John H. Gibbon Jr. Research Scholarship award (2014-2016)

Chronic rejection, represented by bronchiolitis obliterans syndrome (BOS), remains the predominate cause of poor long-term survival following lung transplantation with a reported incidence of over 50% at 5-years. Although the pathogenesis of BOS is a multifactorial, emerging evidence from our laboratory and others suggests that atuoimmunity may play a critical role. CD4+CD25+Foxp3+ regulatory T cells (Tregs) suppress autoreactive T and B cells in lung transplant recipients. Any injury mechanism that induces apoptosis of Tregs, for example respiratory viral infections, results in expansion of autoreactive T cells and de novo autoAB (autoAB) production against the lung-specific self-antigens collagen type V (ColV) and k-alpha 1 tubulin (KAT). The production of autoAbs is an independent risk factor for BOS. In addition, we have recently demonstrated that pre-existing autoAbs cause peri-transplant inflammation and lead to primary graft dysfunction (PGD) that ultimately predisposes to the development of BOS. Collective, these data indicate that activation of B cells and production of autoAbs, both pre-transplant and de novo, may play an important role in mediating lung allograft rejection. The overall goal of this application is to define how autoAbs regulate the outcome of lung grafts.