Direct mechanisms of fibrocyte immunotherapy in sepsis

脓毒症纤维细胞免疫治疗的直接机制

• 批准号: 8962221
• 负责人: JEAN A NEMZEK
• 金额: $ 30.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962221
• 关键词: Activities of Daily Living; Adoptive Transfer; Antigens; Automobile Driving; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Therapy; Cells; Cessation of life; Complication; Data; Disease; Environment; Functional disorder; Future; Goals; Health; Human; Immune; Immune System Diseases; Immunobiology; Immunosuppression; Immunotherapy; In Vitro; Intensive Care Units; Interleukin-15; Interleukin-2; Interleukin-7; Investigation; Kinetics; Laboratories; Lead; Leukopenia; Life; Methods; Microbe; Modeling; Mus; Outcome; Patients; Peritonitis; Phagocytes; Phagocytosis; Population; Reporting; Role; Sepsis; Severities; Subgroup; T-Cell Proliferation; T-Lymphocyte; TCR Activation; Testing; Therapeutic; Tissues; Work; base; cell type; combat; cytokine; design; genetic manipulation; improved; in vivo; insight; killings; novel; public health relevance; receptor; research study; response; septic

 DESCRIPTION (provided by applicant): The life-threatening consequences of sepsis have been attributed to immune imbalance or dysfunction. Our laboratories have discovered major immunomodulatory effects from a novel cell transfer therapy that can counteract many of the well-described immune dysfunctions found in sepsis. Specifically, the adoptive transfer of tissue-derived fibrocytes significantly enhances bacterial clearance and increases splenic T cell populations. Based on our preliminary data, the beneficial effects of the cell transfer appear to be direct influences of the fibrocytes. However, the mechansims behind these effects are not clearly understood. Therefore, we hypothesize: Fibrocytes improve sepsis outcomes through direct mechanisms that improve bacterial clearance and cause proliferation of T cells. Our studies will seek functional differences between resident and transferred fibrocytes to help define the benefits of adoptive transfer. These studies will also consider the influences of fibrocyte transfer on other immune cell populations. Specific Aim I will identify the mechanisms for increased bacterial clearance after adoptive transfer of fibrocytes in the CLP model of sepsis, particularly phagocytosis and bacterial killing. Specific Aim II will explore the role of gamma c cytokines in the innate, antigen- independent proliferation and activation of CD4+ and CD8+ T cells in response to fibrocyte transfer during sepsis. Specific Aim III will mark the first investigation of human fibrocytes in sepsis. This aim will characterize the kinetics and functions of human fibrocytes during sepsis as well as determine the effects of sepsis on cultured fibrocytes that could one day be used in cell therapy. Overall, this proposal will further define te mechanisms driving two distinct, beneficial effects of fibrocyte transfer in sepsis. Ultimately, th results would be used to maximize those effects and optimize the application of the adoptive transfer of fibrocytes in sepsis and other diseases.

 描述（由申请人提供）：脓毒症的危及生命的后果归因于免疫失衡或功能障碍。我们的实验室已经发现了一种新型细胞转移疗法的主要免疫调节作用，该疗法可以抵消脓毒症中发现的许多众所周知的免疫功能障碍。具体而言，组织来源的纤维细胞的过继转移显著增强细菌清除并增加脾T细胞群。根据我们的初步数据，细胞转移的有益效果似乎是纤维细胞的直接影响。然而，这些影响背后的机制并不清楚。因此，我们假设：纤维细胞通过改善细菌清除和引起T细胞增殖的直接机制改善脓毒症结局。我们的研究将寻求居民和转移的纤维细胞之间的功能差异，以帮助确定过继转移的好处。这些研究还将考虑纤维细胞转移对其他免疫细胞群体的影响。具体目的我将确定在CLP脓毒症模型中过继转移纤维细胞后增加细菌清除的机制，特别是吞噬作用和细菌杀伤作用。Specific Aim II将探索γ c细胞因子在脓毒症期间响应纤维细胞转移的CD 4+和CD 8 + T细胞先天性、抗原非依赖性增殖和激活中的作用。具体目标III将标志着脓毒症中人类纤维细胞的首次研究。这一目标将表征脓毒症过程中人类纤维细胞的动力学和功能，并确定脓毒症对培养的纤维细胞的影响，这些细胞有朝一日可能用于细胞治疗。总的来说，该提案将进一步定义驱动脓毒症中纤维细胞转移的两种不同的有益作用的机制。最终，这些结果将用于最大化这些效果，并优化纤维细胞过继转移在脓毒症和其他疾病中的应用。