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The Role of Innate Immunity in Acute Allograft Rejection after Lung Transplantation

Departments of Medicine, Surgery, and Pathology, Duke University Medical Center, and the Veterans Administration Medical Center, Durham, North Carolina

Correspondence and requests for reprints should be addressed to Scott M. Palmer, M.D., M.H.S., DUMC 3876, Room 128, Bell Building, Duke University Medical Center, Durham, NC 27710. E-mail: Palme002{at}mc.duke.edu

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.

Key Words: lung transplant • toll-like receptors • innate immunity • acute rejection

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