Research ArticleTransplantation

Zbtb7a induction in alveolar macrophages is implicated in anti-HLA–mediated lung allograft rejection

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Science Translational Medicine  12 Jul 2017:
Vol. 9, Issue 398, eaal1243
DOI: 10.1126/scitranslmed.aal1243

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Curbing culprits of chronic rejection

De novo donor-specific antibodies generated after organ transplantation can lead to chronic rejection, and Nayak et al. sought to understand the mechanisms leading to production of these antibodies in lung transplantation. Using mouse models and data from human patients, they identified expression of the transcription factor Zbtb7a in alveolar macrophages as a crucial mediator. Patients eventually diagnosed with chronic rejection had higher expression of this transcription factor early on. Preventing macrophages from expressing Zbtb7a ameliorated models of obliterative airway disease and prevented chronic rejection of lung transplants in mice. Interrupting macrophage presentation of donor antigens may be a solution to prevent generation of these destructive antibodies and the ensuing chronic rejection.

Abstract

Chronic rejection significantly limits long-term success of solid organ transplantation. De novo donor-specific antibodies (DSAs) to mismatched donor human leukocyte antigen after human lung transplantation predispose lung grafts to chronic rejection. We sought to delineate mediators and mechanisms of DSA pathogenesis and to define early inflammatory events that trigger chronic rejection in lung transplant recipients and obliterative airway disease, a correlate of human chronic rejection, in mouse. Induction of transcription factor zinc finger and BTB domain containing protein 7a (Zbtb7a) was an early response critical in the DSA-induced chronic rejection. A cohort of human lung transplant recipients who developed DSA and chronic rejection demonstrated greater Zbtb7a expression long before clinical diagnosis of chronic rejection compared to nonrejecting lung transplant recipients with stable pulmonary function. Expression of DSA-induced Zbtb7a was restricted to alveolar macrophages (AMs), and selective disruption of Zbtb7a in AMs resulted in less bronchiolar occlusion, low immune responses to lung-restricted self-antigens, and high protection from chronic rejection in mice. Additionally, in an allogeneic cell transfer protocol, antigen presentation by AMs was Zbtb7a-dependent where AMs deficient in Zbtb7a failed to induce antibody and T cell responses. Collectively, we demonstrate that AMs play an essential role in antibody-induced pathogenesis of chronic rejection by regulating early inflammation and lung-restricted humoral and cellular autoimmunity.

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