Is Aberrant MO Stimulation Pivotal in Post-Trauma MODS?

异常的 MO 刺激对于创伤后 MODS 至关重要吗？

基本信息

批准号：
7917909
负责人：
Carol L. Miller-Graziano
金额：
$ 17.76万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-24 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917909
关键词：
Apoptosis Apoptotic Autocrine Communication Bacteremia Biological Models Blood Circulation CD47 gene Cause of Death Cell Differentiation process Cell model Cell physiology Cell surface Cells Data Defect Dendritic Cells Development Dioxygenases Down-Regulation Feedback Functional disorder Generations HLA-DR Antigens Host Defense Human Immune Immune response Immunity Immunosuppression Immunosuppressive Agents Individual Infection Inflammation Injury Interleukin-2 Ligands Link Maintenance Mediating Mediator of activation protein Modeling Morbidity - disease rate Multiple Organ Failure Opportunistic Infections Pathology Patients Phenotype Plasma Play Population Production Proteins Recovery Role Self Tolerance Signal Pathway Signal Transduction Simulate Source Stimulus T-Cell Activation T-Lymphocyte Testing Thrombospondin 1 Tissues Trauma Up-Regulation Vent anergy cohort depressed immune depression improved indoleamine lymphocyte proliferation macrophage monocyte mortality new therapeutic target novel public health relevance receptor receptor expression research study

项目摘要

DESCRIPTION (provided by applicant): Post-injury morbidity and mortality results from hypo-responsiveness of both the innate and adaptive immune responses resulting in opportunistic infections & multiple organ failure (MOF). Unique tissue damage released mediators including Thrombospondin-1 (TSP-1), and apoptotic cell products pour into the post trauma circulation. Circulating monocytes' (MO) differentiation progeny, macrophage (Mac) & dendritic cells (DC), play key roles in systemic inflammation, induction of specific immunity, and maintenance of self tolerance. Post injury MO differentiation to appropriately activating or dysfunctional DC depends on circulatory mediator upregulation, downregulation, and triggering of constitutively expressed MO receptors. We hypothesize that tissue derived mediators in the post-trauma microenvironment drive aberrant MO->DC differentiation resulting in subsets of defective DC and semi mature inhibitory DC. Emergence of aberrant MO distinguishable by distinctive receptor expression & altered mediator production should correlate to different post injury pathologies. First, we will determine if post trauma MO differentiation to aberrant DC subsets typifies patients developing MOF and bacteremia with 1) MO that express a unique cohorts of interactive, inhibitory mediators/receptors including TSP-1, CD47, SIRP1, 2) inhibitory DC with low costimulatory receptors increased coinhibitory receptors & altered mediators (TSP-1, TGF2, Indoleamine 2-3 dioxygenase) production which inhibit T lymphocyte proliferation and further appropriate MO->DC differentiation. Two trauma relevant model systems for deviating MO differentiation to inhDC (addition of a mimic of TSP-1 or apoptotic T cells to MO differentiating to DC) are assessed for 1) increased coinhibitor/decreased costimulator and elevated inhibitory mediators paralleling pt aberrant DC, 2) emergence of separate inhibitory & stimulatory subsets in the total inhDC populations which can also be detected in pt inhDC, 3) modulation of MO->inhDC differentiation by maturation stimulus or blocade of specific inhibitory mediators/receptors. Successful model inhDC modulation will then be tested for modulation of pt MO differentiating to aberrant DC. These experiments may 1) reveal how novel mediators cause patient MO->DC differentiation dysfunctions, 2) identify pt MO phenotypes indicative of aberrant DC differentiation capacity and immune pathology, and 3) suggest new therapeutic targets for improving post injury recovery. PUBLIC HEALTH RELEVANCE: Infection and multiple organ failure after traumatic injuries are the 8th leading cause of death and are associated with altered differentiation of the blood monocytes (MO) to dendritic cells (DC) and macrophage. These proposed experiments should reveal 1) how trauma-released inhibitory mediators cause patient MO->DC differentiation dysfunctions, 2) delineate detectible MO/DC surface phenotypes that can identify trauma patients developing immune depression, and 3) implicate new therapeutic targets whose modulation can improve post-injury recovery.

描述（由申请人提供）：损伤后发病率和死亡率是由于先天和适应性免疫反应的低反应而导致机会感染和多器官衰竭（MOF）的。独特的组织损伤释放了包括血小板素-1（TSP-1）的介体和凋亡细胞产物涌入创伤后循环。循环单核细胞（MO）分化后代，巨噬细胞（MAC）和树突状细胞（DC），在系统性炎症，诱导特定免疫和维持自耐力中起关键作用。损伤后的MO分化以适当激活或功能失调的DC取决于循环介质的上调，下调和触发组成型表达的MO受体。我们假设组织中的组织中的介体在后自动环境驱动器中异常 - > dc分化，导致DC和半成熟抑制DC的亚群。通过独特的受体表达和介体产生改变的异常MO的出现应与不同的损伤后病理相关。 First, we will determine if post trauma MO differentiation to aberrant DC subsets typifies patients developing MOF and bacteremia with 1) MO that express a unique cohorts of interactive, inhibitory mediators/receptors including TSP-1, CD47, SIRP1, 2) inhibitory DC with low costimulatory receptors increased coinhibitory receptors & altered mediators (TSP-1, TGF2, Indoleamine 2-3二加氧酶）产生，抑制T淋巴细胞增殖并进一步适当的mo-> dc分化。评估了两个相关的模型系统，以偏离MO分化为INHD（添加TSP-1或凋亡T细胞的模拟物或凋亡T细胞与Mo区分与DC的MO分化）的相关模型。 INHDC，3）通过成熟刺激或特定抑制性介体/受体的成熟刺激或blocade调节mo-> inhDC。然后将测试成功的模型INHDC调制，以调制PT MO与异常DC的区分。这些实验5月1）揭示了新型介体如何引起患者MO-> DC分化功能障碍，2）确定表明异常DC分化能力和免疫病理的PT MO表型，3）提出了改善后损伤后恢复的新治疗靶标。公共卫生相关性：创伤后的感染和多器官衰竭是死亡的第8个主要原因，与血液单核细胞（MO）对树突状细胞（DC）和巨噬细胞的分化改变有关。这些提出的实验应揭示1）创伤性抑制性介质如何引起患者MO-> DC分化功能障碍，2）描述可检测可检测的MO/DC表面表面表型，这些表面表面表面表型可以鉴定出可能患有免疫抑郁症的创伤患者，而3）暗示其适应性的新治疗靶标可以改善后罚后的恢复。