Enteral vs. IV Feeding: Effect on Mucosal Immunity

描述（由申请人提供）：在美国，医院获得性肺炎每年花费高达20亿美元，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保健成本。与静脉（IV-TPN）喂养或饥饿相比，肠内喂养可显著减少创伤患者的感染并发症60-70%。我们的实验和临床工作涉及以前未被认识到的粘膜免疫缺陷，发生在肠道不刺激肠内喂养或肠内喂养的替代品（谷氨酰胺或蛙皮素）。粘膜表面的主要免疫防御是由粘膜相关淋巴组织（MALT）产生的分泌型伊加。免疫致敏的主要解剖部位发生在小肠中的派尔集合淋巴结中，随后将致敏细胞递送至呼吸道和胃肠道。IV-TPN降低了重要粘附分子MAdCAM-1的表达，MAdCAM-1通过其整合素将未致敏的免疫细胞引导至派尔集合淋巴结，随后在派尔集合淋巴结中致敏。整联蛋白随着致敏作用而改变，并且细胞被导向肠和肠外位点，在那里它们产生针对这些抗原的伊加。IV-TPN减少这些部位的T和B细胞，并显著降低伊加水平。伊加通常与细菌结合，防止它们附着并防止它们感染。我们广泛的动物实验表明，肠内喂养通过多种机制维持正常的MALT，包括保护负责粘附分子表达和伊加产生的细胞因子。此外，我们已经表明减少运输伊加穿过分泌上皮。目前的建议集中在细胞归巢和伊加递送的其他方面，包括a）控制趋化因子产生的光敏素β受体的表达，在粘膜免疫中重要的粘附分子和细胞因子，B）营养途径和类型对趋化因子水平的影响，所述趋化因子诱导MALT内含有这些趋化因子受体的细胞的位点特异性迁移，和c）在更好地确定了MALT位点内的细胞谱响应于营养途径和类型、谷氨酰胺或铃蟾肽的特定变化之后，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伊加产生缺陷的能力。这些实验旨在确认肠内刺激的关键需求，以最大限度地发挥粘膜免疫功能，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。

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.