PREVENTION OF APOPTOTIC CELL DEATH IN SEPSIS BY BCL-2

描述（由申请人提供）：本项目主要研究免疫治疗逆转持续性败血症中宿主免疫功能损害的能力。脓毒症是大多数重症监护病房最常见的死亡原因，也是美国总死亡率的第10大原因。虽然败血症的早期死亡通常是由于过度炎症，但败血症会发展为高度免疫抑制状态。本建议的基本假设是，脓毒症后期发生的许多死亡是由于由此产生的免疫抑制，而增强宿主免疫的治疗将提高生存率。本应用程序研究了两种新的候选药物，即IL-7和抗程序性细胞死亡1 （PD-1）作为败血症的潜在免疫增强疗法。IL-7是一种多种水平的细胞因子，可以提高宿主的免疫力。它主要作用于CD4和CD8 T细胞。IL-7已显示出对病毒、细菌和真菌感染的疗效。第二种将被测试的免疫治疗剂是抗pd -1抗体。PD-1是一种细胞受体，在脓毒症中淋巴细胞表达上调，导致细胞功能抑制。PD-1抗体在几种感染模型中提高了生存率。IL-7和抗pd -1抗体将在临床相关的脓毒症动物模型中测试其提高生存率的能力。此外，研究还将检测IL-7和抗pd -1改善脓毒症患者白细胞功能的能力。该项目的结果将有助于更好地了解败血症中的宿主免疫，并可能为这种高致命性疾病的潜在治疗方法提供见解。

DESCRIPTION (provided by applicant): This project is focused on examining the ability of immune therapy to reverse the impairment in host immune function that occurs in protracted sepsis. Sepsis is the most common cause of death in most intensive care units and the 10th leading cause of overall mortality in the United States. Although early deaths in sepsis are often due to excessive inflammation, sepsis evolves to a highly immunosuppressive state. The underlying hypothesis of the present proposal is that many of the deaths occurring later in the course of sepsis are due to the resultant immunosuppression and that therapy that augments host immunity will improve survival. This application examines two novel drug candidates, i.e., IL-7 and anti-programmed cell death one (PD-1) as potential immune enhancing therapies of sepsis. IL-7 is cytokine that acts at numerous levels to improve host immunity. Its major actions are on CD4 and CD8 T cells. IL-7 has shown efficacy in viral, bacterial, and fungal infections. A second immunotherapeutic agent that will be tested is anti-PD-1 antibody. PD-1 is a cell receptor that is upregulated on lymphocytes in sepsis and causes inhibition of cell function. Antibodies to PD-1 have improved survival in several infectious models. IL-7 and anti-PD-1 antibody will be tested for their ability to improve survival in clinically relevant animal models f sepsis. In addition, studies will also examine the ability of IL-7 and anti-PD-1 to improve white blood cell function in septic patients. The results of this project will lead to a better understanding of host immunity in sepsis and may provide insight into potential therapies of this highly lethal disorder.