Published ahead of print on May 28, 2003, doi:10.1164/rccm.200303-447OC
Am. J. Respir. Crit. Care Med., Volume 168, Number 6, September 2003, 628-632
A more recent version of this article appeared on September 15, 2003
Submitted on March 31, 2003
Accepted on May 23, 2003
The Role of Innate Immunity in Acute Allograft Rejection after Lung Transplantation
Scott M Palmer1*, Lauranell H Burch1, R. Duane Davis2, Walter F Herczyk3, David N Howell3, Nancy L Reinsmoen3, and David A Schwartz4
1 Pulmonary Medicine, Duke University Medical Center, Durham, NC, USA,
2 Thoracic Surgery, Duke University Medical Center, Durham, NC, USA,
3 Pathology, Duke University Medical Center, Durham, NC, USA,
4 Pulmonary Medicine, Duke University Medical Center, Durham, NC, USA; Veterans Administration Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. 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. In order 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 (PCR) using sequence specific primers. The rate of acute rejection at six months was significantly reduced in recipients, but not donors, with the Asp299Gly or Thr399Ile alleles, as compared to wild type (29% vs. 56%, respectively, p-value=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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