Graft Rejection Mechanisms

Hyperacute rejection is antibody-mediated, occurs within minutes to hours after transplantation, and is NOT reversible with steroids alone. 1

Types of Graft Rejection

Hyperacute rejection is definitively antibody-mediated, occurring within minutes to hours (0-7 days) after transplantation due to preformed donor-specific antibodies (DSAs) binding to donor HLA antigens on the endothelial cells of the graft 1
This process activates the complement cascade, resulting in rapid endothelial damage, microvascular thrombosis, and immediate graft failure 1
Hyperacute rejection is characterized by the deposition of immunoglobulins and complement within the allograft microvasculature 1
Hyperacute rejection is NOT reversible with steroids alone, requiring more aggressive interventions such as plasmapheresis, IVIg, and potentially mechanical circulatory support in severe cases 1, 2
Flow cytometry or complement-dependent cytotoxicity assays are used to detect preformed antibodies against donor tissues, which can predict hyperacute rejection 3

Acute rejection is primarily T-cell mediated (not B-cell mediated), occurring days to months after transplantation 1, 3
The diagnosis of acute cellular rejection is made by histological identification of interstitial leukocyte infiltration with various degrees of myocyte damage 1
Acute rejection responds to anti-cellular rejection therapies such as corticosteroids 1
The Sociedad Internacional de Trasplante de Corazón y Pulmón (ISHLT) classifies acute cardiac rejection into four grades: 0R (no rejection), 1R (mild), 2R (moderate) and 3R (severe), based on histological criteria 4

Biopsy of the transplanted organ remains the gold standard for definitive diagnosis of rejection 4
The determination of anti-HLA or donor-specific antibodies is useful for diagnosing antibody-mediated rejection 4
Modern antibody-detection techniques, such as L-SAB technology, have made acute or hyperacute antibody-mediated rejection of the kidney less frequent 5

High-dose corticosteroids are the first-line treatment for acute rejection, but are not effective for hyperacute rejection 4, 1
For antibody-mediated rejection, treatment protocols typically include: suppression of T-cell dependent antibody response, removal of donor-reactive antibody, blockade of residual alloantibody, and depletion of naive and memory B-cells 2
Rituximab is used for antibody-mediated rejection, and plasma exchange is used for removing donor-specific antibodies 3
Mycophenolate mofetil, in combination with other immunosuppressants, has been shown to reduce the incidence of biopsy-proven rejection in renal, cardiac, and hepatic transplants 6

Optimal matching of donor and recipient HLA antigens can reduce the incidence of acute rejection episodes and improve long-term graft survival 1, 3
Chronic antibody-mediated rejection is considered a major contributor to graft loss in the late post-transplant phase 5
Transplant graft survival after antibody-mediated rejection is jeopardized, with less than 50% graft survival 5 years after this diagnosis 7
The absence of pathological evidence of severe rejection in the presence of unexplained left ventricular dysfunction should not prevent treatment of rejection 4