Enderes Jana, van der Linde Julia, Müller Jan, Tran Bich-Thu, von Bernstorff Wolfram, Heidecke Claus-Dieter, Schulze Tobias
*Department of Surgery, Universitätsmedizin Greifswald, Greifswald, Germany †Department of Surgery, University Hospital of Bonn, Bonn, Germany ‡Department of Immunology, Universitätsmedizin Greifswald, Greifswald, Germany §Department of Vascular Surgery, Krankenhaus Ludmillenstift, Meppen, Germany.
Shock. 2017 Mar;47(3):385-394. doi: 10.1097/SHK.0000000000000739.
FTY720 is an immunosuppressive molecule licensed for the treatment of chronic relapsing multiple sclerosis (MS). It attenuates the adaptive immune response by sequestering T cells within secondary lymphoid organs via its action as functional antagonist of sphingosine-1-phasphate. To date, it is unknown whether FTY-induced lymphopenia puts MS patients at increased risk for severe forms of postoperative infectious complications such as abdominal sepsis.
To determine the effect of FTY720-induced lymphopenia on survival to sepsis secondary to postoperative intraabdominal infections in a murine model of polymicrobial sepsis.
Detailed analysis of cellular dynamics in secondary lymphoid organs and of cytokine profiles was performed in FTY720-treated or placebo-treated C57BL/6 mice after induction of colon ascendens stent peritonitis (CASP). Furthermore, survival analysis was performed in FTY720-treated and placebo-treated animals in severe CASP. Fifty percent of each group were treated with broad spectrum antibiotics.
FTY720 treatment resulted in remodeling of cell populations present in the peripheral blood, the peritoneal cavity, and the spleen after CASP induction. Both lymphoid and myeloid cell lines were affected. However, survival in lymphopenic FTY720-treated animals was similar to placebo-treated mice following CASP. Antibiotic treatment increases survival in untreated as well as FTY720-treated animals to a similar extent.
Our data demonstrate that inhibition of T-cell migration and induction of peripheral lymphopenia did not affect survival in a model of severe murine sepsis. The presence of reduced T- and B-cell numbers in the peripheral blood during a septic challenge did not negatively affect sepsis mortality in our model of severe abdominal sepsis. The absence of increased mortality under FTY720 treatment in the CASP model suggests that FTY720 treatment will probably not result in increased mortality in MS patients suffering from sepsis.
FTY720是一种已获许可用于治疗慢性复发性多发性硬化症（MS）的免疫抑制分子。它通过作为鞘氨醇-1-磷酸的功能拮抗剂，将T细胞隔离在次级淋巴器官内，从而减弱适应性免疫反应。迄今为止，尚不清楚FTY诱导的淋巴细胞减少是否会使MS患者发生诸如腹部脓毒症等严重形式的术后感染并发症的风险增加。
在多微生物脓毒症小鼠模型中，确定FTY720诱导的淋巴细胞减少对术后腹腔内感染继发脓毒症存活的影响。
在诱导升结肠支架腹膜炎（CASP）后，对接受FTY720治疗或安慰剂治疗的C57BL/6小鼠的次级淋巴器官中的细胞动力学和细胞因子谱进行详细分析。此外，对严重CASP中接受FTY720治疗和安慰剂治疗的动物进行存活分析。每组的50%用广谱抗生素治疗。
FTY720治疗导致CASP诱导后外周血、腹腔和脾脏中的细胞群重塑。淋巴细胞系和髓细胞系均受影响。然而，接受FTY720治疗的淋巴细胞减少动物的存活率与CASP后接受安慰剂治疗的小鼠相似。抗生素治疗在未治疗以及接受FTY720治疗的动物中使存活率提高到相似程度。
我们的数据表明，在严重小鼠脓毒症模型中，抑制T细胞迁移和诱导外周淋巴细胞减少并不影响存活率。在脓毒症激发期间外周血中T细胞和B细胞数量减少，在我们的严重腹部脓毒症模型中并未对脓毒症死亡率产生负面影响。CASP模型中FTY720治疗下死亡率未增加表明，FTY720治疗可能不会导致脓毒症MS患者死亡率增加。
