Pathophysiology of anti-factor VIII inhibitor development in patients with hemoph

描述（由申请人提供）：中和性抗因子VIII （fVIII）抗体，抑制剂的发展，是影响血友病A （HA）治疗患者最重要的并发症。一旦抑制剂产生，治疗效果就会降低，费用也会增加。虽然抑制剂最常见于严重血凝素患者，但25%的新抑制剂出现在轻度和中度血凝素患者中。迄今为止，旨在了解轻度和中度HA患者抑制剂发展危险因素的研究仅限于回顾性分析，并已确定强化fVIII治疗和手术是危险因素。在一些但不是所有的研究中，通过持续输注fVIII与轻度和中度HA的抑制剂发展有关。因此，评估抑制剂发展风险的下一个合乎逻辑的步骤是前瞻性观察队列研究。如果持续输注fVIII与抑制剂的发展有关，其部分原因可能是促进了更强大的促炎反应。我的长期目标是减少血凝素中新抑制剂的发生率，本应用程序的目的是确定轻度和中度血凝素患者对fVIII的免疫反应如何以及为什么在那些发展和抑制剂的患者和那些没有变化。特异性目的1将检验轻度和中度血凝素患者围手术期给药方法与抑制剂发展相关的假设。为了验证这一点，我们将进行一项多中心前瞻性观察队列研究，纳入140名接受外科手术的轻度和中度HA患者。持续输注fVIII给药与抑制剂发展之间的关系将根据诸如手术类型、手术时间、fVIII水平和先前fVIII暴露程度等混杂变量进行调整。我们预计，在接受持续输注fVIII的受试者中，会形成更大比例的抑制剂。我们还预计，fVIII给药剂量和手术类型将是削弱这种关系的中介因素。特异性目的2将验证接受手术的轻度和中度血凝素患者的抑制剂发展与以下因素相关的假设：1)术后炎症细胞因子的增加和2)向T辅助（TH） 2适应性免疫反应的偏离。我们预计，在术后第7天，促炎细胞因子增加的受试者将主要对fVIII产生TH2反应，并且与促炎细胞因子很少或没有增加的受试者相比，抑制剂发展的比例更高。这些实验的结果将为外科手术中对fVIII的免疫反应提供重要的见解，并为设计治疗策略以减少HA患者抑制剂的发展提供重要的基础免疫学背景。除了完成具体目标外，拟议的职业发展活动将在埃默里大学进行，这是一个强大而富有成效的研究环境，包括：1)指导课程工作，2)参加会议；3)动手实验室技能的发展，以及3)博士的密切指导。罗拉，齐姆林和莫滕斯。这些活动将建立在我目前的实验室和临床研究基础上，并极大地促进我向独立临床研究者的发展。

DESCRIPTION (provided by applicant): The development of neutralizing anti-factor VIII (fVIII) antibodies, inhibitors, is the most significant complication affecting treated patients with hemophilia A (HA). Once an inhibitor develops, treatment is less effective and costly. Although inhibitors occur most commonly in those with severe HA, 25% of new inhibitors occur in patients with mild and moderate HA. To date, studies that seek to understand risk factors for inhibitor development in those with mild and moderate HA have been limited to retrospective analyses and have identified intensive fVIII treatment and surgery as risk factors. Receiving fVIII by continuous infusion has been associated with inhibitor development in mild and moderate HA in some but not all studies. Accordingly, the next logical step to evaluate the risk of inhibitor development is a prospective observational cohort study. If continuous fVIII infusion is associated with inhibitor development, it may be due in part to the promotion a more robust pro-inflammatory response. Toward my long-term goal of reducing the incidence of new inhibitors in HA, the objective of this application is to identify how and why the immune response to fVIII in patients with mild and moderate HA varies between those that develop and inhibitor and those that do not. Specific Aim 1 will test the hypothesis that the method of peri-operative fVIII delivery in subjects with mild and moderate HA is associated with inhibitor development. To test this we will perform a multicenter prospective observational cohort study enrolling 140 subjects with mild and moderate HA undergoing a surgical procedure. The association between fVIII delivery by continuous infusion and inhibitor development will adjusted for confounding variables such as type of surgery, operative time, fVIII level, and extent of prior fVIII exposure. We anticipate that there will be a greater proportion of inhibitors formed in subjects who receive fVIII delivered by continuous infusion. We also anticipate that the dose fVIII delivered and the type of surgery performed will be mediating factors that attenuate this relationship. Specific Aim 2 will test the hypothesis that inhibitor development in patients with mild and moderate HA undergoing surgery is associated with: 1) post-operative increases in inflammatory cytokines and 2) deviation toward a T helper (TH) 2 adaptive immune response. We anticipate that subjects with increased in proinflammatory cytokines on post-operative day 7 will have a predominantly TH2 response to fVIII and a higher proportion of inhibitor development compared with subjects with little or no increase in proinflammatory cytokines. The results of these experiments will provide significant insight into the immune response to fVIII in the setting of surgery and provide important basic immunologic background to facilitate the design of treatment strategies to reduce inhibitor development in patients with HA. In addition to completion of the Specific Aims, the proposed career development activities will take place at Emory University, a robust and productive research environment, and include: 1) directed course work, 2) conference participation; 3) hands-on laboratory skill development, and 3) close mentorship by Drs. Lollar, Zimring and Mertens. These activities will build on my current foundation in laboratory and clinical research and greatly enhance my development toward an independent clinical investigator. PUBLIC HEALTH RELEVANCE: Patients with hemophilia A (HA) have a deficiency factor VIII (fVIII). Some patients develop antibody to replacement fVIII which makes treatment more difficult to treat and costly. In this project, we will develop a better understanding of why some people develop inhibitors to fVIII.