Novel Immunotherapy of African Trypanosomiasis

非洲锥虫病的新型免疫疗法

• 批准号: 7534762
• 负责人: John M. Mansfield
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534762
• 关键词: Affect; African; African Trypanosomiasis; Agonist; Animals; Antigenic Variation; Antigens; Biological; Cells; Data; Defect; Disease; Elements; Event; Gene Activation; Generations; Genes; Genetic; Host resistance; Human; Image; Immune; Immune system; Immunity; Immunosuppression; Immunotherapy; Individual; Infection; Infection Control; Interferons; Investigational Therapies; Kinetics; Lead; Link; Measures; Methods; Microarray Analysis; Monitor; Mus; Natural Immunity; Parasite Control; Parasites; Parasitic Diseases; Pathway interactions; Production; Public Health; Relative (related person); Research Project Grants; Resistance; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Therapeutic Effect; Time; Tissues; Trypanosoma; Trypanosoma brucei rhodesiense; Trypanosomiasis; base; chemotherapy; disorder control; genetic linkage; innovation; novel; novel therapeutic intervention; resistance mechanism; response

DESCRIPTION (provided by applicant): This is an exploratory research grant that develops a novel therapeutic approach for treating African trypanosomiasis, a fatal human parasitic disease that has proven intractable to conventional immunotherapy. The present proposal examines the novel and exciting result that CpG oligodeoxynucleotide (ODN) treatment significantly enhances host resistance to trypanosomiasis. The biological effects include a marked increase in host survival, decreased parasite burden, enhanced innate and adaptive immunity, and alterations in parasite cellular differentiation. Therefore, the aims of this proposal are to elucidate the kinetics, breadth and the underlying mechanism of optimal CpG ODN therapy of experimental trypanosomiasis. Specific Aim 1 examines CpG ODN-induced alterations in the infected host by measuring control of trypanosome tissue invasion, tissue-specific gene activation, innate immune cell stimulation, and parasite- specific B and T cell responses. Specific Aim 2 tests the mechanistic hypothesis that amplification of the TLR9-, MyD88- and IRF7-dependent Type I IFN (IFN-1/2) pathway underlies CpG ODN enhancement of host resistance. An alternative hypothesis is also presented in which CpG ODN treatment amplifies innate immune system production of Type II IFN (IFN-3) which regulates trypanosome long-slender to short-stumpy cellular differentiation and host resistance. Overall, these novel and exciting studies provide a new therapeutic approach to controlling African trypanosomiasis that avoids many of the issues complicating current therapy of this disease.Project Narrative This exploratory project proposes an innovative approach to the control or cure of African trypanosomiasis, a fatal human parasitic disease. Successful completion of the aims will enable public health officers to treat trypanosome infected individuals with CpG oligodeoxynucleotides which will activate critical components of the innate immune system to control the disease.

描述（由申请人提供）：这是一项探索性研究资助，旨在开发一种治疗非洲锥虫病的新型治疗方法，这是一种致命的人类寄生虫病，已被证明是传统免疫疗法难以治愈的。本提案探讨了新的和令人兴奋的结果，CpG寡脱氧核苷酸（ODN）治疗显着增强宿主的抗锥虫。生物学效应包括显著增加宿主存活率、减少寄生虫负担、增强先天免疫和适应性免疫以及改变寄生虫细胞分化。 因此，本研究的目的是阐明最佳CpG ODN治疗实验性锥虫病的动力学、广度和潜在机制。特异性目的1通过测量锥虫组织侵入、组织特异性基因激活、先天性免疫细胞刺激和寄生虫特异性B和T细胞应答的控制来检查感染宿主中CpG ODN诱导的改变。特异性目的2测试了TLR 9-、MyD 88-和IRF 7-依赖性I型IFN（IFN-1/2）途径的扩增是CpG ODN增强宿主抗性的基础的机制假设。另一种假设是，CpG ODN治疗放大了先天免疫系统产生的II型IFN（IFN-3），调节锥虫细长短的细胞分化和宿主抗性。 总的来说，这些新的和令人兴奋的研究提供了一种新的治疗方法来控制非洲锥虫病，避免了许多复杂的问题，目前这种疾病的治疗。 这一探索性项目提出了一种控制或治愈非洲锥虫病（一种致命的人类寄生虫病）的创新方法。成功完成这些目标将使公共卫生官员能够用CpG寡脱氧核苷酸治疗锥虫感染者，这将激活先天免疫系统的关键组成部分，以控制疾病。