Cell Therapy for Septic Shock

描述（由申请人提供）：组织工程和细胞治疗是治疗急性和慢性疾病的一种新的令人兴奋的方法。这种治疗方法的潜在成功在于人们越来越认识到，大多数疾病过程不是由于缺乏单一蛋白质，而是由于多种细胞产物复杂相互作用的改变而发展。细胞疗法依赖于细胞和组织培养方法来扩增特定细胞，以替代在各种疾病状态中紊乱或丢失的重要分化过程。最近的方法通过将细胞放入中空纤维生物反应器或封装膜作为将细胞活性递送给患者的手段而取得了进展。全身炎症反应综合征（SIRS）是一种由各种临床损伤（包括感染、胰腺炎和心肺转流术）引起的灾难性后遗症，每年在美国夺去4万多人的生命。与该综合征相关的异常高的死亡率部分是由于在患有SIRS的患者亚组中发生高致死性多系统器官衰竭综合征（MOF）。与初始损伤部位明显无关的器官系统的相继衰竭与脓毒症中观察到的血浆细胞因子水平改变相关。合并多器官功能衰竭和急性肾功能衰竭的患者死亡率尤其高。本提案计划进行以下实验：1）在猪中建立10-16小时脓毒性休克模型（具体目标1）和2）利用10- 16小时猪模型评估基于生物工程细胞的治疗器械对逆转脓毒性疾病进程的影响（具体目标2）。在该I期项目中积累的数据将允许概念验证，以证明II期计划的实验是合理的，以开发将通过动脉/静脉导管系统进入的微型细胞装置。在II期结束时，开发的临床前数据将用于IND申请，用于该治疗性细胞器械治疗感染性休克的临床试验。相关性：该提案的目标是开发一种基于细胞的治疗方法，可用于逆转与感染性休克患者相关的严重临床事件。该项目的成功将降低脓毒性休克的高死亡率，从而有助于患者从这种毁灭性的疾病过程中康复。

DESCRIPTION (provided by applicant): Tissue engineering and cell therapy are a new and exciting approach to the treatment of acute and chronic diseases. The potential success of this therapeutic approach lies in the growing appreciation that most disease processes are not due to the lack of a single protein but develop due to alterations in complex interactions of a variety of cell products. Cell therapy is dependent on cell and tissue culture methodologies to expand specific cells to replace important differentiated processes deranged or lost in various disease states. Recent approaches have made progress by placing cells into hollow fiber bioreactors or encapsulating membranes as a means to deliver cell activities to a patient. The systemic inflammatory response syndrome, or SIRS, is a catastrophic sequela of a variety of clinical insults, including infection, pancreatitis, and cardiopulmonary bypass, and claims over forty thousand lives in the U.S. each year. The exceptionally high mortality associated with the syndrome is due in part to the development of the highly lethal multiple system organ failure syndrome (MOF) in a subset of patients with SIRS. The sequential failure of organ systems apparently unrelated to the site of the initial insult has been correlated with altered plasma cytokine levels observed in sepsis. The mortality is especially high in patients with MOF and acute renal failure. This proposal plans experiments to accomplish the following: 1) establish a 10-16 hour model of septic shock in the pig (Specific Aim 1) and 2) to assess the influence of a bioengineered cell based therapeutic device to reverse the progression of the septic disease process (Specific Aim 2) utilizing the 10- 16 hour porcine model. The data accrued in this Phase I program will allow for a proof of concept to justify planned experiments in Phase II to develop a miniature cellular device which will be accessed via an arterial/venous catheter system. At the end of Phase II, the developed pre-clinical data will be used for an IND application for the clinical testing of this therapeutic cellular device in treatment of septic shock. Relevance: The goal of this proposal is to develop a cell based therapy that can be used to reverse the serious clinical events associated with patients who develop septic shock. The success of this project would decrease the very high mortality rate of septic shock and therefore contribute to patient recovery from this devastating disease process.