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: 10027933
• 负责人: VANESSA NOMELLINI
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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/10027933
• 关键词: Acute; Adaptive Immune System; Admission activity; Animals; Basic Science; Blood specimen; Bone Marrow; Caring; Cells; Chronic; Critical Illness; Failure; Health Care Costs; Healthcare; Hospitalization; Human; Immune; Immune System Diseases; Immune response; Immunosuppression; Immunotherapy; Individual; Infection; Inflammatory; Injury; Mus; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Recovery; Regression Analysis; Research Personnel; Risk Factors; Sepsis; Source; Supportive care; Survival Rate; Survivors; Time; Trauma; bone cell; disability; immunosuppressed; improved; improved outcome; mouse model; novel; prevent; primary outcome; response; response to injury; wound healing

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.

项目概要 虽然重症患者在急性疾病期间的生存率不断提高，但长期来看 这些患者的结果令人沮丧。当 ICU 幸存者进展至慢性危重疾病状态时（≥14 在重症监护室（ICU）几天），大多数人出现严重残疾，并且恢复时间延长，充满了多种 并发症。最终，大约 50% 的人最终在一年后死于疾病。不幸的是，有一次 当患者发展为慢性危重疾病时，除了支持治疗之外别无他法。鉴于 管理这些慢性危重症患者所需的医疗费用估计每年超过 200 亿美元 疾病正在造成新的医疗保健危机。作为一名 ICU 医生和基础科学研究人员，我有 具有在床边管理这些患者并积极研究改善他们的新方法的独特能力 关心。尽管为这些患者投入了所有努力来帮助他们度过急性疾病，但这似乎是失败的 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 这可能会发生。在对损伤或感染的正常反应中，先天免疫系统和适应性免疫系统 一旦炎症损伤被清除，就停用。然而，如果发生严重的损伤，例如外伤或败血症， 失活的免疫细胞被来自骨髓的更多未成熟细胞所取代，这些细胞已减少或 压制活动可能无法有效根除源头。许多人已经能够证明这一点 危重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相结合，以更好地了解个体如何 对严重损伤或感染做出反应，并尝试扭转可能发生的任何免疫抑制。在 第一个项目使用了四种不同的小鼠损伤或感染模型，以及每种模型的免疫特征 个体小鼠被识别。如果他们的先天或适应性免疫表现出任何类型的抑制 系统或两者，施用特定的逆转剂以确定我们是否可以改善他们的免疫 回复。在第二个项目中，从外科 ICU 收治的危重患者的血液样本 分析以确定他们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免疫表型相关。 结果，主要结果是慢性危重疾病。成功完成这些研究将 显着推进了免疫表型领域的发展，并为开发个体化奠定了基础 针对多种危重患者的免疫治疗。