Search

We have investigated the influence of mast cells on the barrier function of intestinal epithelium during nematode infection.Trichinella spiralisinfection induces a strong type 2 cytokine-mediated inflammation, resulting in a critical mucosal mastocytosis that is known to mediate expulsion of the parasites from the intestine. The host response to infection is also characterized by an increase in mucosal leakiness. We show here that intestinal epithelial permeability is markedly elevated during infection, with kinetics that mirror the adaptive immune response to primary and secondary infection. Furthermore, we have identified degradation of the tight junction protein, occludin, thereby providing a mechanism for increased paracellular permeability during helminth infection. We further demonstrate by using anti-c-kitantibody and IL-9 transgenic mice that mast cells are directly responsible for increasing epithelial paracellular permeability and that mice deficient in a mast cell-specific protease fail to increase intestinal permeability and fail to expel their parasite burden. These results provide the mechanism whereby mucosal mast cells mediate parasite expulsion from the intestine.

The BALB/c mouse immunized sub-cutaneously (s.c.) with 45 kRad attenuated third stage larvae (L3) of the lymphatic filarial nematode Brugia pahangi is strongly immune to a challenge infection (75-100% reduction in recovery at day six post challenge). Analysis of spleen cell supernatants from immunized mice re-stimulated in vitro, with parasite antigen or the non specific T cell mitogen Con-A reveals a cytokine profile (IL-4, IL-5 and IL-9) which indicates that the Th2 subset of CD4 cells has been expanded. In an attempt to formally prove a critical role for CD4 cells in immunity in this model system, immunized mice were given either anti-CD4 or anti-CD8 neutralizing antibodies. Administration of anti-CD4 antibody had a significant and detrimental effect on the immune response whereas anti-CD8 antibody had a negligible effect on immunity. The efficacy of antibody in neutralizing their target cells was determined by fluorescence activated cell sorting analysis (FACS). Spleen cells from anti-CD4 treated immunized mice, when re-stimulated with parasite antigen had a significantly reduced potential to secrete IL-4, IL-5 and IL-9 in vitro and serum from these mice had reduced levels of parasite specific IgG and IgE. These results demonstrate a critical role for CD4 T cells in host protective immunity to B. pahangi in vivo and strongly suggest that some component of the Th2 response plays an important role in the immune response elicited in this model system.

Resolution of infection with the intestinal nematode Trichinella spiralis depends on the host mounting a T helper 2 (Th2) response. It is known that both mast cells and T cells play a crucial role. We have previously shown that efficient migration of mast cells to the gut during infection depends on their expression of the integrin beta 7. beta 7 forms a heterodimer complex with either alpha E or alpha 4 integrin chains, alpha E beta 7 binding to E-cadherin expressed by epithelial cells and alpha 4 beta 7 binding to mucosal addressin cell adhesion molecule (MAdCAM-1) on the endothelium. We were interested to know whether dysfunctional mast cell localization to the gut in the absence of beta 7 was due to the failure of alpha 4 beta 7 to bind to MAdCAM-1 or the failure of alpha E beta 7 to bind to E-cadherin. We used blocking monoclonal antibodies against alpha E (M290) or alpha 4 (PS2) or beta 7 (HB293) during T. spiralis infection of C57BL/6 mice and found that all antibody treatments reduced mastocytosis. In contrast, none of the antibody treatments prevented the migration of CD3(+) T cells into the intestine. These results indicate that during inflammation (a) there is integrin redundancy for lymphocytes but not for mast cells and (b) both alpha E beta 7 and alpha 4 beta 7 are crucial either for the entry of mast cells into the gut or for their maturation once they have entered.

Intestinal nematode infection is one of the most common forms of parasite infection worldwide. Both man and domestic stock suffer considerable morbidity from these infectious agents. The majority of our current understanding of the host parasite relationship to gut dwelling nematodes comes from well-defined laboratory models. One of the most informative over recent years has been study of whipworm infection in the mouse, Trichuris muris (T. muris). Infection in inbred strains of mouse shows a spectrum of response phenotypes reflecting the variation observed under natural conditions in the wild. Resistance and worm expulsion is mediated by CD4+ T helper two cells with a dominant role for interleukin (IL)-13. The effector mechanisms responsible for worm expulsion remain undefined but new evidence suggests a role for tumour necrosis factor alpha (TNF-alpha). Susceptibility to chronic infection is mediated through a T helper 1 (Th1) response characterised through the secretion of interferon gamma (IFN-gamma). A major new role for IL-18 has been defined in induction of a Th1 response through a novel down-regulation of IL-13. Moreover, progression to chronic infection may involve the parasite itself. T. muris secretes a protein that shares epitopes with host IFN-gamma, which may interfere with host protective cytokine, mediated protection and thus, promotes its own survival.

Production of neutralizing anti-IL-9 antibodies was induced in mice by immunization with mouse IL-9 coupled to ovalbumin. In the six mouse strains tested, a strong and long-lasting anti-IL-9 response developed with seric inhibitory titers of 10−3to 10−5, as measured in anin vitroIL-9-dependent cell proliferation assay.In vivo, this immunization completely abrogated the increase in mast-cell protease-1 levels as well as the eosinophilia observed in mice after implantation of an IL-9-secreting tumor. We took advantage of this method to assess the role of IL-9 in infections with nematodeTrichuris muris, where IL-9 production correlates with the resistant phenotype. C57BL/6 mice, which normally expel the parasite, became susceptible after anti-IL-9 immunization, demonstrating that IL-9 plays a critical role in this model. In addition, neutralization of IL-9 also inhibited parasite-induced blood eosinophilia. Taken together, the present data demonstrate the potency of our strategy to antagonize IL-9in vivoand shows that this cytokine plays a major role in resistance againstT. murisinfection.

Chronic infection with the intestinal nematode Trichuris muris is associated with an inappropriate type 1 cytokine response (production of predominantly IFN-gamma), whereas resistance to infection requires the induction of a protective type 2 response with the production of interleukin (IL)-4, IL-5, IL-9, and IL-13. T. muris inhabits an intracellular niche within murine intestinal epithelial cells of the caecum and in common with other intestinal helminth infections is associated with gross morphological changes in gut architecture. The purpose of this study was to characterise cytokine production during chronic infection in AKR and severe-combined-immunodeficient (SCID) mice and investigate what effect the anti-parasite response had on epithelial cell proliferation and so regulation of intestinal pathology. Pulse labeling with tritiated thymidine is employed to generate a sensitive cell position-linked proliferation index of the intestinal epithelium at various times postinfection. Infection in AKR mice is characterized by a marked elevation in antigen specific IFN-gamma production from restimulated mesenteric lymph node cells and a significant increase in proliferation of pluripotent epithelial stem cells and transit cells within the crypts. Similarly, elevated IFN-gamma production was observed in the mesenteric lymph nodes and intestinal mucosa of infected SCID mice, with epithelial cell hyperproliferation and the development of crypt hyperplasia in the caecum. Critically, in vivo depletion of IFN-gamma during infection in SCID mice resulted in no significant increase in epithelial cell proliferation and effectively precluded the development of crypt hyperplasia without altering infection outcome. Taken together, the data provides the first detailed cell position linked analysis of epithelial dysregulation during chronic T. muris infection and identifies a critical role for IFN-gamma, either directly or indirectly, in regulation of epithelial cell proliferation during the chronic intestinal inflammation associated with infection.

Macrophage-migration-inhibition factor (MIF) is an essential stimulator of mammalian T-lymphocyte-dependent adaptive immunity, hence MIF orthologues might be expressed by infectious organisms as an immunosubversive stratagem. Since MIF actively catalyses the tautomerization of the methyl ester of l-dopachrome (using dopachrome tautomerase), the occurrence of MIF orthologues in several parasitic helminths was investigated by assaying and characterizing such activity. Evidence of MIF orthologues (dopachrome tautomerase) was found in the soluble fraction of the nematodes Trichinella spiralis (stage 4 larvae) and Trichuris muris (adults), and the filarial nematode Brugia pahangi (adults). The MIF orthologues of Tr. muris(TmMIF) and B. pahangi (BpMIF) were purified to homogeneity using phenyl-agarose chromatography, that of T. spiralis (TsMIF) required a further step: cation-exchange FPLC. Retention time on reverse-phase HPLC and Mr on SDS/PAGE of the nematode MIFs were similar to those of human MIF. N-terminal sequences (19 residues) of TsMIF and TmMIF showed 47 and 36% identity, respectively, with human MIF. The N-terminal sequence of BpMIF (14 residues) was identical to that of an MIF orthologue in the genome of B. malayi (Swiss-Prot, P91850) and showed 43% identity to either human or TsMIF. TsMIF had 10-fold higher dopachrome tautomerase activity than MIF from the other sources. The enzyme activities of TsMIF, BpMIF and TmMIF were less sensitive to inhibition by haematin (I50: > 15 µM, > 15 µM and 2.6 µM, respectively) than that of human MIF (I50 0.2 µM). Significant dopachrome tautomerase or phenyl-agarose-purifiable MIF-like protein was not detected in the soluble fraction of the nematodes Heligmosomoides polygyrus and Nippostrongylus brasiliensis, the cestode Hymenolepis diminuta, or the trematodes Schistosoma mansoni, S. japonicum and S. haematobium, or the free-living nematode, Caenorhabditis elegans, which does contain an MIF-related gene.

Resistance and susceptibility to the intestinal parasite Trichuris muris has been shown to be due to a dominant T helper 2 (Th2) and a dominant Th1 response, respectively. The factors determining the initial polarization of the immune response remain largely unresolved, although the cytokine environment at the time of antigen presentation clearly plays an essential role. Interleukin (IL)-12, a cytokine produced mainly by macrophages, dendritic cells, and other monocytes has been shown to be important in driving a strong Th1 response by stimulating the production of interferon (IFN)-gamma from natural killer and Th0 cells and therefore forms a link between the innate and adaptive immune system. IL-12 has been shown to play an important role in resistance to a number of intracellular pathogens, including Listeria and Leishmania. It has also been proposed as an anti-tumor agent and for use in the treatment of HIV. Conversely, IL-12 has been shown to prolong the survival of Nippostrongylus brasiliensis and to accelerate autoimmunity. Our studies demonstrate that by driving a strong Th1 response, IL-12 promotes chronic T. muris infection when given to normally resistant BALB/K mice. Parasite-specific IgG2a, a Th1 parameter of infection, was greatly up-regulated, whereas some Th2 parameters of infection were down-regulated. IL-12 treatment could be delayed until 1 week after infection had started and still promote a strong Th1 response. The actions of IL-12 in promoting a chronic infection were IFN-gamma dependent as an anti-IFN-gamma mAb abrogated the effects of IL-12.

Chronic infection is a prominent feature of many intestinal nematode infections in man and animals. It is also clear that in such situations host immunity is activated but is unable to induce a protective response. A great deal of work has shown that genetic control of host immunity contributes to the variation in worm burdens often observed in the field. There is increasing appreciation, however, of the capability of infectious agents themselves to modulate the host immune response and potentiate their own survival. Using an immunologically well defined model of intestinal nematode infection in mice (Trichuris muris) we have shown that parasite derived molecules share cross reactive epitopes with the host cytokine interferon-γ using cytokine specific monoclonal antibodies in ELISA, Western blotting and immunoprecipitation assays. Furthermore, the parasite molecules can be shown to bind to the interferon-γ receptor and induce change in lymphoid cells similar to those induced by murine interferon-γ. The functional activity of the molecule in vivo remains to be determined. Previous studies have established that interferon-γ is critical for progression to chronic T. muris infection in mice and, therefore, it raises the distinct possibility that the production of an interferon-γ homologue by the worm may be one mechanism whereby the parasite is able to interfere with the regulation of the host immune response and potentiate its own survival.

The development of a strong Th2-type immune response is essential in resistance to the intestinal nematode parasite Trichuris muris. Although the underlying cell-regulatory mechanisms important in protective immunity are well defined, the actual Th2-controlled effector mechanisms culminating in worm expulsion are uncharacterized. Using methodology involving the selective reconstitution of severe combined immunodeficiency mice with highly pure populations of CD4+ T cells from immune BALB/c donors, we show here that antibody is not an essential component in resistance to T. muris. Thus, CD4+ T cells purified from BALB/c donor mice at a time point when Th2 cells are in dominance (days 19 to 21 postinfection) confer resistance to infection on recipient severe combined immunodeficiency mice in the complete absence of an antibody response.

Four short peptides from rubella virus proteins E1 and E2, predicted to contain B cell epitopes, were used to vaccinate BALB/c mice. Sera from peptide-vaccinated animals reacted with viral antigens in ELISA and three of the four induced virus-neutralising antibody (nAb) responses. Peptide PY4, in contrast to the others, induced IgG2a responses upon vaccination and stimulated spleen cells in vitro produced IFN gamma in the absence of IL-5. It was reasoned that vaccination with PY4 caused Th1 subset activation, the appropriate type of response for anti-viral immunity and hence the efficient neutralising antibody response. Presentation of peptide for vaccination proved to be as important as the sequence. Similar profiles of IgG1 and IgG2a were detected in the sera of mice vaccinated with PY4 in Freund's complete adjuvant or alum; however nAb responses were not found when alum was used.

The polymeric mucin component of the intestinal mucus barrier changes during nematode infection to provide not only physical protection but also to directly affect pathogenic nematodes and aid expulsion. Despite this, the direct interaction of the nematodes with the mucins and the mucus barrier has not previously been addressed. We used the well-established Trichuris muris nematode model to investigate the effect on mucins of the complex mixture of immunogenic proteins secreted by the nematode called excretory/secretory products (ESPs). Different regimes of T. muris infection were used to simulate chronic (low dose) or acute (high dose) infection. Mucus/mucins isolated from mice and from the human intestinal cell line, LS174T, were treated with ESPs. We demonstrate that serine protease(s) secreted by the nematode have the ability to change the properties of the mucus barrier, making it more porous by degrading the mucin component of the mucus gel. Specifically, the serine protease(s) acted on the N-terminal polymerising domain of the major intestinal mucin Muc2, resulting in depolymerisation of Muc2 polymers. Importantly, the respiratory/gastric mucin Muc5ac, which is induced in the intestine and is critical for worm expulsion, was protected from the depolymerising effect exerted by ESPs. Furthermore, serine protease inhibitors (Serpins) which may protect the mucins, in particular Muc2, from depolymerisation, were highly expressed in mice resistant to chronic infection. Thus, we demonstrate that nematodes secrete serine protease(s) to degrade mucins within the mucus barrier, which may modify the niche of the parasite to prevent clearance from the host or facilitate efficient mating and egg laying from the posterior end of the parasite that is in intimate contact with the mucus barrier. However, during a TH2-mediated worm expulsion response, serpins, Muc5ac and increased levels of Muc2 protect the barrier from degradation by the nematode secreted protease(s)., Author Summary Gastrointestinal parasitic worm infections cause significant morbidity, affecting up to a third of the world's populationand their domestic pets and livestock. Mucus, the gel-like material that blankets the surface of the intestine, forms a protective barrier that is an important part of our innate immune system. The whipworm Trichuris is closely associated with the intestinal mucus barrier. The major structural component of this barrier, large glycoproteins known as mucins play a significant role in the expulsion of these worms in a mouse model. Using mice that get longterm chronic infections and others able to expel the worms from the intestine, we uncover a novel role for products secreted by the worms. Enzymes secreted by whipworms can disrupt the mucin network that gives mucus its viscous properties. Moreover, we unravel that worm products are unable to degrade forms of mucins present in the mucus barrier during worm expulsion, suggesting that these enzymes may be released by the worm as part of its regime to improve its niche and survival in the host. However, the host is capable of producing mucins and other protective molecules that protect the mucus barrier from degradation and are detrimental to the viability of the worm.

Introduction Inappropriate inflammatory responses to intestinal flora, augmented by host susceptibility genetics, contribute to the pathogenesis of Crohn9s disease (CD). Transmural intestinal inflammation results from innate and adaptive immune cell infiltration, and pro-inflammatory cytokine accumulation. Activated macrophages represent a major source of TNFα production. The treatment of CD with anti-TNFα antibody (Ab) therapy has proved clinically beneficial, yet over 30% of patients fail to respond. We characterised the biological and immunological effects of Infliximab therapy in a model of experimental colitis. Methods Genetically identical mice (AKR), susceptible to chronic Trichuris muris -induced colitis, were infected with 300 T muris eggs. A single 5 mg/kg dose of Infliximab was administered intra-peritoneally once chronic colitis had established (from day 35 post-infection, p.i.). Systemic, mesenteric lymph node (MLN) and colonic effects were analysed at day 45 p.i. MLN cell cytokine bead-array and colonic gene expression (RT-qPCR) analysis were performed. Colonic histopathology, tissue Foxp3 + , and macrophage recruitment and phenotype were determined. The treatment group was compared to untreated-infected, naive, and naive AKR administered Infliximab (n=5 per group). Results Treatment did not alter worm expulsion. Anti–TNFα Ab therapy preserved colonic length compared to untreated disease (p=0.049). Colonic inflammation was less severe with Infliximab treatment (p=0.07). Reduced TNFα, CCL2, and GMCSF proteins were measured in the MLN of Infliximab treated infected AKR. Reduced colonic expression of TNFα, IL-1β, IFNγ and IL-12p40, and increased IL-13 was observed following Infliximab treated disease. Colonic Foxp3 + cell numbers increased with disease but were unaltered by treatment. Infected mice treated with Infliximab demonstrated a 50% reduction in colonic F4/80 + macrophages (p=0.036). A relative increase of the proportion of colonic Arg + alternatively activated macrophages (AAMФ) was observed with Infliximab treatment compared to untreated disease (29% vs 14%). Conclusion Infliximab therapy suppresses TH1-driven experimental colitis. Anti–TNFα Ab treatment reduced pro-inflammatory macrophages recruitment, and for the first time in vivo has been shown to preserve colonic tissue regulatory AAMФ. Whether a result of a fundamental alteration to macrophage recruitment, or the differentiation of a specific macrophage phenotype, requires further study. The presence of AAMФ at index biopsy, or an increase in AAMФ numbers following treatment initiation, may help to identify patient responders to Anti-TNFα Ab therapy. Competing interests None declared.

Introduction Anti-tumour necrosis factor (TNF) α antibody treatment and corticosteroid therapy represent central strategies in the management of Crohn9s disease. Yet, over 30% of patients fail to respond. Understanding the mechanism of effect for each therapy is complicated by disease heterogeneity, and the complexities of effector and regulatory immune cell responses. We characterised the biological and immunological effects of infliximab and hydrocortisone therapy in a genetically identical murine model of experimental colitis. Methods Mice (AKR) susceptible to chronic Trichuris muris -induced colitis were infected with 300 T muris eggs. A single 5 mg/kg dose of Infliximab, or daily hydrocortisone treatment (2 mg/kg, QDS) were administered intraperitoneally once chronic colitis had established (from day 35 post-infection, p.i.). Systemic, mesenteric lymph node (MLN) and colonic effects were analysed at day 45 p.i. MLN cell cytokine bead-array and colonic gene expression (RT-qPCR) analysis were performed. Colonic histopathology, tissue Foxp3 + and macrophage recruitment were determined. Treated groups were compared to naive and untreated-infected AKR (n=5 per group). Results Neither treatment altered worm expulsion. Anti–TNFα Ab and corticosteroid therapy preserved colonic length, compared to untreated disease. Colonic inflammation was less severe with steroid treatment (p=0.005) and infliximab (p=0.07). An increase in MLN TH2 cytokines was suggested with both treatments. Reduced colonic TNFα, IL-1β, IFNγ and IL-12p40, and increased IL-13 expression were observed following Infliximab. Down-regulated TH1 cytokines, elevated TH2 cytokines (IL-4, IL-5, IL-13), and up-regulated colonic IL-10 expression were detected following corticosteroid treatment. Colonic Foxp3 + cell numbers increased with disease but were unaltered by either treatment. A significant reduction in tissue F4/80 + macrophages was observed with infliximab treatment alone. Conclusion Anti–TNFα Ab and corticosteroid therapy suppress TH1-driven experimental colitis. Up-regulated transcription of TH2 and regulatory (IL-10, TGFb, Foxp3) pathway molecules was seen with corticosteroid treatment. This was not accompanied by an increased influx of Foxp3 + T-cell, suggestive that corticosteroids may alter regulatory-cell function more significantly than recruitment, in the reduction of pathology and disease activity. Anti–TNFα Ab treatment reduced colonic pro-inflammatory macrophage recruitment. With differing modalities of immunosuppression demonstrated, this model may increase understanding of why either mode of therapy can induce benefit in man even if the other has failed. Competing interests None declared.

Resistance and susceptibility to the intestinal nematode Trichuris muris has been shown to be dependent upon the induction of T helper type 2 (Th2) or Th1 cells, respectively. This study demonstrates that in a normally resistant strain of mouse, i.e. BALB/K which mounts a dominant Th2 response, sub-threshold levels of infection (< 40 eggs) can survive and become sexually mature adult worms (10-20 adults). The immunological basis of this phenomenon was found to be a dramatically altered polarization of the CD4 response. The Th2-response characteristic of this strain of mouse infected with T. muris was shown to be significantly down-regulated as assessed by in vitro cytokine production [interleukin (IL)-4, IL-5 and IL-9]. In contrast, Th1 parameters of infection such as in vitro interferon-gamma production and the presence of parasite-specific IgG2a were greatly up-regulated in these mice.

A cellular automata (CA) model has been built to study the interaction between T-helper subset cells in a secondary lymphoid organ during chronic and acute infection. The TH subset cells interacted via short range cytokine-like factors, each cell type producing an autocrine factor and another factor which suppressed the development and proliferation of the other TH cell type. A cell death term was also included such that T cells not restimulated by antigen within a certain time died to be replaced with new naive cells. The important parameters in the model were the antigen density entering the lymph node and the propensity of the antigens to induce naive T cells down a specific TH subset pathway. Many features of the response of the CA were found to match those seen in infections known to induce TH subset polarization. For example, it could be seen that TH cell subset polarization arose as a natural consequence of the dynamic competition between TH1 and TH2 cytokines to induce or suppress proliferation and was driven by the antigen produced by the pathogen.

203025(50mg/kg, BID) or PBS were transanally administered for 14 days. After treatment, mice were killed to assess the colon macroand microscopically. Mucosal mRNA expression of pro-inflammatory cytokines and chemokines were examined using RT-PCR. To address differences in action of the two compounds, immunohistochemical staining of ACE and immunofluorescent staining of AT1aR was performed Results: In the DSS model, weight loss and histology score for CCG-203025(-3.6±2.9, 3.9±1.2) were superior(P

Helper T cell subset induction was examined within a single inbred strain of mouse (B10.D2/n) where individuals varied in their ability to expel the nematode parasite Trichuris muris. In this mouse strain approximately half of infected individuals resist infection whilst half are unable to expel the parasite and harbour chronic mature adult worm infections. We here assess various T cell and serological parameters in individual B10.D2/n mice infected with T. muris in relation to the number of parasites harboured. Worm burdens showed very significant negative correlations with five different parameters indicative of the selective expansion within the host of helper T cells of the Th2 subset. Thus, in vitro IL-5 and IL-9 production by restimulated mesenteric lymph node cells, total IgE levels, the early parasite-specific IgG1 response (all P < 0.01) and intestinal eosinophilia (P < 0.05), were all significantly negatively correlated with worm burden. In addition, levels of IL-3 were significantly greater in mice resistant to infection (P < 0.01). In contrast there was a significant positive correlation between worm burden and parasite-specific IgG2a levels (P < 0.05), IgG2a production being under the tight control of the Th1-specific cytokine IFN-gamma and thus a reliable marker for in vivo Th1 cell activation. The data demonstrates that an individual infected with T. muris is capable of mounting either a protective Th2-type response or an inappropriate Th1-type response.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY Cellular and cytokine responses to infection with Eimeria vermiformis were compared in BALB/c (resistant) and C57BL/6 (B6-susceptible) inbred mice. Cellular responses in the mesenteric lymph node (MLN) occurred sooner after primary infection in the resistant BALB/c strain. In contrast, proliferative responses occurred earlier after challenge in B6 mice. Resting levels of CD4 + ve and CD8 + ve T-lymphocytes in the MLN differed between the two strains but the relative numbers of each subset remained relatively constant throughout primary infection. MLN cells taken at intervals after infection were assayed for release of the cytokines IFN-gamma, IL-5 and IL-10 after culture in vitro with the mitogen Concanavalin A (Con-A) or with parasite antigen. With either stimulus cells from resistant BALB/c mice released IFN-gamma and IL-5 earlier after infection than did B6 cells. The strains had a comparable absolute ability to produce IFN-gamma but BALB/c cells released more IL-5 than did B6, levels declining, rather than increasing, during primary infection in the latter. Only cells from BALB/c mice released IL-10 during infection. Cells taken after a secondary infection released relatively little cytokine after pulsing in vitro. These data suggest that the difference in response phenotype between the two strains when infected with E. vermiformis reflect a kinetic, rather than a qualitative, difference in ability to mount protective T-helper (Th) cell subset responses. No evidence was found for a Th2-mediated interference with ability to release IFN-gamma, the cytokine most closely associated with protective immunity.

Background & Aims Hyperplasia of mucin-secreting intestinal goblet cells accompanies a number of enteric infections, including infections by nematode parasites. Nevertheless, the precise role of mucins in host defense in nematode infection is not known. We investigated the role of the mucin (Muc2) in worm expulsion and host immunity in a model of nematode infection. Methods Resistant (BALB/c, C57BL/6), susceptible (AKR), and Muc2-deficient mouse strains were infected with the nematode, Trichuris muris , and worm expulsion, energy status of the whipworms, changes in mucus/mucins, and inflammatory and immune responses were investigated after infection. Results The increase in Muc2 production, observed exclusively in resistant mice, correlated with worm expulsion. Moreover, expulsion of the worms from the intestine was significantly delayed in the Muc2-deficient mice. Although a marked impairment in the development of periodic acid Schiff (PAS)–stained intestinal goblet cells was observed in Muc2-deficient mice, as infection progressed a significant increase in the number of PAS-positive goblet cells was observed in these mice. Surprisingly, an increase in Muc5ac, a mucin normally expressed in the airways and stomach, was observed after infection of only the resistant animals. Overall, the mucus barrier in the resistant mice was less permeable than that of susceptible mice. Furthermore, the worms isolated from the resistant mice had a lower energy status. Conclusions Mucins are an important component of innate defense in enteric infection; this is the first demonstration of the important functional contribution of mucins to host protection from nematode infection.

Genetic influences upon host variation in eosinophilia and resistance to helminth infection, and the relationship between these parameters, were investigated in 7 inbred and 1 hybrid strains of mice infected with Trichinella spiralis. Clear strain-dependent variations were observed in the maximum peripheral blood, bone marrow and spleen eosinophilia attained in infected animals. SWR, NIH and SJL strains of mice all gave high responses to infection; four congenic strains sharing the B10 background (C57BL10 [B10], B10.S, B10.G and B10.BR) were low responders. Some of the genes for high responsiveness appeared to be dominant, as F1 hybrids from high- and low-response phenotype parental strains showed intermediate to high responses to infection. Intestinal eosinophilia showed no correlation with either peripheral blood or bone marrow responses (NIH and B10 strains having similar levels of eosinophil response in gut tissue) and was unrelated to the level of resistance to infection. Whereas NIH were highly resistant, with adult worm burdens at 13 days post-infection and muscle larval burdens at 35 days post-infection significantly lower than all other strains, B10 were quite susceptible, retaining substantial worm burdens at day 13 and harbouring large numbers of muscle larvae. Measurements of the level of the eosinophilopoietic cytokine IL-5 in sera during infection showed that the two strains differed in the kinetics of release but not in their absolute capacity to produce this cytokine. NIH mice released high levels during a primary infection, B10 released high levels during a secondary infection. The relationship between eosinophilia and resistance and the differences seen between responses in different body compartments are discussed in terms of genetically determined influences operating at the levels of T helper cell populations, T cell cytokines and bone-marrow precursor cell populations.

Immunity to infection with Eimeria vermiformis was transferred in NIH mice by both the nylon wool-adherent (B-cell-enriched) and nonadherent (T-cell-enriched) fractions of lymphocytes (spleen and mesenteric lymph node) taken from infected donors. Transfer was more variable with the adherent fraction, and when contaminating T cells were removed by treatment with anti-Thy1 monoclonal antibody (MAb) and complement, this fraction lost all protective activity. The protective effect of T-cell-enriched populations of mesenteric lymphocytes was abrogated by treatment with anti-L3T4 MAb and complement in vitro before transfer or by opsonization with this MAb in vitro before intravenous inoculation into recipients. Similar treatments of cells with anti-Lyt2 MAb did not have this effect, confirming that Thy1+ L3T4+ cells mediate the adoptive transfer of immunity to E. vermiformis. Thy1+ L3T4+ cells were also shown to limit the replication of E. vermiformis in primary infections: mice depleted of this subset (by thymectomy followed by intravenous injection of anti-L3T4 MAb) passed greater numbers of oocysts over a longer period of time than did mice similarly depleted of Lyt2+ cells.

Infection with soil-transmitted gastrointestinal parasites, such as Trichuris trichiura, affects more than a billion people worldwide, causing significant morbidity and health problems especially in poverty-stricken developing countries. Despite extensive research, the role of the immune system in triggering parasite expulsion is incompletely understood which hinders the development of anti-parasite therapies. Trichuris muris infection in mice serves as a useful model of T. trichiura infection in humans and has proven to be an invaluable tool in increasing our understanding of the role of the immune system in promoting either susceptibility or resistance to infection. The old paradigm of a susceptibility-associated Th1 versus a resistance-associated Th2-type response has been supplemented in recent years with cell populations such as novel innate lymphoid cells, basophils, dendritic cells and regulatory T cells proposed to play an active role in responses to T. muris infection. Moreover, new immune-controlled mechanisms of expulsion, such as increased epithelial cell turnover and mucin secretion, have been described in recent years increasing the number of possible targets for anti-parasite therapies. In this review, we give a comprehensive overview of experimental work conducted on the T. muris infection model, focusing on important findings and the most recent reports on the role of the immune system in parasite expulsion.