Soluble mediators of relapse

摘要 原发性肾小球疾病（如微小病变）复发前最常见的事件 疾病与局灶性节段性肾小球硬化症是普通感冒。治疗疾病 复发是一个漫长的过程，涉及糖皮质激素和其他免疫抑制药物， 具有多系统毒性。我们假设复发是由“细胞因子风暴”引起的， 是由鼻病毒等普通感冒病毒引起的。设计了一种“细胞因子鸡尾酒”， 可溶性鼻病毒受体，并诱导小鼠单次静脉注射后急性蛋白尿 足细胞Zhx2表达较低，这是MCD和FSGS患者的共同特征。这种细胞因子 鸡尾酒由先天性和适应性免疫应答的必要组分组成， 足以引起急性蛋白尿。从细胞因子混合物或注射中排除任何成员 个体成员的尿不会引起蛋白尿。 在这项提案中，我们将制定治疗策略，以防止肾小球疾病复发后， 普通感冒，通过消耗细胞因子风暴中的可溶性细胞因子，或阻断细胞因子风暴中的受体， 肾小球 在目标1中，将进行足细胞中细胞因子耗竭或受体阻断的研究， 确定了受体依赖性和非依赖性机制。 在目标2中，将对内皮细胞和系膜细胞中细胞因子耗竭或受体阻断进行研究。 进行，并确定受体依赖和独立的机制。 在目标3中，将细胞因子耗竭与受体阻断相结合的治疗策略将是： 开发

Abstract The most common event preceding relapse of primary glomerular diseases like Minimal Change Disease and Focal and Segmental Glomerulosclerosis is the common cold. Treatment of disease relapse is a lengthy process involving glucocorticoids and other immunosuppressive medications, some of which have multi-system toxicity. We hypothesized that relapse is induced by a “cytokine storm” that follows infection by common cold viruses like Rhinovirus. A “cytokine cocktail” was designed around the soluble Rhinovirus receptor and induces acute albuminuria after single intravenous injection in mice with low podocyte Zhx2 expression, a common feature in MCD and FSGS patients. This cytokine cocktail comprises of components of the innate and adaptive immune response that are necessary and sufficient to induce acute albuminuria. Exclusion of any member from the cytokine cocktail, or injection of individual members does not induce albuminuria. In this proposal, we will develop therapeutic strategies to prevent relapse of glomerular diseases after a common cold, by depleting soluble cytokines in the cytokine storm, or blocking their receptors in the glomerulus. In Aim 1, studies on cytokine depletion or receptor blockage in the podocyte will be conducted, and receptor dependent and independent mechanisms identified. In Aim 2, studies on cytokine depletion or receptor blockage in endothelial and mesangial cells will be conducted, and receptor dependent and independent mechanisms identified. In Aim 3, a therapeutic strategy that combines cytokine depletion with receptor blockage will be developed.