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，影响着全世界大量的个体；仅在美国，每年就有多达3.3万例新病例发生。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）难以治愈，并且具有致命性出血的高风险。目前还没有可行的替代疗法。由于在ITP患者中进行调查存在困难，并且无法获得适当的动物模型，开发新治疗方法的进展受到阻碍。这一建议的主要意义在于其潜在的发展机制相关，定量的免疫血小板减少动物模型。我们实验室在ITP被动和主动动物模型的开发方面取得了非常有希望的结果。Aim 1中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估。该项目计划利用动物模型来检验关于一种有效但不可行的慢性ITP治疗方法——混合免疫球蛋白（IVIG, Aim 2）的作用机制的假设。描述IVIG实现效果的途径可能会导致开发具有改进的药物和治疗特性的新疗法。此外，该提案计划开发和测试ITP的两种新疗法：(1)用于抗原特异性去除致病性抗体的新型生物反应器（Aim number 3），预计将比临床批准的ITP治疗方法（例如，蛋白a免疫吸附）具有显著优势；(2)一种新的脂质体免疫疗法（Aim number 4），旨在改进抗rho (D)免疫疗法，该疗法已被批准用于未切除脾的ITP患者，作为自身抗体介导的血小板消除抑制剂。从拟议的研究中收集的结果可能为设计治疗ITP和其他自身免疫性疾病的有效联合疗法提供见解，这些疾病作为一个群体影响着5000多万美国人。

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.