Helogmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity

Authors: HANG, LONG - Tufts - New England Medical Center; SETIAWAN, TOMMY - Tufts - New England Medical Center; BLUM, ARTHUR - Tufts - New England Medical Center; Urban, Joseph; STOYANOFF, KORYNN - Tufts - New England Medical Center; REINECKER, HANS - Massachusetts General Hospital; WEINSTOCK, JOEL - Tufts - New England Medical Center

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2010
Publication Date: 9/15/2010
Citation: Hang, L., Setiawan, T., Blum, A., Urban Jr, J.F., Stoyanoff, K., Reinecker, H.C., Weinstock, J. 2010. Helogmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity. Journal of Immunology. 185(6):3184-9.

Interpretive Summary: Mouse models of inflammatory bowel disease (IBD) demonstrated that infection with worms can prevent or ameliorate colitis. These experimental models were designed to test the hypothesis that individuals from industrialized Western countries with few worm infections demonstrate abnormal immune responses that result in IBD compared to individuals in lesser developed countries where worm infections are common and IBD is infrequent. The current studies use a mouse model to investigate how IBD occurs by studying dendritic cells that are important in initiating a type of immune response (T cell) in the intestine that can either prevent or promote IBD. It was observed that mice infected with the worm parasite, Heligmosomoides polygyrus, produced lower amounts of the gene product for important proteins like IFN-g and IL-17 which increase inflammation, and were less able to respond to bacterial products which produce additional pro-inflammatory proteins. The results suggest that therapy, including dietary manipulation, can be used to alter the activity of these dendritic cells in the intestine to improve disease outcome. This work is important to scientists and clinicians that explore treatment and prophylactic procedures to correct intestinal disorders and the absorption of nutrients from the intestine. The impact will be related to better control procedures for inflammatory diseases of the intestine.

Technical Abstract: Less developed countries have a low incidence of immunological diseases like inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections in their populations. In the Rag IL10-/- T cell transfer model of colitis, Heligmosomoides polygyrus (Hp), an intestinal helminth, prevents and reverses intestinal inflammation. This model of colitis was used to explore the importance of innate immunity in Hp protection from IBD. Rag mice briefly exposed to Hp before reconstitution with IL10-/- colitogenic T cells are protected from colitis. Exposure to Hp before introduction of IL10-/- and OT2 T cells reduced the capacity of the intestinal mucosa to make IFN-g and IL17 after either anti-CD3 mAb- or OVA-stimulation. This depressed cytokine response was evident even in the absence of colitis suggesting that the down-modulation in pro-inflammatory cytokine secretion was not just secondary to improvement in intestinal inflammation. Following Hp infection, DCs from the lamina propria of Rag mice displayed decreased expression of CD80 and CD86, and heightened expressions of PDCA-1 and CD40. They also were less responsive to LPS producing less IL12p40 and IL10. Also diminished was their capacity to present OVA to OT2 T cells. These experiments infer that Hp does not require direct interactions with T or B cells to render animals resistant to colitis. DCs have an important role in driving both murine and human IBD. Data suggest that phenotypic alternations in mucosal DC function are part of the regulatory process.