The effect of a novel immunosuppressive drug, a PAK-2 inhibitor, on macrophage differentiation/polarization in a rat small intestinal transplantation model.,Transplant Immunology

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The effect of a novel immunosuppressive drug, a PAK-2 inhibitor, on macrophage differentiation/polarization in a rat small intestinal transplantation model.
Transplant Immunology ( IF 1.6 ) Pub Date : 2019-09-14 , DOI: 10.1016/j.trim.2019.101246
Tasuku Kodama ₁ , Akira Maeda ₁ , Pei-Chi Lo ₁ , Yuki Noguchi ₁ , Chiyoshi Toyama ₁ , Yuichi Takama ₁ , Takehisa Ueno ₁ , Yuko Tazuke ₁ , Hiroshi Eguchi ₁ , Katsuyoshi Matsunami ₂ , Shuji Miyagawa ₃ , Hiroomi Okuyama ₁

Affiliation

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.

中文翻译：

新型免疫抑制药物PAK-2抑制剂对大鼠小肠移植模型中巨噬细胞分化/极化的影响。

目的

据报道，PQA-18（烯丙基化的喹啉羧酸-18）是一种新型的免疫抑制剂，可通过抑制PAK2减弱各种细胞因子的产生以及巨噬细胞的分化。在这项研究中，我们使用大鼠小肠移植模型研究了该药物主要在巨噬细胞上的功能。

方法

分别使用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至受体大鼠。从术后第1天开始，通过腹膜内注射（ip）将接受大鼠的PQA-18（4mg / kg /天）治疗2周。根据体重和每种血细胞类型的变化评估该药物的体内作用。还使用POD6上移植物的肠系膜肠淋巴结（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和嫁接的Payer贴片（PP）的总细胞，并确定浸润的巨噬细胞的数量。

结果

对照组的生存时间为7.0±0.77天（n  = 9），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的移植物有相对明显的差异。此外，接受PQA-18治疗的受者的MLR反应显着降低，表明PQA-18很好地抑制了T细胞。此外，在对照组中观察到MLN和PP中MHC II类和CD11b / c阳性细胞均显着增加（据估计是分化/极化的巨噬细胞），而PQA-18给药显着抑制了MLN中巨噬细胞的分化＆PP。