The effect of a novel immunosuppressive drug, a PAK-2 inhibitor, on macrophage differentiation/polarization in a rat small intestinal transplantation model
The effect of a novel immunosuppressive drug, a PAK-2 inhibitor, on macrophage differentiation/polarization in a rat small intestinal transplantation model
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DOI：
10.1016/j.trim.2019.101246
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发表时间：
2019-12-01
影响因子：
1.5
通讯作者：
Okuyama, Hiroomi
中科院分区：
文献类型：
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作者：
Kodama, Tasuku;Maeda, Akira;Okuyama, Hiroomi
目的：据报道，PQA-18（异戊二烯基喹啉羧酸-18）是一种新型免疫抑制剂，可通过抑制 PAK2 来减弱各种细胞因子的产生以及巨噬细胞的分化。在本研究中，我们利用大鼠小肠移植模型，主要研究了该药物对巨噬细胞的作用。方法：分别采用7-9周龄的雄性Dark Agouti (DA)和Lewis大鼠(LEW)作为供体和受体。将约15cm的肠移植物异位移植到受体大鼠体内。从术后第一天起，通过腹膜内注射（ip）对受体大鼠进行 PQA-18（4 mg/kg/天）治疗，持续 2 周。该药物的体内作用是根据体重变化和每种血细胞的数量来评估的。还使用来自 POD6 移植物肠系膜淋巴结 (MLN) 的 T 细胞评估了混合淋巴细胞反应 (MLR)。接下来在 POD6 上收集来自 MLN 和移植 Payer's 补片 (PP) 的总细胞，并测定浸润巨噬细胞的数量。结果：对照组 (n = 9) 的生存时间为 7.0 +/- 0.77 天，而 PQA-18 组的生存时间为 10.7 +/- 1.26 天 (n = 10) (p < .001)。组织学检查显示两组移植物存在相对明显的差异。此外，接受 PQA-18 治疗的受者的 MLR 反应显着较低，表明 PQA-18 很好地抑制了 T 细胞。此外，虽然在对照组中观察到 MLN 和 PP 中 MHC II 类和 CD11b/c 阳性细胞（估计为分化/极化巨噬细胞）显着增加，但 PQA-18 给药显着抑制 MLN 和 PP 中巨噬细胞的分化。结论：PQA-18 显着延长了肠移植大鼠的存活率，并抑制了 淋巴细胞和巨噬细胞浸润至移植物。
Objective: PQA-18 (Prenylated quinolinecarboxylic acid-18) has been reported to be a novel immunosuppressant that attenuates the production of various cytokines, and the differentiation of macrophages by inhibiting PAK2. In this study, we investigated the function of this drug mainly on macrophages using a rat small intestinal transplant model.Methods: Male Dark Agouti (DA) and Lewis rats (LEW), 7-9 weeks of age, were used as donor and recipient, respectively. Approximately 15 cm intestinal grafts were heterotopically transplanted to the recipient rats. The recipient rat was treated with PQA-18 (4 mg/kg/day) by intraperitoneal injection (ip) from postoperative day 1 for 2 weeks. The in vivo effects of this drug were evaluated based on changes in body weight, and the population of each type of blood cell. Mixed lymphocyte reaction (MLR) was also assessed, using the T cells from intestinal mesenteric lymph nodes (MLN) of the grafts on POD6. Total cells from MLN and graft Payer's patch (PP) were next collected on POD6, and the number of infiltrated macrophages was determined.Results: While the survival time was 7.0 +/- 0.77 days for the control group (n = 9), that for the PQA-18 group was 10.7 +/- 1.26 days (n = 10) (p < .001). Histological examinations showed a relatively clear difference in the grafts for both groups. In addition, the MLR response was significantly lower in recipients treated with PQA-18, suggesting PQA-18 well suppressed the T cells. Moreover, while a significant increase of both MHC class II and CD11b/c positive cells, estimated as differentiated/polarized macrophages, in MLN & PP was observed in the control group, PQA-18-administration significantly suppressed the differentiation of macrophages in the MLN & PP.Conclusion: PQA-18 significantly prolonged the survival of the rats with intestinal grafts, and also suppressed the infiltration of lymphocytes, and macrophages to the grafts.