TREATING RESPIRATORY ALLERGY WITH IMMUNOSTIMULATORY DNA

利用免疫刺激寡核苷酸（ISS）上调Th1、下调Th2细胞对过敏原的应答是一种新的变态反应免疫治疗方法。在小鼠中的初步结果表明，某些ISS是这种反应的有效调节剂，并有效治疗呼吸道过敏。不幸的是，虽然小鼠是监测特异性免疫反应的良好模型，但对于人类过敏和哮喘来说，它是一个很差的模型。相比之下，犬的呼吸道过敏似乎与人的呼吸道过敏非常相似，可以为免疫治疗提供有意义的临床终点。在本项目的I期，将检测ISS制剂降低致敏犬肺豚草激发后过敏反应的能力。将检测豚草变应原-ISS结合物的免疫治疗是否诱导Th1型免疫应答（高IgG，低IgE），以及在致敏犬中激发后是否减少肺部过敏症状。如果第一阶段的研究证明是阳性的话。II期研究将继续定义用于预防或治疗对Amb a 1的肺过敏反应的最佳ISS制剂、方案和递送方法，以及ISS或豚草-ISS缀合物在狗模型中的作用的寿命。拟议的商业应用：本研究的目的是开发新的过敏原和免疫刺激寡核苷酸制剂，可用于预防或治疗呼吸道过敏和哮喘。I期可行性的证明将导致研究优化递送途径、剂量、制剂和方案，以及II期活性相关性的研究。狗呼吸道过敏模型中的阳性结果对于决定将这些新型免疫治疗产品用于治疗人类肺部过敏的临床试验非常重要。

A novel approach to immunotherapy of allergy is to use immunostimulatory oligonucleotides (ISS) to up-regulate Th1 and down-regulate Th2 responses to allergens. Preliminary results in mice demonstrate that certain ISS are potent modulators of such responses and are effective in treating respiratory allergy. Unfortunately, while the mouse is a good model for monitoring specific immune responses, it is a poor model for human allergy and asthma. In contrast, respiratory allergy in dogs appears to be very similar to human respiratory allergy and can provide meaningful clinical endpoints to immunotherapy. In the Phase I period of this project, ISS formulations will be tested for their ability to reduce allergic responses upon pulmonary ragweed challenge in sensitized dogs. Immunotherapy with ragweed allergen- ISS conjugate will be tested for induction of Th1-type immune responses (high IgG, low IgE) and reduction of pulmonary allergic symptoms upon challenge in sensitized dogs. If Phase I studies prove positive. Phase II studies would go on to define the optimal ISS formulations, regimens and delivery methods for preventing or treating pulmonary allergic responses to Amb a 1, and longevity of the effects of ISS or ragweed-ISS conjugate in the dog model. PROPOSED COMMERCIAL APPLICATIONS: The goal of this research is to develop novel formulations of allergens and immunostimulatory oligonucleotides that could be used in the prevention or treatment of respiratory allergies and asthma. Proof of feasibility in Phase I would lead to studies to optimize delivery route, dose, formulation, and regimen as well as investigation of correlates of activity in Phase II. Positive results in the dog respiratory allergy model would be important in decisions to move these novel immunotherapy products into clinical testing for treating human pulmonary allergies.