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

基本信息

批准号：
9916789
负责人：
Alfred Ayala
金额：
$ 68.49万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
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/9916789
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 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 macrophage member mortality mouse model neonatal sepsis neonate neutrophil novel organ injury patient population protein expression public health relevance receptor response septic septic patients severe injury

项目摘要

DESCRIPTION (provided by applicant): 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, e 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 kidey 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.

描述（由适用提供）：虽然通过败血症运动，Ardsnet和其他人等努力，但支持疗法改善了重伤和/或化粪池患者的生存，尽管如此，仍然有大量数量仍会发展出这种病态的综合征和死亡。不幸的是，由于没有提出真正的药用/分子热层剂来治疗这些个体中发育的免疫/器官功能障碍或诊断/预测其轨迹，因此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，以识别此类药物。在这方面，我们最近发现了与细胞相关的共同抑制受体，程序性细胞死亡受体1 [PD-1]和B-/T-淋巴细胞衰减剂[BTLA]及其各自的配体（通常称为检查点蛋白）的新作用。我们在现场开发的数据和信息告诉我们，这些受体的潜水细胞/器官靶标可能比我们历史上所欣赏的人数要多得多。虽然CD4/CD8淋巴样细胞上的检查点蛋白在这些功能障碍的化粪池过程中具有作用，但我们做出的新型观察结果之一是，它们似乎对吞噬细胞以及“先天调节性淋巴样细胞”的功能似乎也有助于增加。严重受伤和/或化粪池/动物的敏感性/免疫抑制。考虑到这一点，E提出的提议旨在检查该MIRA中的以下一般假设：经典的共同抑制剂，PD-1，BTLA和/或其配体，在确定通过新颖的细胞和/或选择调节性的细胞与其他免疫相互作用或其他不同的脂肪相互作用或不适合其他互相相互作用或不适合其他互相互动来确定冲击/败血性免疫/器官功能在确定冲击/败血性免疫/器官功能方面发挥了新作用。在第一个下区域，我们将确定在髓样细胞上PD-1或BTLA的选择表达如何改变与脓毒症相关的病态事件的发展；然后，这些共同抑制分子的配体在白细胞和/或内皮/上皮细胞上的表达如何有助于败血性肝脏，肠和/或基迪人功能障碍的发作。在我们的第二次下保护区，我们将利用一种新型的间接急性肺损伤的鼠模型（IALI）（IALI）（双重损害出血休克，然后是CLP），询问检查点蛋白表达不仅会影响病原体机能如何促进IALI的发育，还可以使这些共同抑制细胞的发育改变了启动的失败。最后，（第三名）由于新生儿的可能性是一种独特/幼稚的免疫系统，面对感染挑战时，可能更容易受到病态反应。我们询问PD-1家族成员和/或其配体的表达不仅对化粪池损伤的反应有比较的影响，还可以如何介导？为此，我们将通过应用组合遗传小鼠模型，自适应转移和/或嵌合小鼠构建体来检查这3种败血症，休克/败血症和/或新生儿败血症的3个可感染模型，以检查这些问题/假设，以及重症患者的精选临床研究。