Regulatory myeloid cells in inflammatory disease: Therapy and targeted generatio

描述（由申请人提供）：慢性炎症越来越多地被认为是导致多种疾病的原因，但免疫抑制剂的全身给药受到显著脱靶效应的限制。需要更有针对性的抗炎治疗。发展中国家是理想的目标，因为它们在调节 体外产生的致耐受性DC（tDC）的免疫和细胞治疗在治疗炎症中显示出巨大的前景。炎症抗性tDC的靶向诱导受到我们对tDC的理解和在炎症性疾病期间体内产生这些tDC的能力的限制。我们已经发现，妊娠特异性激素雌三醇（E3）产生tDC，保护免受实验性自身免疫性脑脊髓炎（EAE），慢性炎症和脱髓鞘疾病多发性硬化症（MS）的动物模型。具有治疗重要性的是，E3保护MS患者免于复发，并且E3 tDC在面临炎症挑战时限制疾病。我们假设E3的保护作用主要是由于诱导tDC抑制致病性炎症免疫反应而介导的。在该提案中，我们研究了使用新开发的包封E3（特异性目标1）的微粒（MP）在体内靶向诱导tDC。此外，鉴于tDC治疗炎症性疾病的治疗用途受到我们对tDC诱导机制的理解的限制，我们将研究tDC诱导中涉及的雌激素信号传导途径（具体目标2）。应用这种MP技术进行靶向tDC诱导和更好地理解对诱导tDC至关重要的信号传导途径在许多免疫介导的、自身免疫性和慢性炎性疾病中具有直接的治疗应用。 公共卫生相关性：实验性自身免疫性脑炎（EAE）是多发性硬化症的一种疾病模型，目前尚无治愈方法。致耐受性DC（tDC）的诱导是 这是一种治疗这种疾病和其他炎症性疾病的令人兴奋的新方法。目前，这种方法受到我们对tDC的理解以及在炎症性疾病期间体内产生这些tDC的能力的限制。我们的研究表明，雌三醇（E3），产生tDC，保护小鼠免受炎性EAE。在这个建议中，我们使用新开发的微颗粒（MP）封装E3诱导tDC在体内治疗炎症性疾病EAE和研究参与E3 tDC诱导的信号转导机制。这种MP技术的使用和对tDC诱导关键的信号传导途径的更好理解在许多免疫介导的、自身免疫和慢性炎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. PUBLIC HEALTH RELEVANCE: Experimental autoimmune encephalitis (EAE) is a disease model for multiple sclerosis, for which there is no cure. The induction of tolerogenic DCs (tDC) is an exciting new approach for the treatment of this and other inflammatory diseases. Currently, this approach is limited by our understanding of tDCs and by the ability to generate these tDCs in vivo during inflammatory disease. Our studies show that estriol (E3), generates tDCs, which protect mice from inflammatory EAE. In this proposal, we use newly developed micro particles (MPs) encapsulating E3 to induce tDCs in vivo to treat inflammatory disease EAE and investigate the signaling mechanisms involved in E3 tDC induction. The use of such MP technology and a better understanding of signaling pathways critical for tDCs induction has direct therapeutic applications in numerous immune- mediated, autoimmune and chronic inflammatory diseases.