Mechanisms of Immune Dysfunction and Morbid Outcome in Response to Shock/Sepsis

响应休克/脓毒症的免疫功能障碍和病态结果的机制

• 批准号: 9768788
• 负责人: Alfred Ayala
• 金额: $ 2.43万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768788
• 关键词: Acute Lung Injury; Adoptive Transfer; Animals; Anti-Inflammatory Agents; Antibiotics; Apoptosis; Area; Automobile Driving; Belief; CD8B1 gene; Caring; Cell surface; Cells; Clinical; Clinical Research; Complex; Critical Illness; Data; Development; Diagnosis; Endothelial Cells; Endothelium; Epithelial Cells; Event; Experimental Models; Family; Functional disorder; Gene Proteins; Genetic; Hemorrhagic Shock; Immune; Immune System Diseases; Immune system; Immunologic Memory; Immunosuppression; Individual; Injury; Intensive Care Units; Intervention; Intestines; Leukocytes; Ligands; Liver; Lymphoid; Lymphoid Cell; Mediating; Mind; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Myelogenous; Myeloid Cells; Organ; Outcome; Patient observation; Patients; Phagocytes; Pharmaceutical Preparations; Play; Predisposition; Process; Proteins; Role; Sepsis; Septic Shock; Series; Shock; Supportive care; Surgical Intensive Care; Syndrome; T-Lymphocyte; Therapeutic Agents; Tissues; Traumatic Shock; attenuation; base; comparative; design; improved; inhibitor/antagonist; injured; kidney dysfunction; macrophage; member; mortality; mouse model; neonatal sepsis; neonate; neutrophil; novel; patient population; protein expression; receptor; response; septic; septic patients

Project Summary/Abstract While through efforts like the Surviving Sepsis Campaign, ARDSNet and others, supportive therapies have improved survival of the critically injured and/or septic patient, nonetheless, a substantial number still develop this morbid syndrome and die. Unfortunately, as no true medicinal/ molecular therapeutic agent is presently available to treat the developing immune/ organ dysfunction in these individuals or diagnose/ prognose their trajectory, the need remains to further clarify the complex pathobiology of traumatic shock and/or sepsis so as to identify such agents. In this regard, we have recently uncovered a novel role for a family of cell-associated co-inhibitory receptors, Programmed Cell Death Receptor-1 [PD-1] and B-/T-Lymphocyte Attenuator [BTLA] and their respective ligands, popularly referred to as checkpoint proteins. What our data and information developing in the field tell us is that a number of these receptors may have far more diverse cell/organ targets than those of us historically appreciated. While checkpoint protein expression on CD4/CD8 lymphoid cells has a role in these dysfunctional septic processes, one of the novel observations we have made is that they appear to have unanticipated effects on phagocyte as well as `innate regulatory lymphoid cell' functions that also seems to contribute to the increased susceptibility/ immune suppression in the critically ill injured and/or septic patient/ animal. With this in mind, we propose to examine the following general hypothesis in this MIRA: that the classic co-inhibitory receptor(s), PD-1, BTLA and/or their ligands, play a novel role(s) in regulating the development of shock/septic immune/ organ dysfunction via novel myeloid cell and/or select regulatory lymphoid subset interactions with other immune or non-immune cells present in a given tissue. In the 1st sub-project area we will determine how the select expression of PD-1 or BTLA, on myeloid as opposed to lymphoid cells alters the development of morbid events associated with sepsis; then, how the expression of ligands for these co-inhibitory molecules, on leukocytes and/or endothelial/ epithelial cells, contribute to the onset of septic liver, intestine and/or kidney dysfunction. In our 2nd sub-project area, we will utilize a novel murine model of indirect-acute lung injury (iALI)(dual insults of hemorrhage shock followed by CLP) to ask how checkpoint protein expression not only effect the patho-mechanisms driving the development of iALI, but how are these co-inhibitors altering cell `priming'/'innate immune memory'/function. Finally, (3rd) since the neonate possesses a unique/naïve immune system and is more susceptible to morbid response in the face of infectious challenge; we ask if the expression of members of the PD-1 family and/or their ligands not only have a comparative impact on the response to septic insult, but how it might be mediated? To do this we will interrogate these 3 cogent models of sepsis, shock/sepsis and/or neonatal sepsis, by applying a combination genetic mouse models, adoptive transfer and/or chimeric mouse constructs to examine these questions/ hypotheses along with select observational clinical studies in the critical ill patient population.

项目摘要/摘要 通过诸如尚存的败血症运动，Ardsnet等人的努力，支持疗法已经 尽管如此，急剧受伤和/或化粪池患者的生存率提高了，尽管如此，仍有大量数量发展 这种病态综合征死亡。不幸的是，由于没有真正的药用/分子治疗剂 可用于治疗这些个体中发展的免疫/器官功能障碍或诊断/预测其 轨迹，仍然需要进一步阐明创伤性休克和/或败血症的复杂病理学 识别此类代理。在这方面，我们最近发现了与细胞相关系列的新作用 共抑制受体，程序性细胞死亡受体-1 [PD-1]和B/T淋巴细胞衰减剂[BTLA] 以及它们各自的配体，通常称为检查点蛋白。我们的数据和信息是什么 在现场发展告诉我们，这些受体可能具有更多的潜水细胞/器官目标 比我们历史上那些值得赞赏的。 CD4/CD8淋巴样细胞上的检查点蛋白表达具有 在这些功能失调的化粪池过程中的作用，我们做出的新颖的观察结果之一是 对吞噬细胞以及“先天调节性淋巴样细胞”功能有意外影响 似乎有助于增加严重受伤和/或化粪池的易感性/免疫抑制 病人/动物。考虑到这一点，我们建议在此mira中检查以下一般假设： 经典的共同抑制剂接收器，PD-1，BTLA和/或其配体，在调节中发挥了新作用 通过新型的髓样细胞和/或选择，开发休克/化粪池免疫/器官功能障碍 调节性淋巴样子集与给定的其他免疫或非免疫细胞相互作用 组织。在第1个子项目区域，我们将确定在髓样上的PD-1或BTLA的选择表达方式 与淋巴样细胞相反，会改变与败血症相关的病态事件的发展。然后，如何 这些共抑制分子，白细胞和/或内皮/上皮细胞的配体的表达， 有助于脓毒症，肠和/或肾功能障碍的发作。在我们的第二次小项目中，我们将 利用一种新型的间接急性肺损伤（IALI）的鼠模型（出血冲击的双重侮辱，然后 clp）询问检查点蛋白表达如何不仅影响驱动发展的病情机制 iali，但是这些共同抑制剂如何改变细胞“启动”/“先天免疫记忆”/功能。最后，（第三名） 由于新生儿具有独特/幼稚的免疫系统，并且更容易受到病态反应的影响 传染性挑战的面孔；我们询问PD-1家族和/或其配体成员的表达是否 不仅对化粪池损伤的反应产生了比较的影响，而且如何介导？为此 我们将通过应用A来询问这3种败血症，冲击/败血症和/或新生儿败血症的模型 组合遗传小鼠模型，自适应转移和/或嵌合小鼠构建体以检查这些构建 问题/假设以及重症患者人群中的某些观察性临床研究。