Heligmosomoides polygyrus bakeri Induces Tolerogenic Dendritic Cells that Block Colitis and Prevent Antigen-Specific Gut T Cell Responses

Abstract

Immunological diseases like IBD are infrequent in less developed countries possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri (Hpb) prevents colitis. It was determined if Hpb mediated IBD protection by altering DC function. We used a Rag IBD model where animals were reconstituted with IL10-/- T cells making them susceptible to IBD and with OVA antigen-responsive OT2 T cells allowing study of a gut antigenic response. Intestinal DC from Hpb-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFNg/IL17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from Hpb-infected mice into Rag mice reconstituted with IL10-/- T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered antigen-nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be Treg independent. Thus, Hpb modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which Hpb suppresses colitis. IFNg and IL17 are colitogenic. The capacity of these DC to block a gut antigen-specific IFNg/IL17 T cell response also is significant.

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

“…DCs typically acquire regulatory properties in the presence of TGF-b (47). Although the effect of HES in our in vitro cocultures was mainly on the T cells, H. polygyrus and the excretory-secretory products are also know to facilitate regulatory and Th2-promoting DC (31,(48)(49)(50). Interestingly, we found that preconditioning the site of BCG infection with TGF-b or HES significantly reduced BCGtriggered migration of DC (MHC-II hi CD11c +/int cells) to the draining LN.…”

Helminth Infections Decrease Host Susceptibility to Immune-Mediated Diseases

“…Compared to DCs from uninfected animals, intestinal DCs after Hpb infection only weakly support antigen-driven IFNγ secretion. Furthermore, DCs isolated from the intestines or MLN of Hpb -infected Rag mice transferred into colitis-susceptible block colitis and mucosal antigen-induced, IFNγ and IL17 responses (27). …”

Helicobacter pylori–specific Protection Against Inflammatory Bowel Disease Requires the NLRP3 Inflammasome and IL-18

“…3 Alternative therapeutic strategies in (pre) clinical development target cytokines involved in IBD pathogenesis (IL-12 and IL-23), the a4b7 integrin involved in lymphocyte homing to the gut, and JAK3 kinase, which is involved in cytokine signaling. 4 Additionally, rather experimental strategies attempt to modulate pathogenic immune responses in models of IBD by the introduction of helminths, such as Heligmosomoides polygyrus 5,6 or Trichuris suis 7,8 or of probiotics (especially Lactobacillus or Bifidobacterium species or the Escherichia coli strain Nissle). 9 Chronic gastric infection with the bacterial pathogen Helicobacter pylori causes gastritis and peptic ulcer disease 10 and represents the most important risk factor for gastric cancer 11,12 but has also been linked inversely to the risk of developing allergic diseases and IBD in large epidemiological studies and Supplemental digital content is available for this article.…”