Utilizing Immune Phenotypes to Prevent Chronic Critical Illness

利用免疫表型预防慢性危重疾病

• 批准号: 10739888
• 负责人: VANESSA NOMELLINI
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739888
• 关键词: Utilizing; Immune; Phenotypes; Prevent; Chronic

Project Summary While survival rates for critically ill patients during their acute illness continues to improve, the long-term outcomes for these patients are dismal. When ICU survivors progress to a state of chronic critical illness (≥14 days in the ICU), the majority develop significant disability and prolonged recovery times fraught with multiple complications. Ultimately, about 50% eventually succumb to their illness at one year. Unfortunately, once patients progress to a state of chronic critical illness, there is nothing more than supportive care. Given that the healthcare costs required to manage these patients is estimated to be over $20 billion per year, chronic critical illness is creating a new health care crisis. As an ICU physician and basic science researcher, I have the unique ability to both manage these patients at the bedside and actively investigate new ways to improve their care. With all the effort invested in these patients to help them survive their acute illness, it seems like a failure that we are not able to help them long term. The greatest risk factor for the progression to chronic critical illness is the profound immunosuppression that can occur. In the normal response to injury or infection, both the innate and adaptive immune systems deactivate once the inflammatory insult is cleared. However, with a significant insult, such as trauma or sepsis, deactivated immune cells are replaced by more immature cells from the bone marrow that have decreased or suppressive activity and may be unable to effectively eradicate the source. Many have been able to show this immunosuppressed state in critically ill patients, but no one has been able to reverse this response. This proposal synergizes both human and animal studies to better understand the diversities on how individuals respond to a significant injury or infection and attempt to reverse any immunosuppression that may occur. In the first project, four different murine models of injury or infection are utilized and the immune profile of each individual mouse is identified. If they display any type of suppression in their innate or adaptive immune system, or both, specific reversal agents are administered to determine if we can improve their immune response. In the second project, blood samples from critically ill patients admitted to the Surgical ICU are analyzed to determine their immune profiles over the first two weeks of admission. Univariate and multivariate regression analyses will then be performed to determine which immune phenotypes are associated with worse outcomes, with the primary outcome being chronic critical illness. Successful completion of these studies will significantly advance the field of immune phenotypes and set the groundwork for developing individualized immune therapies for a variety of critically ill patients.

项目摘要 虽然重症患者在急性疾病期间的存活率继续提高，但长期而言， 这些患者的结果令人沮丧。当ICU幸存者进展为慢性危重病状态（≥14 在ICU的几天），大多数人发展出严重的残疾和延长的恢复时间， 并发症最终，大约50%的人最终在一年内死于疾病。不幸的是， 病人发展到慢性危重病的状态，除了支持性护理外，别无他法。鉴于 据估计，管理这些患者所需的医疗保健成本每年超过200亿美元， 疾病正在造成新的医疗危机。作为一名ICU医生和基础科学研究人员，我有 独特的能力，既管理这些病人在床边，并积极研究新的方法，以改善他们的 在乎所有的努力都投入到这些病人身上，帮助他们度过他们的急性疾病，这似乎是一个失败 我们无法长期帮助他们。 进展为慢性危重病的最大危险因素是严重的免疫抑制 这是可能发生的。在对损伤或感染的正常反应中，先天性和适应性免疫系统 一旦炎症被清除就会失效然而，如果有严重的损伤，如创伤或败血症， 失活的免疫细胞被来自骨髓的更多未成熟细胞所取代， 抑制活性，并且可能无法有效地根除来源。许多人已经能够证明这一点 重症患者的免疫抑制状态，但没有人能够逆转这种反应。这 该提案将人类和动物研究结合起来，以更好地了解个体如何 对重大损伤或感染作出反应，并试图逆转可能发生的任何免疫抑制。在 第一个项目是利用四种不同的损伤或感染的小鼠模型， 识别个体小鼠。如果他们在先天或适应性免疫系统中表现出任何类型的抑制， 系统，或两者，给予特异性逆转剂，以确定我们是否可以提高他们的免疫力， 反应在第二个项目中，从外科ICU收治的重症患者中抽取血液样本， 分析以确定他们在入院前两周的免疫状况。单变量和多变量 然后将进行回归分析，以确定哪些免疫表型与更差的 结果，主要结果是慢性危重病。成功完成这些研究将 显著推进免疫表型领域，并为开发个体化 免疫疗法用于各种重症患者。