Novel Therapy for Pemphigus Vulgaris by Treatment with a Cholinergic Agonist

描述(申请人提供)：寻常型天疱疮(PV)是一种以皮肤和粘膜为靶点的慢性自身免疫性疾病，特征是上皮内黏液松弛的水泡和糜烂。它是由致病的自身抗体引起的，导致角质形成细胞(KC)相互分离，这一过程被称为棘层松解，并导致在基底层上方形成水泡(Bystryn，2005)。这种疾病的自然病程是渐进的，未经治疗的患者由于脓毒症而在发病几年内死亡(Veldman，2008)。标准疗法(糖皮质激素)可能会有严重的副作用，一些患者没有反应。因此，迫切需要新的治疗方法来治疗这种严重的皮肤病。本申请的目标是开发一种基于17烟碱型乙酰胆碱受体选择性激动剂GTS-21的光伏疗法的新方法。基于胆碱能系统维持表皮动态平衡的已知功能，这种激动剂被预测可以促进稳定的KC凝聚力和逆转棘层松解。GTS-21还有望介导抗炎和免疫抑制作用，部分原因是它在各种模型系统中抑制细胞因子的合成。我们将测试这样的假设，即GTS-21将阻断磷酸化信号事件，该信号事件导致来自PV患者血清(PV IgG)的自身抗体刺激的KCs棘层松解。我们还将测试一种新的理论，即GTS-21将抑制PV IgG诱导的培养的KCs产生细胞因子(TNF-1和IL-11)，这些细胞因子通常促进棘层溶解过程。GTS-21预防静脉注射免疫球蛋白引起的KC凝聚力丧失的能力将在体外棘层松解试验中进行测试。将使用新生小鼠PV模型来评估GTS-21预防静脉注射免疫球蛋白引起的皮肤起泡和棘层松解的效果。这些研究的结果将为该药物未来的商业化提供基础，最终导致在PV患者中进行临床试验。与标准疗法相比，GTS-21具有独特的作用机制，对标准疗法无效的患者可能特别有用。公共卫生相关性：该项目的目标是开发一种新的治疗危及生命的皮肤病--寻常型天疱疮的方法。

DESCRIPTION (provided by applicant): Pemphigus vulgaris (PV) is a chronic autoimmune disease targeting skin and mucous membranes, characterized by intraepithelial aphlegmasic flaccid blisters and erosions. It is caused by pathogenic autoantibodies that induce the separation of keratinocytes (KC) from one another, a process known as acantholysis, and leads to the formation of blisters just above the basal layer (Bystryn, 2005). The natural course of the disease is progressive with death occurring within a few years of onset due to sepsis in untreated patients (Veldman, 2008). The standard therapy (glucocorticosteroids) can have severe side effects, and some patients do not respond. Therefore there is a great need for new therapeutic approaches for this serious skin disease. The goal of this application is to develop a novel approach to PV therapy based on the 17 nicotinic acetylcholine receptor selective agonist, GTS-21. This agonist is predicted to promote stable KC cohesion and reverse acantholysis, based on the known function of the cholinergic system to maintain epidermal homeostasis. GTS-21 is also expected to mediate anti-inflammatory and immunosuppressive effects in part due to its well-documented suppression of cytokine synthesis in various model systems. We will test the hypothesis that GTS-21 will block phosphorylation signaling events that lead to acantholysis in KCs stimulated with autoantibodies derived from PV patient serum (PV IgG). We will also test a new theory that GTS-21 will inhibit PV IgG-induced production of cytokines (TNF-1 and IL-11) from cultured KCs that normally promote the acantholytic process. The ability of GTS-21 to prevent IV IgG-induced loss of KC cohesion will be tested in an in vitro acantholysis assay. A neonatal mouse model of PV will be used to evaluate the efficacy of GTS-21 to prevent IV-IgG-induced skin blistering and acantholysis. The findings of these studies will provide the basis for future commercialization of this drug, ultimately leading to clinical trials in PV patients. GTS-21 has a unique mechanism of action compared to standard therapies for PV and may be especially useful for patients refractory to standard therapies. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a novel therapy for the life-threatening skin disease, pemphigus vulgarus.