Immuno-modulatory Effects of Parenteral Nutrition After Intestinal Failure

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DESCRIPTION (provided by applicant): Individuals with intestinal failure require long-term parenteral nutrition (LTPN) therapy for survival. LTPN patients are at risk for parenteral nutrition (PN)-associated liver disease, central venous catheter-related septicemia and metabolic bone disease. These conditions suggest LTPN use is associated with chronic inflammatory sequelae and a potential for associated immune dysfunction. While PN animal models support this contention, there are no clinical investigations that have systematically examined the relationship between PN and immune and inflammatory mediators in a stable group of LTPN patients. We hypothesize that LTPN is associated with a cytokine mediated inflammatory process that influences T cell activity and impairs subsequent cellular and humoral defenses. Our long-term goal is elucidation of LTPN-associated events responsible for inflammation and immune dysfunction to allow development of novel therapeutic approaches to attenuate LTPN associated complications. The aims of this R21 proposal are: (Aim 1) To establish whether LTPN patients exhibit a chronic state of inflammation that results in abnormal modulation of cytokines, cytokine receptors and accessory membrane molecules related to immune stress. (Aim 2) To establish whether LTPN patients exhibit altered numbers and responses of T cells through (a) enumeration of (1) T cells, (2) helper and cytotoxic subsets and ratios, (3) the percentage of naive T cells versus effector and memory T cells and (4) the percentage of CD3+CD28(-) T cells and (b) assessment of T cell proliferative responses by mitogen stimulation and co-stimulation through the T cell antigen receptor (CDS) and CD28. (Aim 3) To determine whether LTPN patients exhibit a reduced humoral immune response against Influenza virus vaccine. This study will provide the first comprehensive assessment of stable LTPN patients' inflammatory and immune status. The data obtained will position the research team to develop more mechanistically in-depth RO1 proposals that investigate human patients and a murine PN animal model.