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Enteral vs. IV Feeding: Effect on Mucosal Immunity

肠内喂养与静脉注射喂养：对粘膜免疫的影响

基本信息

批准号：
7780438
负责人：
KENNETH A KUDSK
金额：
$ 28.07万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7780438
关键词：
Acute Anatomic Sites Animals Anti-Bacterial Agents Antibodies Antigen-Presenting Cells Antigens Antiviral Agents B-Lymphocytes Bacteria Binding Biological Models Biological Preservation Bombesin CD4/CD8 ratio procedure Cell Adhesion Molecules Cell surface Cells Chimeric Proteins Clinical Data Defect Diffuse Endothelium Enteral Enteral Feeding Epithelium Genes Glutamine Gut associated lymphoid tissue Health Care Costs Homing Immune Immune system Immunization Immunoglobulin A Immunoglobulin Isotypes Immunologics Impairment Inbred BALB C Mice Inbred ICR Mice Inbred Mouse Infection Injury Integrins Interleukin-10 Interleukin-4 Intestines Intravenous L-Selectin Lamina Propria Ligands Lung Lymphocyte Lymphoid Tissue Mediating Mucosal Immunity Mus NF-kappa B Neuropeptides Nosocomial pneumonia Pathway interactions Patients Phenotype Plasma Cells Pneumonia Polymeric Immunoglobulin Receptors Production Research Personnel Role Route SELL gene Secretory Component Secretory Immunoglobulin A Site Small Intestines Starvation Structure Structure of aggregated lymphoid follicle of small intestine Surface Testing Tissues Trauma Tumor Necrosis Factor-Beta United States Work cell motility cell type chemokine chemokine receptor cost cytokine design feeding in vivo lymphotoxin beta receptor male migration mouse model mucosal site nutrition pathogen prevent programs receptor research study respiratory response response to injury sensitizing antigen septic trafficking

项目摘要

DESCRIPTION (provided by applicant): Hospital acquired pneumonia costs up to $2-billion per year in the United States and inexpensive therapies which reduce these septic complications could greatly impact healthcare costs. Enteral feeding significantly reduces infectious complications compared with intravenous (IV-TPN) feeding or starvation by 60-70% in trauma patients. Our experimental and clinical work implicates previously unrecognized defects in mucosal immunity which occur when the intestinal tract is not stimulated with enteral feeding or by administration of surrogates of enteral feeding (glutamine or bombesin). The principle immunological defense of mucosal surfaces is secretory IgA produced by mucosal-associated lymphoid tissue (MALT). The principle anatomic site for immunologic sensitization occurs in Peyer's patches in the small intestine with subsequent delivery of sensitized cells to the respiratory and Gl tracts. IV-TPN reduces expression of an important adhesion molecule MAdCAM-1 which directs unsensitized immunocytes via their integrins into Peyer's patches where they are subsequently sensitized. The integrins change with sensitization and the cells are directed to both intestinal and extra-intestinal sites where they produce IgA against those antigens. IV-TPN reduces T and B cells within these sites and significantly reduces IgA levels. IgA normally binds to bacteria, preventing their attachment and their ability to infect. Our extensive animal work demonstrates that enteral feeding maintains normal MALT through multiple mechanisms including preservation of cytokines responsible for adhesion molecule expression and IgA production. In addition, we have shown reduced transport of IgA across the secretory epithelium. The current proposal focuses on other aspects of cell homing and IgA delivery including a) the expression of lymphotoxin beta receptor which controls the production of chemokines, adhesion molecules and cytokines important in mucosal immunity b) the effect of route and type of nutrition on levels of chemokines which induce site specific migration of cells containing receptors to these chemokines within the MALT and c) after better defining specific changes in cell profiles within MALT sites in response to route and type of nutrition, glutamine, or bombesin, we will track homing of subpopulations of MALT cells in vivo using inbred mice. We will test the ability of these cells to reverse a defect in production of IgA that occurs after injury. These experiments are designed to confirm the critical need for enteral stimulation to maximize function of mucosal immunity and further define the diffuse effects that route and type of nutrition generates throughout the mucosal immune system.

描述（由申请人提供）：在美国，每年医院获得性肺炎的成本高达20亿美元，而减少这些脓毒性并发症的廉价疗法可能会极大地影响医疗成本。在创伤患者中，与静脉（IV-TPN）喂养或饥饿相比，肠内喂养可显著减少60-70%的感染并发症。我们的实验和临床工作表明，当肠道未被肠内喂养或肠内喂养的代用品（谷氨酰胺或bombesin）刺激时，粘膜免疫就会出现以前未被认识到的缺陷。粘膜表面的主要免疫防御是由黏膜相关淋巴组织（MALT）分泌的IgA。免疫致敏的主要解剖部位发生在小肠的Peyer's斑块，随后致敏细胞被递送到呼吸道和胃肠道。IV-TPN降低了一种重要的粘附分子MAdCAM-1的表达，该分子通过整合素引导未致敏的免疫细胞进入Peyer's补丁，随后使其致敏。整合素随着致敏而改变，细胞被引导到肠道和肠外的部位，在那里它们产生针对这些抗原的IgA。IV-TPN减少这些部位的T和B细胞，并显著降低IgA水平。IgA通常与细菌结合，阻止细菌附着和感染。我们大量的动物实验表明，肠内喂养通过多种机制维持正常的MALT，包括保存负责粘附分子表达和IgA产生的细胞因子。此外，我们还发现IgA在分泌上皮中的转运减少。目前的建议侧重于细胞归巢和IgA递送的其他方面，包括a)淋巴蛋白β受体的表达，该受体控制趋化因子的产生；b)营养途径和类型对趋化因子水平的影响，这些趋化因子诱导含有受体的细胞向MALT内这些趋化因子的位点特异性迁移；c)在更好地定义了MALT内细胞谱对营养途径和类型（谷氨酰胺或bombesin）的响应后，我们将使用近交系小鼠在体内追踪MALT细胞亚群的归巢。我们将测试这些细胞逆转损伤后产生的IgA缺陷的能力。这些实验旨在确认肠内刺激对最大化粘膜免疫功能的迫切需要，并进一步确定营养途径和类型在整个粘膜免疫系统中产生的扩散效应。

项目成果

期刊论文数量（55）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intestinal polymeric immunoglobulin receptor is affected by type and route of nutrition.

DOI：
10.1177/0148607107031005351
发表时间：
2007-09
期刊：
JPEN. Journal of parenteral and enteral nutrition
影响因子：
0
作者：
Y. Sano;F. E. Gomez;W. Kang;J. Lan;Y. Maeshima;J. Hermsen;C. Ueno;K. Kudsk;K. Kudsk
通讯作者：
Y. Sano;F. E. Gomez;W. Kang;J. Lan;Y. Maeshima;J. Hermsen;C. Ueno;K. Kudsk;K. Kudsk

l-selectin and alpha4beta7 integrin, but not ICAM-1, regulate lymphocyte distribution in gut-associated lymphoid tissue of mice.

L-选择素和 α4β7 整合素（但不是 ICAM-1）调节小鼠肠道相关淋巴组织中的淋巴细胞分布。