Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 ⁺ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

Abstract

Awareness of the immunological underpinnings of host-parasite interactions may reveal immune signaling pathways that could be used to treat inflammatory disease in humans. Previously we showed that infection with the rat tapeworm, Hymenolepis diminuta, used as a model helminth, or systemic delivery of worm antigen (HdAg) significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice. Extending these analyses, intraperitoneal injection of HdAg dosedependently suppressed dextran sodium sulfate (DSS)-induced colitis, and this was paralleled by reduced gamma interferon (IFN-␥), interleukin-17 (IL-17), and tumor necrosis factor alpha (TNF-␣) production and increased IL-10 production from mitogen-activated splenocytes. Until relatively recently, analysis of the host response to infection with helminth parasites focused almost invariably on TH2 immunity; however, it has emerged that helminth parasites trigger a complex regulatory network in their mammalian hosts that is characterized by cytokines (e.g., interleukin-10 [IL-10] and transforming growth factor ␤ [TGF-␤]) and cellular components (e.g., regulatory macrophages and T cells) (1). Indeed, the development of an immunoregulatory environment likely contributes to the chronicity of helminth infection and asymptomatic disease. Moreover, individuals infected with a variety of species of helminths can be protected from concomitant disease as demonstrated in animal models of multiple sclerosis (2-4), joint (5-7) and gut (8-10) inflammation, and allergy (11, 12). In addition, treatment with somatic extracts or secreted products can significantly attenuate disease severity in models of inflammatory diseases (13-15), raising the possibility that isolation and purification of helminth-derived molecules could result in new anti-inflammatory drugs.The inverse relationship between the geographical distribution of inflammatory bowel disease (IBD) (i.e., Crohn's disease and ulcerative colitis) and areas of endemic helminth infection suggests that infection with helminth parasites may protect against IBD (16). Testing this hypothesis, infections with Trichinella spiralis, Schistosoma mansoni, and Heligmosomoides polygyrus were shown to inhibit inflammation in dinitrobenzene sulfonic acid (DNBS)-and dextran-sodium sulfate (DSS)-induced colitis and piroxicam-treated IL-10 Ϫ/Ϫ mice, respectively (8, 9, 17)-all established mouse models of colitis that share some similarities to human IBD. Similarly, and as an alternative to viable infection, systemic administration of helminth-derived antigens can ameliorate colitis in animal models. As examples, the excretory/secretory (E/S) products from adult T. spiralis reduced DSS-induced colitis (18) and S. mansoni egg antigens ameliorated immunemediated colitis (19): in both instances, suppression of TH1 and TH17 cytokines correlated with the beneficial anticolitic effect. While encouraging, the precise mechanism of action of any helminth-derived extract or molecule to block colitis or other inflammatory dis...

Triggering immunological memory against the tapeworm Hymenolepis diminuta to protect against colitis

“…Corroborating previous data, Hd Ag alone suppressed DNBS‐induced colitis with a threshold dose of ~500 μg (ip.) and was most effective with repeated dosing . We extend these findings, demonstrating subcutaneous, but not intramuscular, administration could block colitis.…”

“…In addition, it will be important to define the mechanistic basis of the memory response that inhibits the colitis. We surmise that this could be via a T‐cell response that mobilizes IL‐10, akin to what we observed with a viable infection, although the possibilities that regulatory T cells or T cell interaction with a regulatory macrophage cannot be overlooked.…”

“…Thus, the questions arises, in a system in which primary infection blocks disease, is the response more rapid with a secondary infection and, more pertinently, can protection be triggered in previously infected mice with helminth antigen. Prior to addressing this issue in the H. diminuta ‐DNBS murine colitis model, there was an additional challenge—a crude extract of the worm is anticolitic in naïve mice: a finding not unlike that from Dwindell et al who reported that extracts of H. diminuta evoked changes in myoelectrical activity in the small intestine of naïve rats.…”

Macrophages treated with antigen from the tapeworm Hymenolepis diminuta condition CD25 + T cells to suppress colitis

“…However, and unlike M (IL‐4) , intraperitoneal delivery of M (HdAg) did not affect the outcome of DNBS‐induced colitis. Intraperitoneal injection of HdAg into mice elicits an MDSC‐like cell, the adoptive transfer (intraperitoneally) of which reduced the severity of DNBS‐induced inflammation (18). The data herein suggest that the MDSC‐like cell develops because of the peritoneal microenvironment after HdAg injection and not solely via HdAg binding to a monocyte/macrophage.…”

“…In addition, given that a variety of regulatory macrophages (M regs ) can suppress colitis (19, 20) and the mobilization of a myeloid‐derived suppressor cell (MDSC) with anticolitic potential after intraperitoneal injection of HdAg (18), we hypothesized that HdAg‐pulsed macrophages would be anticolitic. In testing this, we uncovered that HdAg‐treated macrophages [M (HdAg) ] can mobilize CD4 + CD25 + T cells that can block colitis.…”