What Stimulates the Development of De Novo Donor Specific Antibodies in Cardiac Transplant Recipients?

IntroductionThe formation of de novo donor specific antibodies (dDSAs) has been implicated in the development of antibody-mediated rejection (AMR) and coronary allograft vasculopathy (CAV) after cardiac transplantation. dDSAs can develop at any time following transplantation and are associated with a poor prognosis, but the reason dDSAs develop after the initial injury of the transplant surgery is unknown. Since the detection of dDSAs often triggers the use of potentially toxic therapies to reduce these antibodies, it is important to understand whether dDSAs are a mediator of poor outcomes or a marker of a harmful underlying process.HypothesisIn some cases, the development of dDSAs is precipitated by the development of CAV or other myocardial injury which can expose myocardial cell epitopes.MethodsWe reviewed the medical record of 217 patients followed at our institution who underwent heart transplantation between 2014 and 2017, were not desensitized prior to transplant and did not have pre-transplant donor specific antibodies. Of these, we identified 36 patients with dDSAs, 16 of whom did not develop dDSAs until ≥ 6 months post-transplant, as detected by the modern bead-based multiplex assay on routine measurement every 3 months.ResultsMajor findings are shown in Figure 1. In 10 of 16 patients with dDSAs but without evidence of AMR, CAV diagnosis or significant elevation in BNP suggestive of myocardial injury preceded dDSA development.ConclusionsThese findings suggest that CAV or other myocardial injury may precede the development of dDSAs in some cardiac transplant recipients and would explain why dDSAs signal a poor prognosis. These findings may shift the therapeutic focus from direct suppression of dDSAs to earlier detection, prevention and therapy of CAV or other injury that may trigger these antibodies' delayed appearance.