Underlying Mechanisms of Protection Involved in Immunocloak.
Underlying Mechanisms of Protection Involved in Immunocloak.
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DOI：
10.1097/tp.0000000000001537
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发表时间：
2017-03
期刊：
影响因子：
6.2
通讯作者：
Stubenitsky B
中科院分区：
文献类型：
--
作者：
Brasile L;Henry N;Stubenitsky B
我们之前报道过一种新型的器官特异性免疫调节疗法，该疗法可以在没有全身免疫抑制药物的情况下提供针对早期同种异体移植排斥的保护。这种新颖的疗法是一种名为“ImmunoCloak”的纳米屏障膜，由层粘连蛋白、蛋白聚糖、纤连蛋白和胶原蛋白的基质组成。该膜通过覆盖供体血管内皮细胞和受体免疫细胞之间的接触点，对肾脉管系统内的管腔表面进行“免疫覆盖”；对肾功能无不良影响。由此产生的非血栓形成和非免疫原性顶端表面比未处理的对照显着延迟了排斥反应的发生 5 倍。目前，我们的重点是阐明放置膜所提供的保护机制。使用人外周血单核细胞评估ImmunoCloak治疗保护作用的机制，并使用Luminex平台通过细胞因子/趋化因子分析测试抗原呈递，通过流式细胞术测量T细胞同种异体反应，并使用transwell板评估血细胞渗出。我们现在报告说，ImmunoCloak 会中断抗原呈递，从而阻止早期 T 细胞激活并干扰血细胞渗出。促炎细胞因子的合成受到显着抑制，并同时阻断 T 细胞介导的反应。 ImmunoCloak 的放置还使白细胞穿过内皮细胞层的迁移显着减少了 93%。在移植后早期消除对肾毒性免疫抑制药物的需求可能有助于改善移植物功能延迟的严重程度，并可能为利用更多缺血性同种异体移植肾提供一条途径。
We have previously reported on a novel organ-specific immunomodifying therapy that provides protection from early allograft rejection in the absence of systemic immunosuppressive drugs. This novel therapy is a nano-barrier membrane called ImmunoCloak, consisting of a matrix of laminin, proteoglycans, fibronectin and collagens. The membrane “immunocloaks” the luminal surfaces within the renal vasculature by covering the point of contact between donor vascular endothelial cells and the recipient’s immune cells; without adversely affecting renal function. The resulting nonthrombogenic and nonimmunogenic apical surface significantly delays the onset of rejection 5-fold over untreated controls. Currently, our focus is to elucidate the mechanisms of protection provided by placement of the membrane. The mechanisms underlying the protective effect of the ImmunoCloak treatment was evaluated using human peripheral blood mononuclear cells and by testing for antigen presentation by cytokine/chemokine analysis using the Luminex platform, T cell allogeneic responses were measured by flow cytometry and diapedesis was assessed using transwell plates. We now report that ImmunoCloak interrupts antigen presentation thereby preventing early T cell activation and interferes with diapedesis. There was significant inhibition in the synthesis of proinflammatory cytokines with a concordant blockade of T cell mediated responses. The placement of the ImmunoCloak also significantly reduced leukocyte migration through the endothelial cell layer by 93%. Eliminating the need for nephrotoxic immunosuppressive drugs during the early posttransplant period could help to ameliorate the severity of delayed graft function and could provide a path to utilizing more ischemically damaged renal allografts.