Novel Chemical and Immunological Approaches to Influenza Therapy

描述（由申请人提供）：流感病毒仍然是美国和世界的主要公共卫生问题。为了最好地确保像 1918-1919 年那样的大流行不会再次发生，需要进行国家和国际监测、有效的疫苗以及新颖有效的抗病毒治疗。在这里，我们提出了一个多机构合作研究项目，重点是发现和使用新型化学物质，选择性地操纵肺部的免疫反应，作为更好地控制流感病毒感染的治疗方法。 我们和其他人在动物模型中的证据表明，对流感的免疫反应（免疫病理学）对发病率和死亡率有显着影响。我们有初步但令人印象深刻的数据表明，低剂量的鞘氨醇类似物作为单剂量气管内给药，但不会在肺部局部全身发挥作用，特异性抑制抗病毒 T 细胞增殖反应。我们建议：1）肺部单次气溶胶暴露于鞘氨醇类似物将抑制抗病毒增殖，从而调节由此产生的免疫病理损伤； 2）该机制将与经典的抗病毒保护治疗产生协同作用； 3）这些治疗方法的组合将在H5N1感染期间保护宿主。 为了测试这一提议，拥有免疫学、药物化学和人类治疗学专业知识的 Hugh Rosen 将继续与 Michael Oldstone 一起开发鞘氨醇化合物并进行测试，Michael Oldstone 在病毒免疫生物学和使用表达 LCMV 免疫显性 CDS 和 CD4 T 细胞表位的 WSN 重组病毒方面经验丰富。 WSN 重组感染之前，将 GFP、RFP 或 Th1.1 同源标记的 CD4 和 CDS T 细胞转移到这些 LCMV 表位，从而可以对肺部的流感特异性 T 细胞进行定量。所使用的LCMV重组以及GFP标记的WSN病毒是由该企业的第三位合作伙伴、流感病毒专家Yoshihiro Kawaoka制备的。 Kawaoka 将测试针对 H5N1 流感病毒的新型鞘氨醇类似物。

DESCRIPTION (provided by applicant): Influenza virus remains a major public health concern for the USA and the world. To best insure that a pandemic like the 1918-1919 episode does not reoccur, national and international surveillance, effective vaccine and novel and effective antiviral therapy are required. Here we propose a multi-institute cooperative research project focused on discovery and use of novel chemicals that selectively manipulate the immunologic response in the lung as a therapeutic approach to better control influenza viral infection. We and others have evidence in animal models that the immune response (immunopathology) to influenza contributes significantly to morbidity and mortality. We have preliminary but impressive data that low doses of sphingosine analogs administered as a single dose intratracheally but not systemically acts locally in the lung to specifically suppress antiviral T cell proliferative responses. We propose that: 1) single aerosol exposure of the lungs to a sphingosine analog will inhibit antiviral proliferation thus modulating the resultant immunopathologic injury; 2) this mechanism will synergize with classic antiviral protective therapy; 3) combination of these therapeutic approaches will protect the host during H5N1 infection. To test this proposal Hugh Rosen, with expertise in immunology, medicinal chemistry and human therapeutics, will continue the development of sphingosine compounds and their testing with Michael Oldstone, experienced in viral-immunobiology and use of the WSN recombinant virus expressing immunodominant CDS and CD4 T cell epitopes of LCMV. WSN recombinant infection is preceded with transfer of GFP, RFP or Th1.1 congenically labeled CD4 and CDS T cells to these LCMV epitopes allowing quantitation of flu-specific T cells in the lung. The LCMV recombinant as well as GFP-labeled WSN virus used has been prepared by the third partner in this enterprise, Yoshihiro Kawaoka, an expert in influenza viruses. Kawaoka will test novel sphingosine analogs against H5N1 influenza virus.