Zbtb7a induction in alveolar macrophages is obligatory in anti-human leukocyte antigen-mediated lung allograft rejection

摘要

Chronic rejection (CR) significantly limits long-term success of solid organ transplantation. De novo antibodies to mismatched donor human leukocyte antigen (DSA) following human lung transplantation (LTx) predispose lung grafts to CR. We sought to delineate mechanisms and mediators of DSA pathogenesis, and to define early inflammatory events that trigger CR in LTx recipients and obliterative airway disease (a correlate of human CR) in a murine model. Induction of transcription factor Zn finger BTB domain containing protein 7A (Zbtb7a) was an early response critical in DSA-induced CR. A cohort of human LTx recipients that developed DSA and CR demonstrated greater Zbtb7a expression long before clinical diagnosis of CR compared to non-rejecting LTx recipients with stable pulmonary function. Expression of DSA-induced Zbtb7a was restricted to alveolar macrophage (AM), and selective disruption of Zbtb7a in AM resulted in less bronchiolar occlusion, low immune responses to lung-restricted self-antigens, and high protection from CR. Additionally, in allogeneic cell transfer protocol, antigen presentation by AM was Zbtb7a-dependent, whereas AMs deficient in Zbtb7a failed to induce antibody and T cell responses. Collectively, we demonstrate that AM plays an essential role in antibody-induced pathogenesis of CR by regulating early inflammation and lung-restricted humoral and cellular autoimmunity. The AM-centric responses were Zbtb7a-dependent, whereas Zbtb7a-sufficient AM (not Zbtb7a-deficient AM) initiated and/or amplified DSA and DSA-induced effector functions.