Tissue-restricted humoral autoimmunity lead to lung allograft rejection

Lung allografts have the worst survival of all solid organs with a reported incidence of only about 50% at 5 years [1]. The poor long-term survival is due to the development of chronic lung allograft rejection, also known as Bronchiolitis Obliterans Syndrome (BOS). While the development of BOS appears to be multifactorial, emerging data strongly supports the role of early post-transplant events in the development of BOS. In particular, primary graft dysfunction (PGD) that occurs within 24 hours of transplantation, characterized by hypoxemia and pulmonary infiltrates [2], has emerged as one of the most important risk factors for BOS development [3]. Studies have further shown that risk of BOS is increased up to 7-fold following development of severe forms of PGD [4]. We have previously shown that PGD induces an inflammatory state augmenting donor-specific alloimmunity, leading to chronic rejection. Further, we have described the immunological link between PGD and chronic rejection [5-6]. PGD is associated with an all-cause 30-day mortality of 63.3% versus 8.8% in recipients without PGD, mean hospital length of 47 days versus 15 days, and duration of mechanical ventilation 15 days versus 1 day [7]. As such, therapies directed against improving PGD will directly translate into improved short- and long-term outcomes following lung transplantation. While several clinical risk factors have been identified for PGD [1], the mechanisms of PGD pathogenesis remain unclear.