Published ahead of print on January 7, 2005, doi:10.1164/rccm.200408-1129OC Am. J. Respir. Crit. Care Med., Volume 171, Number 7, April 2005, 780-785 A more recent version of this article appeared on April 1, 2005
Submitted on September 1, 2004 Innate Immunity Influences Long-Term Outcomes after Human Lung TransplantScott M Palmer1*,1 Department of Medicine, Duke University Medical Center, Durham, NC, USA, 2 Department of Surgery, Duke University Medical Center, Durham, NC, USA, 3 Department of Pathology, Duke University Medical Center, Durham, NC, USA, 4 Department of 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.
Rationale: Lung transplantation is characterized by very high rates of acute and chronic allograft rejection. We hypothesize that activation of innate immunity augments adaptive immunity leading to rejection after lung transplantation. In support of this idea, we have recently demonstrated that lung recipients heterozygous for either of two functional polymorphisms (Asp299Gly or Thr399Ile) in toll-like receptor-4 (TLR4) associated with endotoxin hyporesponsiveness have decreased acute rejection over the first six months posttransplant. Objectives: In the current analysis, we sought to extend our initial observations and investigate the effect of these TLR4 polymorphisms upon posttransplant acute rejection beyond the first six months, bacterial infections, bronchiolitis obliterans syndrome (BOS) and survival. Methods: Genotyping was performed on 170 lung transplant recipients. Measurements and Main Results: Recipients heterozygous for either Asp299Gly or Thr399Ile had significantly reduced frequency (p-value=0.02) and incidence of acute rejection (p-value=0.04) sustained over three years posttransplant, but no differences were observed in the overall onset of BOS. A trend, however, towards reduced onset of BOS grade 2,3 was observed in TLR4 heterozygotes. Conclusions: Our results demonstrate that activation of recipient innate immune responses through TLR4 has a significant and sustained effect on the development of acute lung rejection. Targeting innate immune signaling represents a promising area for future clinical studies in the prevention of lung allograft rejection. Key words: lung transplant, innate immunity, TLR4
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