Novel Chemical and Immunological Approaches to Influenza Therapy

描述(申请人提供)：流感病毒仍然是美国和世界关注的主要公共卫生问题。为了最好地确保类似1918-1919年的大流行不会重演，需要国家和国际监测、有效的疫苗和新颖有效的抗病毒治疗。在这里，我们提出了一个多研究所合作研究项目，重点是发现和使用新的化学物质，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有证据表明，对流感的免疫反应(免疫病理学)极大地促进了发病率和死亡率。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，而不是全身给药，在肺内局部作用，特异性抑制抗病毒T细胞增殖反应。我们认为：1)单一的气雾剂暴露于一种鞘氨醇类似物会抑制抗病毒的增殖，从而调节由此产生的免疫病理损伤；2)这一机制将与经典的抗病毒保护疗法协同作用；3)这些治疗方法的组合将在H5N1感染期间保护宿主。为了测试这一建议，在免疫学、药物化学和人类治疗学方面拥有专业知识的休·罗森将继续开发鞘氨醇化合物，并与Michael Oldstone一起进行测试。Michael Oldstone在病毒免疫生物学和使用表达LCMV免疫优势CDS和CD4T细胞表位的WSN重组病毒方面经验丰富。在WSN重组感染之前，将GFP、RFP或Th1.1基因标记的CD4和CDS T细胞转移到这些LCMV表位，从而对肺中的流感特异性T细胞进行定量。使用的LCMV重组和GFP标记的WSN病毒是由该企业的第三个合作伙伴、流感病毒专家河冈义弘制备的。川冈将测试新的鞘氨醇类似物对抗H5N1流感病毒。

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.