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Interleukin-7 Dose-Dependently Restores Parenteral Nutrition–Induced Gut-Associated Lymphoid Tissue Cell Loss but Does Not Improve Intestinal Immunoglobulin A Levels

Kazuhiko Fukatsu, MD, PhD^*, Tomoyuki Moriya, MD, Fumie Ikezawa, MD^*, Yoshinori Maeshima, MD, Jiro Omata, MD, Yoshihisa Yaguchi, MD, Koichi Okamoto, MD, Hidetaka Mochizuki, MD, PhD and Hoshio Hiraide, MD, PhD^*

From the ^* Division of Basic Traumatology, National Defense Medical College Research Institute, Tokorozawa, Japan; Department of Surgery I, Chiba University, Chiba, Japan; and the Department of Surgery I, National Defense Medical College, Tokorozawa, Japan

Correspondence: Kazuhiko Fukatsu, MD, Division of Basic Traumatology, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa, Saitama, Japan, 359-8513. Electronic mail may be sent to fukatsu{at}ndmc.ac.jp.

Background: Without enteral nutrition, the mass and function of gut-associated lymphoid tissue (GALT), a center of systemic mucosal immunity, are reduced. Therefore, new therapeutic methods, designed to preserve mucosal immunity during parenteral nutrition (PN), are needed. Our recent study revealed that exogenous interleukin-7 (IL-7; 1 µg/kg twice a day) restores the GALT cell mass lost during intravenous (IV) PN but does not improve secretory immunoglobulin A (IgA) levels. Herein, we studied the IL-7 dose response to determine the optimal IL-7 dose for recovery of GALT mass and function during IV PN. We hypothesized that a high dose of IL-7 would increase intestinal IgA levels, as well as GALT cell numbers. Methods: Male mice (n = 42) were randomized to chow, IL-7-0, IL-7-0.1, IL-7-0.33, IL-7-1 and IL-7-3.3 groups and underwent jugular vein catheter insertion. The IL-7 groups were fed a standard PN solution and received IV injections of normal saline (IL-7-0), 0.1, 0.33, 1, or 3.3 µg/kg of IL-7 twice a day. The chow group was fed chow ad libitum. After 5 days of treatment, the entire small intestine was harvested and lymphocytes were isolated from Peyer's patches (PPs), intraepithelial (IE) spaces, and the lamina propria (LP). The lymphocytes were counted and phenotypes determined by flow cytometry (βTCR, TCR, CD4, CD8, B cell). IgA levels of small intestinal washings were also examined using ELISA (enzyme-linked immunoabsorbent assay). Results: IL-7 dose-dependently increased total lymphocyte numbers in PPs and the LP. The number of lymphocytes harvested from IE spaces reached a plateau at 1 µg/kg of IL-7. There were no significant differences in any phenotype percentages at any GALT sites among the groups. IgA levels of intestinal washings were significantly higher in the chow group than in any of the IL-7 groups, with similar levels in all IL-7 groups. Conclusions: Exogenous IL-7 dose-dependently reverses PN-induced GALT cell loss, with no major changes in small intestinal IgA levels. IL-7 treatment during PN appears to have beneficial effects on gut immunity, but other therapeutic methods are needed to restore secretory IgA levels.

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