Department of Surgery Medicine, The University of Chicago, Chicago, IL, USA.
Am J Transplant. 2011 May;11(5):936-46. doi: 10.1111/j.1600-6143.2011.03476.x. Epub 2011 Mar 30.
Clinical correlations between bacterial infections and rejection suggest a hypothesis that innate immune stimulation by bacterial infections results in the production of inflammatory cytokine that facilitate bystander T-cell activation, increased alloreactivity and inhibition of tolerance induction. Previous studies demonstrated that IFNβ produced during an infection with a model bacterium, Listeria monocytogenes, prevented the induction of transplantation tolerance in mice with anti-CD154 and donor-specific transfusion (DST) (1). We investigated the impact of two clinically relevant bacterial infections at the time of transplantation on the ability of anti-CD154 and DST to induce skin allograft acceptance in mice. Staphylococcus aureus (SA) infection prevented skin allograft acceptance whereas maximally tolerated doses of Pseudomonas aeruginosa infection had no effect. SA induced an acute production of IL-6, which was necessary and sufficient for the prevention of skin allograft acceptance. Furthermore, a single pulse of methylprednisolone modulated IL-6 production during SA infection and facilitated skin allograft acceptance in SA-infected recipients. Taken together, our results suggest that bacterial infections elicit specific proinflammatory cytokines signatures that can serve as barriers to tolerance induction, and that inhibiting the production of or neutralizing these inflammatory cytokines can synergize with costimulatory blockade-based therapies to facilitate the development of transplantation tolerance.
临床研究表明，细菌感染与排斥反应之间存在关联，这一关联提出了一种假设，即细菌感染引起的固有免疫刺激会导致炎症细胞因子的产生，从而促进旁观者 T 细胞的激活、增强同种异体反应性，并抑制诱导耐受。先前的研究表明，在感染模型细菌李斯特菌时产生的 IFNβ 可防止抗 CD154 和供体特异性输血（DST）在小鼠中诱导移植耐受（1）。我们研究了移植时两种临床相关细菌感染对抗 CD154 和 DST 诱导小鼠皮肤同种异体移植物接受能力的影响。金黄色葡萄球菌（SA）感染可防止皮肤同种异体移植物的接受，而最大耐受剂量的铜绿假单胞菌感染则没有影响。SA 诱导了 IL-6 的急性产生，这是预防皮肤同种异体移植物接受所必需和充分的。此外，单次甲泼尼龙脉冲可调节 SA 感染期间的 IL-6 产生，并促进 SA 感染受者的皮肤同种异体移植物接受。综上所述，我们的研究结果表明，细菌感染会引发特定的促炎细胞因子特征，这些特征可能成为诱导耐受的障碍，而抑制这些炎症细胞因子的产生或中和这些炎症细胞因子可以与基于共刺激阻断的治疗协同作用，促进移植耐受的发展。
