) cells, in a process known as antibody-dependent cellular cytotoxicity (ADCC). These recruited cells release toxic substances that cause cell death. This dual assault results in inflammation, capillary damage (capillaritis), and microvascular injury, leading to impaired organ function.
Identifying Antibody Mediated Rejection
Confirming a diagnosis of antibody-mediated rejection requires clinical, histological, and immunological evidence. The first indicator is often clinical dysfunction, such as a decline in organ function measured by rising creatinine levels or changes in cardiac function. Since these symptoms are non-specific, a definitive diagnosis requires physical examination of the organ tissue.
The gold standard for diagnosis is an organ biopsy, where a small tissue sample is examined under a microscope. Histological evidence of AMR includes signs of microvascular inflammation, such as glomerulitis or peritubular capillaritis. These microscopic injuries result directly from the antibody-mediated attack on the blood vessels.
A specific immunological marker, the complement fragment C4d, is used to confirm the role of the complement system. C4d is a stable breakdown product of the complement cascade that remains affixed to the site of antibody-antigen binding on the capillary walls. The presence of linear C4d staining in the peritubular capillaries is a strong indicator of recent or ongoing antibody-mediated injury.
Immunological evidence is also gathered by testing the recipient’s blood for Donor Specific Antibodies (DSAs). Sensitive laboratory methods identify and quantify the specific HLA antibodies targeting the donor organ. The final diagnosis of definite AMR requires evidence of organ dysfunction, characteristic histological injury in the biopsy, and the presence of circulating DSAs.
Managing and Reversing AMR
Treatment for active antibody-mediated rejection involves a multi-pronged approach to neutralize existing antibodies and eliminate the cells that produce them. The goal is to rapidly reduce the concentration of circulating DSAs to halt ongoing damage. This is achieved through therapeutic plasma exchange (plasmapheresis), which physically removes the patient’s plasma containing harmful antibodies and replaces it with a substitute solution.
Following antibody removal, Intravenous Immunoglobulin (IVIG) is administered to neutralize remaining DSAs and modulate the immune system. IVIG is a purified blood product containing pooled antibodies from healthy donors, which interferes with the binding of the recipient’s DSAs to the graft. This combined approach is the standard initial treatment for acute AMR.
Targeted immunosuppressive drugs are used to eliminate antibody-producing cells and prevent the production of new DSAs. Rituximab, an anti-CD20 monoclonal antibody, targets B-cells, the precursor cells to plasma cells. Bortezomib, a proteasome inhibitor, is sometimes used to target the long-lived plasma cells themselves.
The response to treatment differs between acute and chronic forms of AMR. Acute AMR, occurring soon after transplantation, is more responsive to intensive therapies. Chronic active AMR develops slowly over months or years, involves irreversible tissue scarring, and is much more difficult to reverse, often leading to long-term graft loss.