Splenic Modulation of SHP-2 Activity as a Therapeutic Option for Systemic Lupus Erythematosus

项目总结 系统性红斑狼疮(SLE)是一种以耐受性丧失为特征的多系统自身免疫性疾病 与多种内源性抗原有关，目前还没有治愈的方法。目前SLE患者的治疗选择包括 各种非特异性免疫抑制或抗炎药，具有显著的相关副作用 效果不佳，往往不够充分。因此，开发这种疾病的根治疗法是一项尚未得到满足的巨大需求。 在SLE中，组织损伤通常是由免疫调节信号蛋白的异常表达所介导的。在……里面 特别是，含有Src同源区域2结构域的磷酸酶-2(SHP-2)已被证明增强 疾病活性T细胞的增殖和促进下游细胞因子的产生，每一个都是与生俱来的 与疾病的病理生理学有关。这种磷酸酶在促进系统性红斑狼疮中的重要性一直是 进一步证明，它的抑制，其中系统治疗正常化的许多症状 疾病伴随着寿命的延长。然而，SHP-2在全身都有表达，因此 系统疗法产生偏离目标的效果的可能性很大。脾是最大的次级淋巴组织 器官和免疫反应的主动调节器，其结构旨在增加 罕见的细胞之间的相互作用，特别是同源淋巴细胞和抗原提呈细胞。而脾则 不被认为是SLE的靶器官，它是产生自身抗体和积聚自身抗体的活跃部位 致病细胞，包括DNTCs，它们在全身运输以引起观察到的多器官 损坏。因此，我们假设治疗药物的定位于脾，特别是调节因子 SHP-2，可能足以实现全身治疗效果。为了实现这一点，我们建议利用 经过工程处理的模拟衰老红细胞的纳米杂交物，专门输送小分子抑制剂或 以寡核苷酸为基础的脾环境疗法。如果成功，产生的物质可能会增强 发现治疗系统性红斑狼疮的新的治疗方案，具有提高特异性和 副作用减少。

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by a loss of tolerance to multiple endogenous antigens, for which there is no cure. Current therapeutic options for SLE patients involve a variety of non-specific immunosuppressive or anti-inflammatory agents that have significant associated side effects and are often inadequate. There is thus a great unmet need to develop curative therapies for this disease. In SLE, tissue injury is often mediated by aberrant expression of immunoregulatory signaling proteins. In particular, Src homology region 2 domain-containing phosphatase-2 (SHP-2) has been shown to enhance disease-active T cell proliferation and promote downstream cytokine production, each of which are innately tied to the pathophysiology of the disease. The importance of this phosphatase in the promotion of SLE has been further demonstrated by its inhibition, wherein systemic treatment normalized many of the symptoms of the disease concomitant with an extension of lifespan. Yet, SHP-2 is expressed throughout the body, thus the potential for off-target effects from systemic therapies is great. The spleen is the largest secondary lymphoid organ and an active regulator of the immune response, with a structure designed to increase the likelihood of rare interactions between cells, in particular cognate lymphocytes and antigen-presenting cells. While the spleen is not considered a target organ in SLE, it is an active site for autoantibody generation and the accumulation of pathogenic cells, including DNTCs, which are trafficked throughout the body to elicit the observed multi-organ damage. We thus hypothesize that the localization of therapeutics to the spleen, in particular modulators of SHP-2, may be sufficient to enable a systemic therapeutic effect. To accomplish this, we propose to utilize engineered senescent red blood cell mimetic nanohybrids to specifically deliver small molecule inhibitors or oligonucleotide-based therapeutics to the splenic milieu. If successful, the generated materials may potentiate the discovery of novel therapeutic options for the treatment of SLE with the capacity for increased specificity and decreased side effects.