Antibody-mediated rejection is an immunologic response to the cardiac allograft distinct from cellular rejection by its biology and histologic findings. It is characterized by complement-mediated endothelial damage to the allograft and is classically considered to be devoid of a significant lymphocytic response. The main mechanism of injury in antibody-mediated rejection involves the activation of the classical pathway of the complement cascade. In contrast to acute cellular rejection (see Chapter 168), which has been extensively studied and well defined both clinically and pathologically, there is little consensus regarding the histopathologic diagnosis of antibody-mediated rejection.

The first recognition of antibody-mediated rejection described a small-vessel vasculitis associated with a poor graft outcome.¹ Later, immunofluorescence demonstrated immunoglobulin and complement deposition in the absence of a significant inflammatory reaction,² and the term “vascular rejection” was often used.³ The concept that antibody-mediated rejection causes heart graft dysfunction in the absence of lymphocytic infiltrates has gradually been modified to include intravascular macrophages and possibly endotheliitis (or intimitis) as a component.^4,5

The pathophysiology of antibody-mediated rejection involves a stepwise progression that begins with circulating immunoglobulins, followed by deposition of the endothelium of myocardial capillaries with complement activation, then involves tissue damage with or without inflammation, and finally culminates in graft dysfunction. The relationship between antibody-mediated rejection and the development of cardiac allograft vasculopathy in epicardial vessels remains unclear.

Antibody-mediated rejection usually occurs within the first month after transplantation, but episodes of antibody-mediated rejection can happen many months or years after transplantation.³ The alleged prevalence for cardiac antibody-mediated rejection is 7% to 18%, and antibody-mediated rejection associated with acute cellular rejection can be detected in as high as 23% of patients.⁶ The clinical findings are generally those of graft dysfunction that mimic cellular rejection. Graft dysfunction ranges from decreased cardiac output with a rise in capillary wedge and pulmonary artery pressures to hypotension and shock.⁶ Depending on the clinical and pathologic criteria for diagnosis, antibody-mediated rejection can be detected in asymptomatic patients.⁵ The treatment of cardiac antibodymediated rejection consists of increase in immunosuppression, plasmapheresis, intravenous immunoglobulin, and rituximab (anti-CD20). Associated cellular rejection is not uncommon, in both the adult and pediatric populations.⁷

Allosensitized patients are at increased risk of developing a rejection. The most common clinical settings are pregnancy, prior transplantation, and previous ventricular assist device use, and others include blood transfusions, cytomegalovirus seropositivity, elevated response to a panel of reactive antibodies, and sensitization by OKT3 induction therapy.⁸

Patients with a diagnosis of antibody-mediated rejection have worse graft survival, possibly an increased risk for cardiac allograft vasculopathy (see Chapter 29) and decreased overall survival.^5,6 It has been suggested that even asymptomatic antibody-mediated rejection may portend a higher risk of developing cardiac allograft vasculopathy. 5 This may suggest that attempts of early detection and treatment even for patients without symptoms may be advisable.