Encapsulated Active Vitamin D Vaccine for the Treatment of Multiple Sclerosis

用于治疗多发性硬化症的封装活性维生素 D 疫苗

• 批准号: 8190802
• 负责人: Kristy M Ainslie
• 金额: $ 22.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190802
• 关键词: Acetone; Acids; Adoptive Transfer; Adverse effects; Affect; Alcohols; American; Antigens; Autoimmune Diseases; Autoimmune Process; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Calcitriol; Cell Culture Techniques; Cells; Clinical; Coculture Techniques; Data; Dendritic Cells; Development; Dexamethasone; Dextrans; Disease; Disease Progression; Dose; Emulsions; Encapsulated; Environment; Evaluation; Experimental Autoimmune Encephalomyelitis; Figs - dietary; Flow Cytometry; Freund' s Adjuvant; Glycolates; Goals; Grant; Image; Immune; Immune response; Immune system; Immunization; Immunosuppression; In Vitro; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Lethal Dose 50; Lipopolysaccharides; Lysosomes; Measurement; Measures; Mediating; Metabolic; Methods; Modeling; Multiple Sclerosis; Mus; Myelin Basic Proteins; Nanotechnology; Outcome; Particle Size; Pathogenesis; Patients; Peptides; Phagocytes; Phagocytosis; Phagosomes; Pharmaceutical Preparations; Polymers; Population; Proteins; Rheumatoid Arthritis; Surface; System; Techniques; Technology; Testing; Tissues; Vaccines; Vitamin D; calcification; central nervous system demyelinating disorder; comparative efficacy; cytokine; design; dextran; in vivo; innovation; nano; nanoforms; nanoparticle; novel; particle; prevent; response

DESCRIPTION (provided by applicant): We present a translational method for developing a tolerogenic vaccine to drastically decrease the burden of patients with multiple sclerosis (MS) by using nanotechnology. We hypothesize that nano/microparticles fabricated from the polymer acetalated dextran (Ac-DEX) that encapsulate the active form of vitamin D, and myelin basic protein (MBP) will initiate the formation of MBP specific inducible T-reg cells (iT-regs) capable of suppressing MS in an antigen specific manner. Our project is innovative because: 1.) Passive in vivo targeting: Previous methods to develop tolerogenic DCs to treatment MS require ex vivo manipulation. Phagocytic dendritic cells (DCs) allow passive targeting since the nanoparticles are too large to be taken up by non-phagocytes. Passive targeting leads to in vivo delivery of tolerogenic agents to the DCs, such as the active form of vitamin D (calcitriol). Currently, calcitriol is ineffective at treating MS because at the concentrations necessary to ameliorate the disease, whole tissue calcification is prominent. 2.) Dose sparing: Our preliminary studies indicate that encapsulation of immunomodulatory agents leads to dose sparing. We hypothesize that we will be able to target DCs in vivo and deliver payload intracellularly, thus decreasing the amount of calcitriol needed, thereby preventing tissue calcification. The targeted DCs will become tolerogenic, which will then be capable of inducing the formation of MS suppressing iT-reg cells. 3.) Acid sensitive nanoparticles: Acid sensitive nanoparticles exposed to the acidic environment of the phagocyte lysosome will degrade, releasing the encapsulated antigen and initiating an immune response. We have previously shown that using our pH sensitive polymer Ac-Dex, we can drastically increase both CD4 and CD8 presentation compared to free protein, and protein encapsulated in other common polymeric carriers. 4.) Specific immune dampening: Current methods of MS treatment require non-specific systemic immune suppression. We present a method in which we can generate a MBP specific iT-reg population that can suppress against MS without suppressing the entire immune system. We present preliminary data that shows encapsulation of dexamethasone and MBP peptide results in increased formation of MBP specific iT-regs in the CNS and reduced disease progression with treatment before experimental autoimmune encephalomyelitis (EAE) onset in mice. In order to develop these nanoparticles and test their efficacy we present the following three specific aims: Specific Aim 1 will focus on calcitriol and MBP peptide encapsulation in nanoparticles. Specific Aim 2 will focus on evaluating calcitriol encapsulated nanoparticles in inducing tolerogenic DC and iT-regs in vitro. Specific Aim 3 will be testing the formation of iTregs in vivo by the immunization with co-encapsulated MBP and calcitriol. Finally, by using the EAE model of MS, we will treat mice with our nanoparticles. If successful, we will take the data generated in this grant and apply for an R01. In addition, our nanoparticle system could be applied to other autoimmune diseases such as Type 1 diabetes and rheumatoid arthritis. PUBLIC HEALTH RELEVANCE: Our project has the potential of treating a myriad of autoimmune diseases such as multiple sclerosis and type 1 diabetes. Current treatments of autoimmune diseases systemically suppress the immune system, which have long term side effects. We present a method that targets the autoimmune disease specifically without suppressing the entire immune system.

描述（由申请人提供）：我们提出了一种利用纳米技术开发致耐受性疫苗的转化方法，以大幅降低多发性硬化症（MS）患者的负担。我们假设，由封装活性形式的维生素D和髓鞘碱性蛋白（MBP）的聚合物缩醛化葡聚糖（Ac-DEX）制成的纳米/微米颗粒将启动能够以抗原特异性方式抑制MS的MBP特异性诱导型T-reg细胞（iT-reg）的形成。我们的项目是创新的，因为：1。被动体内靶向：先前开发致耐受性DC以治疗MS的方法需要离体操作。吞噬性树突状细胞（DC）允许被动靶向，因为纳米颗粒太大而不能被非吞噬细胞吸收。被动靶向导致致耐受性剂体内递送至DC，例如活性形式的维生素D（骨化三醇）。目前，骨化三醇在治疗MS方面无效，因为在改善疾病所需的浓度下，整个组织钙化是突出的。2.）的情况。剂量节省：我们的初步研究表明，免疫调节剂的封装导致剂量节省。我们假设我们将能够在体内靶向DC并在细胞内递送有效载荷，从而减少所需的骨化三醇的量，从而防止组织钙化。靶向的DC将成为致耐受性的，其然后将能够诱导MS抑制性iT-reg细胞的形成。3.）第三章酸敏感纳米颗粒：暴露于吞噬细胞溶酶体的酸性环境的酸敏感性纳米颗粒将降解，释放包封的抗原并引发免疫应答。我们之前已经表明，使用我们的pH敏感性聚合物Ac-Dex，与游离蛋白质和包封在其他常见聚合物载体中的蛋白质相比，我们可以显著增加CD 4和CD 8的呈递。4.）特异性免疫抑制：目前的MS治疗方法需要非特异性全身免疫抑制。我们提出了一种方法，其中我们可以产生MBP特异性iT-reg群体，该群体可以抑制MS而不抑制整个免疫系统。我们目前的初步数据显示，地塞米松和MBP肽的封装导致在CNS中MBP特异性iT-T细胞的形成增加，并且在小鼠实验性自身免疫性脑脊髓炎（EAE）发作之前治疗减少疾病进展。为了开发这些纳米颗粒并测试其功效，我们提出了以下三个具体目标：具体目标1将专注于纳米颗粒中的骨化三醇和MBP肽包封。具体目标2将集中于评价骨化三醇包封的纳米颗粒在体外诱导致耐受性DC和iT-T细胞中的作用。Specific Aim 3将通过用共包封的MBP和钙三醇免疫来测试体内iTreg的形成。最后，通过使用MS的EAE模型，我们将用我们的纳米颗粒治疗小鼠。如果成功，我们将使用此资助产生的数据并申请R 01。此外，我们的纳米颗粒系统可以应用于其他自身免疫性疾病，如1型糖尿病和类风湿性关节炎。 公共卫生相关性：我们的项目具有治疗多种自身免疫性疾病的潜力，如多发性硬化症和1型糖尿病。目前对自身免疫性疾病的治疗系统性地抑制免疫系统，这具有长期的副作用。我们提出了一种专门针对自身免疫性疾病而不抑制整个免疫系统的方法。