TY - JOUR
T1 - Zbtb7a induction in alveolar macrophages is implicated in anti-HLA-mediated lung allograft rejection
AU - Nayak, Deepak K.
AU - Zhou, Fangyu
AU - Xu, Min
AU - Huang, Jing
AU - Tsuji, Moriya
AU - Yu, Jinsheng
AU - Hachem, Ramsey
AU - Gelman, Andrew E.
AU - Bremner, Ross M.
AU - Smith, Michael A.
AU - Mohanakumar, Thalachallour
N1 - Funding Information:
This research was supported by Flinn Foundation (award 2095 to D.K.N. and M.A.S.) and NIH (R01HL056643 and R01HL092514 to T.M. and R01AI102891 to M.T.). Author contributions: D.K.N. and T.M. conceived the idea and designed the research studies. D.K.N. and F.Z. conducted the experiments. J.H. and M.T. developed/provided reagents used in the study. M.X. assisted with the immunofluorescence studies. J.Y. evaluated the microarray data. R.H. assisted with patient selection and clinical sample procurement. D.K.N., F.Z., R.H., and T.M. evaluated the clinical history of lung transplant recipients. A.E.G. assisted with the mouse lung transplant study. D.K.N., F.Z., and T.M. analyzed the data. D.K.N. and T.M. wrote and revised the manuscript. J.H., M.T., A.E.G., R.M.B., M.A.S., and T.M. reviewed the manuscript.
Publisher Copyright:
©2017 The Authors, somerights reserved.
PY - 2017/7/12
Y1 - 2017/7/12
N2 - 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 alveolarmacrophages (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.
AB - 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 alveolarmacrophages (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.
UR - http://www.scopus.com/inward/record.url?scp=85023748030&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aal1243
DO - 10.1126/scitranslmed.aal1243
M3 - Article
C2 - 28701473
AN - SCOPUS:85023748030
SN - 1946-6234
VL - 9
JO - Science translational medicine
JF - Science translational medicine
IS - 398
M1 - eaal1243
ER -