W. Allan Walker
Director, Mucosal Immunology Laboratory
Massachusetts General Hospital
114 16th Street (114-3503)
Charlestown, MA 02129-4404
The overall mission of this laboratory is to determine the mechanism of “crosstalk” between colonizing bacteria and the developing human intestine immune function. We know from a decade of investigation that for the mucosal immune system in the human intestine at birth to be operational, it must have the stimulus of colonizing bacteria interacting with both epithelial cells and appendages of sub-mucosal dendritic cells extending into the lumen. Using established models for human intestinal development (a fetal cell line, primary fetal enterocytes, organ culture and fetal intestinal xenograft transplants), we have determined that the immature gut produces an excessive inflammatory response to both pathogens and commensal bacteria because of an increased expression of surface toll receptors and an underexpression of negative regulators (e.g., IRAK-M, A-20, etc.). We believe this immaturity of interaction by colonizing bacteria in the human gut accounts for the severe necrotizing enterocolitis which is common in human prematures. Our current studies attempt to define other immaturities in “crosstalk” between colonizing bacteria and the immature human intestine.
Another major project in this laboratory is to determine the effect of human breast milk on the maturation of intestinal host defenses in the immature human intestine. We have published several observations on the effect of hydrocortisone and transforming growth factor beta on inflammation and immune barrier function. These studies use the same human models to determine the mechanism of anti-inflammation by protective nutrients in breast milk.
Chen C-C, Louie S, Shi H, Walker WA. Precolonization with the probiotic lactobacillus acidophilus early in life effectively inhibits murine Citrobacter rodentium colits. Ped Res 2005; 58:1185-1191.
Savidge TC, Newman PG, Pan W-H, Weng M, McCormick, Quaroni A, Walker WA. Lipopolysaccharide-induced human enterocyte tolerance to cytokine-mediated interleukin-8 production may occur independently of TLS-4/MD-2 signalling. Ped Res 2006; 59:89-95.
Chen C-C, Louie S, McCormick B, Walker WA, Shi H. Helminth-primed dendritic cells alter the host response to enteric bacterial infection. J Immunol 2006; 176:472-483.
Rautava S, Nanthakumar NN, Dubert-Ferrandon, Lu L, Rautava J, Walker WA. Breast milk transforming growth factor-β2 specifically attenuates IL-1β-induced inflammatory responses in the immature human intestine via a SMAD6 and ERK-dependent mechanism. Neonatology 2010 (in press).
Lu K, Li T, William G, Petit E, Walker WA. Transcriptional modulation by hydrocortisone of human small intestinal development genes. Am J Phys- Gastroin and Liver Physiol 2010 (in press).
Immunology webpage updated 7/29/2010