Pharmacology and bioengineering of new treatments of ITP

免疫性血小板减少症（ITP）是一种常见的自身免疫性疾病，影响着全球范围内的大量人群;仅在美国，每年就有多达33，000例新发病例。大约25- 30%的慢性ITP患者对标准治疗（皮质类固醇免疫抑制和脾切除术）难治，并且具有致死性出血的高风险。 目前没有可行的替代疗法。 由于在ITP患者中进行研究的困难以及缺乏合适的疾病动物模型，阻碍了新治疗方法的开发。这一建议的主要意义在于它的潜力，开发机制相关的，定量的免疫性血小板减少症的动物模型。 我们实验室在ITP的被动和主动动物模型的开发中取得了非常有前途的结果。 如目标1中所提出的，这些实验模型的进一步验证和完整开发将首次允许对现有和新疗法的疗效进行定量评价。 该项目计划利用动物模型来检查关于慢性ITP有效但不可行的治疗方法的作用机制的假设，即合并免疫球蛋白（IVIG，目标编号2）。 IVIG实现效果的途径的描述可能导致开发具有改进的药学和治疗特性的新疗法。 此外，该提案计划开发和测试两种用于ITP的新疗法：（1）用于抗原特异性去除病原性抗体的新型生物反应器（目标3），预计其比临床批准的ITP治疗方法（例如，蛋白A免疫吸附）;和（2）一种新的脂质体免疫疗法（目的编号4），设计用于改善抗Rho（D）免疫疗法，其被批准用于非脾切除ITP患者作为自身抗体介导的血小板消除的抑制剂。从拟议的研究中收集的发现可能会为治疗ITP和其他自身免疫性疾病的有效组合疗法的设计提供见解，这些疾病作为一个群体，影响超过5000万美国人。

Immune thrombocytopenia (ITP), a common autoimmune disease, affects a large population of individuals worldwide; in the U.S. alone, as many as 33,000 new cases occur each year. Approximately 25-30 percent of chronic ITP patients are refractory to standard therapy (corticosteroid immunosuppression and splenectomy), and are at high risk for fatal hemorrhage. No feasible alternative therapies are presently available. Progress toward the development of new treatments has been impeded by difficulties associated with conducting investigations in ITP patients and by the unavailability of suitable animal models of the disease. A primary significance of this proposal lies in its potential to develop mechanistically relevant, quantitative animal models of immune thrombocytopenia. Extremely promising results have been obtained in our laboratory in the development of passive and active animal models of ITP. Further validation and complete development of these experimental models, as proposed in Aim number 1, will permit, for the first time, quantitative evaluation of the efficacy of existing and new therapies. The project plans to take the advantage of the animal models to examine hypotheses regarding the mechanisms of action of an effective, yet unfeasible therapy of chronic ITP, pooled immunoglobulin (IVIG, Aim number 2). Delineation of the pathways by which IVIG achieves effects may lead to the development of new therapies with improved pharmaceutical and therapeutic characteristics. Furthermore, the proposal plans to develop and test two new therapies for ITP: (1) a novel bioreactor for the antigen-specific removal of pathogenic antibodies (Aim number 3), which is expected to carry significant advantages over clinically approved methods for ITP treatment (e.g., Protein A immuno- adsorption); and (2) a new liposomal immunotherapy (Aim number 4), designed to improve upon anti-Rho(D) immunotherapy, which is approved for use in non-splenectomized ITP patients as an inhibitor of auto-antibody mediated elimination of platelets. Findings gathered from the body of proposed studies may offer insight in the design of effective combination therapy for treating ITP and other autoimmune diseases, which, as a group, affect over 50 million Americans.