Innate immunity influences long-term outcomes after human lung transplant
Innate immunity influences long-term outcomes after human lung transplant
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DOI：
10.1164/rccm.200408-1129oc
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发表时间：
2005-04-01
影响因子：
24.7
通讯作者：
Schwartz, DA
中科院分区：
文献类型：
--
作者：
Palmer, SM;Burch, LH;Schwartz, DA
肺移植的特点是急性和慢性排斥反应的发生率非常高。我们假设先天免疫的激活增强了适应性免疫，导致肺移植后的排斥反应。为了支持这一观点，我们最近证明，肺受体的两个功能多态性（Asp299Gly或Thr39911e）在Toll样受体4（TLR4）与抗毒素低反应性杂合移植后的第一个6个月减少急性排斥反应。目的：在目前的分析中，我们试图扩大我们的初步观察，并调查这些TLR4多态性对移植后急性排斥反应超过前6个月，细菌感染，闭塞性细支气管炎综合征和生存的影响。方法：对170例肺移植受者进行基因分型。测量和主要结果：Asp299Gly或Thr399lle杂合子受体在移植后3年内持续急性排斥反应的频率（p = 0.02）和发生率（p = 0.04）显著降低，但在闭塞性细支气管炎综合征的总体发作方面没有观察到差异。然而，在TLR4杂合子中观察到闭塞性细支气管炎综合征2级或3级发病减少的趋势。结论：我们的研究结果表明，通过TLR4激活受体先天免疫应答对急性肺排斥反应的发展具有显著和持续的影响。靶向先天免疫信号传导是未来预防肺移植排斥反应的临床研究的一个有前途的领域。
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 Thr39911e) in Toll-like receptor 4 (TLR4) associated with enclotoxin hyporesponsiveness have decreased acute rejection over the first 6 months after transplant. Objectives: In the current analysis, we sought to extend our initial observations and investigate the effect of these TLR4 polymorphisms on post-transplant acute rejection beyond the first 6 months, bacterial infections, bronchiolitis obliterans syndrome, and survival. Methods: Genotyping was performed on 170 lung transplant recipients. Measurements and main results: Recipients heterozygous for either Asp299GIy or Thr399lle had significantly reduced frequency (p = 0.02) and incidence of acute rejection (p = 0.04) sustained over 3 years after transplant, but no differences were observed in the overall onset of bronchiolitis obliterans syndrome. A trend, however, toward reduced onset of bronchiolitis obliterans syndrome grade 2 or 3 was observed in TLR4 heterozygotes. Conclusion: 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.