TREATING RESPIRATORY ALLERGY WITH IMMUNOSTIMULATORY DNA

一种新的变态反应免疫治疗方法是使用免疫刺激寡核苷酸(ISS)上调Th1和下调Th2对变应原的反应。在小鼠身上的初步结果表明，某些ISS是这种反应的有效调节剂，在治疗呼吸道过敏方面有效。不幸的是，尽管小鼠是监测特定免疫反应的好模型，但它对人类过敏和哮喘却不是一个好的模型。相比之下，狗的呼吸道过敏似乎与人类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。在该项目的第一阶段，将测试ISS制剂在致敏狗肺豚草攻击时减少过敏反应的能力。豚草变应原-ISS结合物的免疫治疗将在致敏狗身上测试诱导Th1型免疫反应(高免疫球蛋白G，低免疫球蛋白E)和减少攻击时的肺部过敏症状。如果第一阶段的研究证明是阳性的。第二阶段的研究将继续确定用于预防或治疗对AmbA 1的肺部过敏反应的最佳ISS配方、方案和给药方法，以及ISS或豚草-ISS结合物在狗模型中的作用寿命。拟议的商业应用：这项研究的目标是开发可用于预防或治疗呼吸道过敏和哮喘的过敏原和免疫刺激寡核苷酸的新配方。第一阶段的可行性证明将导致进行研究，以优化给药路线、剂量、配方和方案，并调查第二阶段活动的相关性。狗呼吸道过敏模型的阳性结果将对决定将这些新型免疫疗法产品应用于治疗人类肺部过敏的临床测试具有重要意义。

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.