Regulatory myeloid cells in inflammatory disease: Therapy and targeted generatio

描述(由申请人提供)：慢性炎症越来越被认为是导致多种疾病的原因，但免疫抑制剂的全身应用受到显著的非靶标效应的限制。需要更有针对性的抗炎疗法。鉴于其在调节中的关键作用，DC是理想的目标 体外产生的耐受树突状细胞(TDCs)的免疫和细胞治疗在治疗炎症方面显示出巨大的前景。我们对tDCs的理解以及在炎症性疾病期间体内产生这些tDCs的能力都限制了抗炎tDCs的靶向诱导。我们发现，妊娠特异性激素雌三醇(E3)产生tDCs，可预防实验性自身免疫性脑脊髓炎(EAE)，EAE是慢性炎症性和脱髓鞘疾病多发性硬化症(MS)的动物模型。具有重要治疗意义的是，E3保护MS患者免受复发，并在面临炎症挑战时保护E3 tDCs限制疾病。我们推测，E3‘S的保护作用在很大程度上是通过诱导抑制致病性炎症免疫反应的TDCs来实现的。在这项建议中，我们研究了使用新开发的包裹E3的微粒子(MPS)在体内靶向诱导tDCs(特定目标1)。此外，鉴于TDC在治疗炎症性疾病方面的应用受到我们对TDC诱导机制的了解的限制，我们将研究TDC诱导的雌激素信号通路(特异性目标2)。这种靶向诱导TDC的MP技术的应用，以及对诱导TDC的关键信号通路的更好理解，在许多免疫介导、自身免疫和慢性炎症性疾病中具有直接的治疗应用。

DESCRIPTION (provided by applicant): Chronic inflammation is increasingly being recognized as contributing to a wide array of diseases but systemic administration of immunosuppressive agents is limited by significant off-target effects. There is a need for more targeted anti-inflammatory therapies. DCs are ideal targets given their critical role in regulating immunity and cellular therapy with in vitro generated tolerogenic DCs (tDCs) showing great promise in treating inflammation. Targeted induction of inflammation-resistant tDCs is limited both by our understanding of tDCs and ability to generate these tDCs in vivo during inflammatory disease. We have found that the pregnancy-specific hormone estriol (E3) generates tDCs that protect against experimental autoimmune encephalomyelitis (EAE), an animal model for chronic inflammatory and demyelinating disease multiple sclerosis (MS). Of therapeutic importance, E3 protects MS patients from relapses and E3 tDCs limit disease in the face of inflammatory challenge. We hypothesize that E3's protective effects are mediated largely due to induction of tDCs that suppress pathogenic inflammatory immune responses. In this proposal, we investigate the targeted induction of tDCs in vivo using newly developed microparticles (MPs) encapsulating E3 (Specific Aim 1). Additionally, given that the therapeutic use of tDC to treat inflammatory disease is limited by our understanding of mechanisms involved in tDC induction, we will investigate the estrogenic signaling pathways involved in the induction of tDCs (Specific Aim 2). The application of such MP technology for targeted tDC induction and a better understanding of signaling pathways critical for the induction of tDCs have direct therapeutic applications in numerous immune-mediated, autoimmune and chronic inflammatory diseases.