Activation of aryl hydrocarbon receptor prolongs survival of fully mismatched cardiac allografts

Recent data suggest that activation of aryl hydrocarbon receptor (AhR) by its high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in expansion of regulatory T (Treg) cells and suppresses the development of autoimmune and allergic diseases in several models. Treg cells have been increasingly documented to suppress allograft rejection and even to establish stable long-term graft acceptance. However, the involvement of TCDD in the regulation of solid organ transplantation rejection is largely unknown. Here, we examined whether activation of AhR with TCDD altered cardiac allograft rejection in an allogeneic heart transplant model. Recipient C57BL/6 (H-2b) mice were adminis-trated with a single intraperitoneal injection of TCDD, and the murine cardiac transplant models from BALB/c (H-2d) to C57BL/6 (H-2b) were built 24 h later. The complete cessation of cardiac contractility was defined as the observation endpoint. The effect of TCDD on T-cell proliferation was assessed by mixed lymphocyte reaction (MLR). Histological and immunohistochemical analyses were performed to estimate the severity of rejection. The phenotype and cytokine profile of lymphocytes were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Activation of AhR remarkably prolonged the survival of cardiac allografts to more than 20 days. In vitro, TCDD ugregulated the frequency of CD4+CD25+Foxp3+ Treg cells and suppressed the proliferation of T lymphocytes. In vivo, the prolonged survival time was associated with increased number of Treg cells in allografts and spleens. Furthermore, the secretion of interferon-γ (IFN-γ) and interleukin-17 (IL-17) was reduced to less than 50% of that of the PBS treatment control group by TCDD treatment, whereas IL-10 was elevated to 10-fold of that of the PBS treatment control group. Collectively, our data indicate that activation of AhR with a single dose of TCDD significantly prolonged the survival of fully allogeneic cardiac grafts, and the mechanism underlying this effect might be involved in the induction of Treg cells.     

弓形虫可溶性抗原混合液延长小鼠移植心脏存活时间

目的 探讨弓形虫可溶性抗原混合液(STAgs)延长小鼠移植心脏存活时间的作用及其作用机制.方法 通过在冰浴中超声粉碎弓形虫速殖子制备弓形虫STAgs.实验分为3组,每组受者9只.STAgs组和急性排斥反应(AR)组:供者为Balb/c小鼠,受者为C57BL/6小鼠,移植前4 d两组受者分别皮下注射STAgs 5μg和磷酸盐缓冲液100μl,同系对照组供、受者均为C57BL/6小鼠,术前未进行任何处理.分组后建立小鼠颈部异位心脏移植模型.术后观察移植心脏存活时间,术后第7天每组处死3只受者,获取移植心脏行病理学检查观察排斥反应,采用免疫组织化学检测移植心中CD4+和CD8+T淋巴细胞.结果 同系移植组在观察终点100 d时均存活,AR组和STAgs组移植心脏存活时间分别为(6.7±0.5)和(70.8±3.5)d,3组间两两比较,差异均有统计学意义(P＜0.05).术后第7天,同系移植组、AR组和STAgs组移植心排斥反应分级分别为0级、Ⅲ～Ⅳ级和0～Ⅰ级;免疫组织化学检测显示STAgs组CD4+和CD8+T淋巴细胞比例明显少于AR组,差异有统计学意义(P＜0.05).结论 弓形虫STAgs能显著延长小鼠移植心脏的存活时间,减轻移植心脏的排斥反应,县体机制可能与弓形虫STAgs可影响TH1/TH2比例相关,也可能通过刺激机体产生脂氧素A4抑制树突状细胞活化发挥作用.

Abstract：

Objective To investigate the effects of T. gondii soluble tachyzoite antigen (STAgs) on the survival time of mouse heart allograft and the possible mechanism. Methods The STAgs were prepared by pulverizing T. gondii tachyzoite with ultrasound on ice. Cervical heterotopic heart transplantations were done by using Balb/c mice as donors, and C57BL/6 mice as recipients.The recipients were classified randomly into three groups: syngeneic group, acute rejection group and STAgs-treated group. The recipients in acute rejection group and STAgs-treated group were injected subcutaneously with 0. 1 ml PBS and 0. 1 ml (5 μg) STAgs at the 4th day before transplantation respectively, and those in syngeneic group were not subjected to any treatment. The grafts were observed daily by cervical palpation, and the total cessation of cardiac contraction was defined as the endpoint. The heart allografts were harvested at the 7th day after transplantation for pathological examination and immunohistochemical staining for CD4+ T, CD8+ T. Results The recipients in syngeneic group were all alive at the 100th day after transplantation. The average survival time in acute rejection group and STAgs-treated group was (6.7± 0.5) days and (70.8± 3.5) days,respectively (P＜0.05). HE staining showed that the rejection on the 7th day after transplantation in syngeneic group, acute rejection group and STAgs-treated group was fallen into 0 degree, Ⅲ-Ⅳ degree and 0- Ⅰ degree, respectively. Immunohistochemical staining revealed that the CD4+ T and CD8+T were markedly down-regulated in STAgs-treated group as compared with those in acute rejection group. Conclusion T. gondii STAgs can significantly prolong the survival time of mouse heart allograft and inhibit the rejection probably by changing the ratio of TH1/TH2, or inhibiting the effect of dendritic cells by inducing the lipoxin A4.     

激活芳香烃受体抑制同种异体小鼠心脏移植物急性排斥反应

目的:验证在小鼠心脏移植中,2,3,7,8-四氯二苯二氧芑(TCDD)激活芳香烃受体(AHR)是否可以诱导调节性T细胞(Treg)扩增以及减轻急性排斥反应。方法:建立小鼠心脏移植模型,给予TCDD,观察对排斥反应及移植物生存期的影响。体外实验评估TCDD对Treg细胞比例的影响。检测受者体内Treg细胞比例及白细胞介素(白介素)-10表达水平。结果:TCDD激活AHR明显减轻心脏移植物内急性排斥反应,延长移植物存活时间[MST=(23.5±7.7)d]。体外实验中TCDD明显提升CD4+CD25+Foxp3+调节性T细胞比例[TCDD组(15.3±2.6)%;PBS组(4.7±2.4)%,P<0.01)],而受者体内脾脏和移植物内Treg细胞比例相比对照组也明显升高(P<0.05)。同时,TCDD明显提升了受者体内白介素-10的表达水平。结论:术前单次给予TCDD激活AHR可以明显抑制小鼠同种心脏移植物急性排斥反应,其机制可能与扩增Treg亚群有关。     

胰源性区域性门脉高压症术后并发胃结肠瘘1例

胰源性区域性门脉高压症是肝外型门脉高压症的一种,与门脉高压症一样可以上消化道出血、脾功能亢进为主要临床症状就诊;施行脾切除联合胃贲门周围血管离断术仍是治疗该类疾病的有效方法,但手术难度及术后并发症的发生率较非胰源性门脉高压症高。现将本科室2012年收治的1例胰源性区域性门脉高压症术后并发胃结肠瘘诊治体会报道如下。     

胰腺癌组织ICAM-1、LRG1、TRIM14的表达及临床意义

目的 分析胰腺癌组织细胞间黏附分子-1(ICAM-1)、富亮氨酸α2糖蛋白1(LRG1)、三结构域蛋白14(TRIM14)表达及临床意义.方法 收集2016年3月—2018年3月收治的86例胰腺癌作为研究对象,均通过手术获取癌组织及对应癌旁组织,采用免疫组织化学法测定胰腺癌组织及癌旁组织ICAM-1、LRG1、TRIM...