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的费用高达20亿美元，减少这些败血症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，在创伤患者中，肠内喂养显著减少感染并发症60%-70%。我们的实验和临床工作涉及到以前未知的粘膜免疫缺陷，当肠道没有被肠道喂养或通过给予肠道喂养替代品(谷氨酰胺或蛙皮素)刺激时，就会发生这种缺陷。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IgA。免疫致敏的主要解剖部位发生在小肠的Peyer氏斑，随后致敏细胞被输送到呼吸道和Gl管。IV-TPN减少一种重要的黏附分子MAdCAM-1的表达，MAdCAM-1通过整合素引导未致敏的免疫细胞进入Peyer‘s斑块，在那里它们随后被致敏。整合素随着致敏作用的变化而变化，细胞被定向到肠道和肠外部位，在那里它们产生针对这些抗原的IgA。IV-TPN可减少这些部位的T和B细胞，并显著降低IgA水平。免疫球蛋白通常与细菌结合，防止细菌附着和感染能力。我们广泛的动物研究表明，肠内喂养通过多种机制维持正常的麦芽，包括保存负责黏附分子表达和IgA产生的细胞因子。此外，我们还发现免疫球蛋白A通过分泌上皮的转运减少。目前的建议集中在细胞归巢和IgA递送的其他方面，包括a)淋巴毒素β受体的表达，它控制着趋化因子、黏附分子和在粘膜免疫中至关重要的细胞因子的产生；b)营养路线和类型对趋化因子水平的影响，这些趋化因子水平诱导包含受体的细胞在MALT内向这些趋化因子的位点特异性迁移；c)在更好地确定MALT位点内细胞形态的特定变化后，我们将使用近交系小鼠在体内追踪MALT细胞亚群的归巢情况。我们将测试这些细胞逆转损伤后产生的免疫球蛋白A缺陷的能力。这些实验旨在确认肠道刺激的迫切需要，以最大限度地发挥粘膜免疫功能，并进一步确定营养路线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.