Potential of human helminth therapy for resolution of inflammatory bowel disease: The future ahead.

Inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response in the gastrointestinal tract. The number of patients with IBD has increased worldwide, especially in highly industrialized western societies. The population of patients with IBD in North America is forecasted to reach about four million by 2030; meanwhile, there is no definitive therapy for IBD. Current anti-inflammatory, immunosuppressive, or biological treatment may induce and maintain remission, but not all patients respond to these treatments. Recent studies explored parasitic helminths as a novel modality of therapy due to their potent immunoregulatory properties in humans. Research using IBD animal models infected with a helminth or administered helminth-derived products such as excretory-secretory products has been promising, and helminth-microbiota interactions exert their anti-inflammatory effects by modulating the host immunity. Recent studies also indicate that evidence that helminth-derived metabolites may play a role in anticolitic effects. Thus, the helminth shows a potential benefit for treatment against IBD. Here we review the current feasibility of "helminth therapy" from the laboratory for application in IBD management.

Maternal nematode infection upregulates expression of Th2/Treg and diapedesis related genes in the neonatal brain.

Intestinal nematode infections common during pregnancy have recently been shown to have impacts that extend to their uninfected offspring including altered brain gene expression. If maternal immune signals reach the neonatal brain, they might alter neuroimmune development. We explored expression of genes associated with four distinct types of T cells (Th1, Th2, Th17, Treg) and with leukocyte transendothelial migration and endocytosis transport across the blood-brain barrier (BBB) in the postnatal brain of offspring of nematode-infected mice, through secondary analysis of a whole brain gene expression database. Th1/Th17 expression was lowered by maternal infection as evidenced by down-regulated expression of IL1ß, Th1 receptors and related proteins, and of IL22 and several Th17 genes associated with immunopathology. In contrast, Th2/Treg related pathways were upregulated as shown by higher expression of IL4 and TGF-ß family genes. Maternal infection also upregulated expression of pathways and integrin genes involved in transport of leukocytes in between endothelial cells but downregulated endosome vesicle formation related genes that are necessary for endocytosis of immunoglobulins across the BBB. Taken together, pup brain gene expression indicates that maternal nematode infection enhanced movement of leukocytes across the neonatal BBB and promoted a Th2/Treg environment that presumably minimizes the proinflammatory Th1 response in the pup brain.

Rescue of maternal immune activation-induced behavioral abnormalities in adult mouse offspring by pathogen-activated maternal Treg cells.

Maternal immune activation (MIA) induced by lipopolysaccharides or polyinosinic:polycytidylic acid injections can induce behavioral abnormalities in adult mouse offspring. Here, we used the soluble tachyzoite antigen from Toxoplasma gondii, a parasite that infects approximately two billion people, to induce MIA in mice. The adult male offspring showed autism-relevant behaviors and abnormal brain microstructure, along with a pro-inflammatory T-cell immune profile in the periphery and upregulation of interleukin-6 in brain astrocytes. We show that adoptive transfer of regulatory T (Treg) cells largely reversed these MIA-induced phenotypes. Notably, pathogen-activated maternal Treg cells showed greater rescue efficacy than those from control donors. Single-cell RNA sequencing identified and characterized a unique group of pathogen-activated Treg cells that constitute 32.6% of the pathogen-activated maternal Treg population. Our study establishes a new preclinical parasite-mimicking MIA model and suggests therapeutic potential of adoptive Treg cell transfer in neuropsychiatric disorders associated with immune alterations.

NLRP3 played a role in Trichinella spiralis-triggered Th2 and regulatory T cells response.

Trichinella spiralis maintains chronic infections within its host. Muscle larvae excretory-secretory products (MLES) typically induce parasite-specific immune responses such as the Th2 response and regulatory T cells (Tregs) by modulating dendritic cell (DC) phenotype via the recognition of pattern recognition receptors (PRRs), such as Nod-like receptors (NLRs). We aimed to investigate the role of NLRP3 in T. spiralis-triggered immune response. We found that larvae burden was increased in NLRP3-/- mice compared to wild type (WT) mice. Administration of MLES induced higher levels of IL-4, IL-10, TGF-ß and population of Tregs in WT mice than in NLRP3-/- mice. In vitro, we showed that increased expression of CD40 on the surface of MLES-treated DCs was inhibited after NLRP3 knockout. Increased production of IL-1ß, IL-18, IL-10 and TGF-ß, but not IL-12p70, was significantly diminished in the absence of NLRP3. Furthermore, our results demonstrated that MLES-treated DCs induced higher levels of IL-4, IL-10 and TGF-ß and populations of Tregs in vitro. These inductions were abolished by NLRP3 deficiency in DCs, suggesting that NLRP3 in MLES-treated DCs plays a role in promoting the Th2 and Treg response. Taken together, we identified for the first time the involvement of NLRP3 in host defences against T. spiralis.

Plasmodium yoelii 17XL infection modified maturation and function of dendritic cells by skewing Tregs and amplificating Th17.

BACKGROUND: Emerging data has suggested that Tregs, Th17, Th1 and Th2 are correlated with early immune mechanisms by controlling Plasmodium infection. Plasmodium infection appeared to impair the antigen presentation and maturation of DCs, leading to attenuation of specific cellular immune response ultimately. Hence, in this study, we aim to evaluate the relevance between DCs and Tregs/Th17 populations in the process and outcomes of infection with Plasmodium yoelii 17XL (P.y17XL). METHODS: DCs detection/analysis dynamically was performed by Tregs depletion or Th17 neutralization in P.y17XL infected BALB/c mice via flow cytometry. Then the levels of cytokines production were detected using enzyme-linked mmunosorbent assay (ELISA). RESULTS: Our results indicated that Tregs depletion or Th17 neutralization in BALB/c mice infected with P.y17XL significantly up-regulated the percentages of mDC and pDC, increased the expressions of major histocompatibility complex (MHC) class II, CD80, CD86 on DCs and the levels of IL-10/IL-12 secreted by DCs, indicating that abnormal amplification of Tregs or Th17 may damage the maturation and function of DCs during the early stage of malaria infection. Interestingly, we also found that the abnormal amplification of Th17, as well as Tregs, could inhibit the maturation of DCs. CONCLUSIONS: Tregs skewing or Th17 amplification during the early stage of malaria infection may inhibit the maturation and function of DCs by modifying the subsets of DCs, expressions of surface molecules on DCs and secretion mode of cytokines.

Immunomodulatory effect of Syphacia obvelata in treatment of experimental DSS-induced colitis in mouse model.

The ability of helminth parasite infections to manipulate the immune system of their host towards T regulatory responses has been proposed to suppress the inflammatory response. The aim of this study was to investigate the protective and therapeutic effect of Syphacia obvelata in the treatment of experimental DSS -induced colitis. 50 male C57BL/6 mice were divided into 5 groups: healthy uninfected controls, DSS colitis, receiving only S. obv, preventive (S. obv + DSS) and therapeutic group (DSS + S.obv). Colitis intensity was investigated by measuring body weight changes, stool consistency/bleeding and colon length. To evaluate the immune responses induced by this nematode, TNF-α, IL-10, IL-17, IFN-γ and expressing of FoxP3+ T cells were measured in mesenteric lymph nodes and Peyer's patches cells. Mice in preventive and therapeutic groups treated with S. obv egg significantly ameliorated the severity of the DSS colitis, indicated by the reduced disease manifestations, improved histopathological scores correlated with the up regulation of Treg responses and down regulation of proinflammatory cytokines. S. obv can prevention and reverse on-going murine DSS colitis. The data suggest that induction of Tregs and change in cytokine profiles during helminthic therapies were responsible for reversed inflammatory events in IBD.

Variability in the virulence of specific Mycobacterium tuberculosis clinical isolates alters the capacity of human dendritic cells to signal for T cells.

BACKGROUND: Once in the pulmonary alveoli, Mycobacterium tuberculosis (Mtb) enters into contact with alveolar macrophages and dendritic cells (DCs). DCs represent the link between the innate and adaptive immune system owing to their capacity to be both a sentinel and an orchestrator of the antigen-specific immune responses against Mtb. The effect that the virulence of Mtb has on the interaction between the bacilli and human DCs has not been fully explored. OBJECTIVE: To evaluate the effect of Mtb virulence on human monocyte-derived DCs. METHODS: We exposed human monocyte-derived DCs to Mtb clinical strains (isolated from an epidemiological Mtb diversity study in Mexico) bearing different degrees of virulence and evaluated the capacity of DCs to internalise the bacilli, control intracellular growth, engage cell death pathways, express markers for activation and antigen presentation, and expand to stimulate autologous CD4+ T cells proliferation. FINDINGS: In the case of the hypervirulent Mtb strain (Phenotype 1, strain 9005186, lineage 3), we report that DCs internalise and neutralise intracellular growth of the bacilli, undergo low rates of apoptosis, and contribute poorly to T-cell expansion, as compared to the H37Rv reference strain. In the case of the hypovirulent Mtb strain (Phenotype 4, strain 9985449, lineage 4), although DCs internalise and preclude proliferation of the bacilli, the DCs also display a high level of apoptosis, massive levels of apoptosis that prevent them from maintaining autologous CD4+ T cells in a co-culture system, as compared to H37Rv. MAIN CONCLUSIONS: Our findings suggest that variability in virulence among Mtb clinical strains affects the capacity of DCs to respond to pathogenic challenge and mount an immune response against it, highlighting important parallels to studies previously done in mouse models.

Concurrent decreases in the prevalence of wheezing and Ascaris infection among 5-year-old children in rural Bangladesh and their regulatory T cell immunity after the implementation of a national deworming program.

INTRODUCTION: Epidemiological research on the prevalence of asthma and helminthic infections in various countries has led to the hypothesis that helminthic infections protect against asthma by suppressing the host's immune response. This study was conducted to elucidate whether decreased Ascaris infection following a national deworming program was associated with increased recurrent wheezing among rural Bangladeshi children and to test their anti-inflammatory immunity. METHODS: This nested case-control study was conducted from December 2015 to October 2016 in the rural service area of the International Centre for Diarrhoeal Disease Research, Bangladesh. Of the 1800 5-year old children randomly selected for the study, informed consent was obtained from the guardians of 1658 children. Data were collected using a semistructured questionnaire adopted from the International Study of Asthma and Allergies in Childhood and blood samples for the analysis of regulatory T (Treg) cell immune responses and the balance between Th1 and Th2 immunity in Ascaris infections. RESULTS: A total of 145 children were found to have wheezing, yielding a prevalence rate of 8.7%, which was significantly lower than the rate found in 2001 (16.2%, P < .001); Ascaris infection also decreased from 2001 to 2016. The 127 wheezing children who agreed to participate further were compared to 114 randomly selected never-wheezing children. Wheezing had a significant positive association with antibiotic use, history of pneumonia, parents' history of asthma, and Ascaris infection; children with Ascaris infection were twice as likely to have wheezing (adjusted odds ratio = 2.31, P = .053). Flow cytometry found no significant differences in the rates of Th1, Th2, and CD4 + CD25 + CD127low cells by the wheezing group. CONCLUSIONS: Ascaris infection had a positive rather than a negative association with wheezing and the rates of wheezing and Ascaris infections both decreased from 2001 to 2016. These findings undermines the hypothesis that such infections provide protection against asthma.

Effect of Cytotoxic T-Lymphocyte Antigen-4 on the Efficacy of the Fatty Acid-Binding Protein Vaccine Against Schistosoma japonicum.

The present study evaluated the impact of blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) activity on the protective effect elicited by the fatty acid binding protein (FABP) vaccine against Schistosoma japonicum infection. Mice were randomly divided into uninfected, infected control, anti-CTLA-4 monoclonal antibody (anti-CTLA-4 mAb), FABP, and combination (anti-CTLA-4 mAb and FABP) groups. An assessment of the S. japonicum worm and egg burden in the infected mice revealed that the worm reduction-rate induced by FABP administration was increased from 26.58 to 54.61% by co-administration of the monoclonal anti-CTLA antibody (anti-CTLA-4 mAb). Furthermore, the regulatory T cell (Treg) percentage was significantly increased in mice after administration of the anti-CTLA-4 mAb, but not the FABP vaccine, and elevated levels of the cytokines interferon (IFN)-γ, interleukin (IL)-2, IL-4, and IL-5 were observed in infected mice that were administered the anti-CTLA-4 mAb. Notably, the diameter of egg granulomas in the anti-CTLA-4 mAb and combination groups was significantly increased compared to that observed in the infected control group. Together, these results suggest that co-administering the FABP vaccine and anti-CTLA-4 treatment may have synergistically increased the immunoprotective effect of the FABP vaccine by promoting T-helper 1-type immune responses, while incurring increased tissue damage.

Wuchereria bancrofti filaria activates human dendritic cells and polarizes T helper 1 and regulatory T cells via toll-like receptor 4.

Interaction between innate immune cells and parasite plays a key role in the immunopathogenesis of lymphatic filariasis. Despite being professional antigen presenting cells critical for the pathogen recognition, processing and presenting the antigens for mounting T cell responses, the dendritic cell response and its role in initiating CD4+ T cell response to filaria, in particular Wuchereria bancrofti, the most prevalent microfilaria is still not clear. Herein, we demonstrate that a 70 kDa phosphorylcholine-binding W. bancrofti sheath antigen induces human dendritic cell maturation and secretion of several pro-inflammatory cytokines. Further, microfilarial sheath antigen-stimulated dendritic cells drive predominantly Th1 and regulatory T cell responses while Th17 and Th2 responses are marginal. Mechanistically, sheath antigen-induced dendritic cell maturation, and Th1 and regulatory T cell responses are mediated via toll-like receptor 4 signaling. Our data suggest that W. bancrofti sheath antigen exploits dendritic cells to mediate distinct CD4+ T cell responses and immunopathogenesis of lymphatic filariasis.

Systemic Antibiotic Therapy Reduces Circulating Inflammatory Dendritic Cells and Treg-Th17 Plasticity in Periodontitis.

Periodontitis (PD) is a common dysbiotic inflammatory disease that leads to local bone deterioration and tooth loss. PD patients experience low-grade bacteremias with oral microbes implicated in the risk of heart disease, cancer, and kidney failure. Although Th17 effectors are vital to fighting infection, functional imbalance of Th17 effectors and regulatory T cells (Tregs) promote inflammatory diseases. In this study, we investigated, in a small pilot randomized clinical trial, whether expansion of inflammatory blood myeloid dendritic cells (DCs) and conversion of Tregs to Th17 cells could be modulated with antibiotics (AB) as part of initial therapy in PD patients. PD patients were randomly assigned to either 7 d of peroral metronidazole/amoxicillin AB treatment or no AB, along with standard care debridement and chlorhexidine mouthwash. 16s ribosomal RNA analysis of keystone pathogen Porphyromonas gingivalis and its consortium members Fusobacterium nucleatum and Streptococcus gordonii confirmed the presence of all three species in the reservoirs (subgingival pockets and blood DCs) of PD patients before treatment. Of the three species, P. gingivalis was reduced in both reservoirs 4-6 wk after therapy. Further, the frequency of CD1C+CCR6+ myeloid DCs and IL-1R1 expression on IL-17A+FOXP3+CD4+ T cells in PD patients were reduced to healthy control levels. The latter led to decreased IL-1ß-stimulated Treg plasticity in PD patients and improvement in clinical measures of PD. Overall, we identified an important, albeit short-term, beneficial role of AB therapy in reducing inflammatory DCs and Treg-Th17 plasticity in humans with PD.

Effect of 25-hydroxycholecalciferol supplementation on turkey performance and immune cell parameters in a coccidial infection model.

This study was conducted to identify the effects of 25-OH cholecalciferol supplementation to turkeys on the immune cells parameters, fecal coccidial oocyst shedding, macrophage nitric oxide production, T regulatory cell cytokine production, and production parameters during a coccidial challenge. A total of 200 1-day-old turkey poults were supplemented with 27.5, 55, 82.5, or 110 µg/kg 25-OH cholecalciferol and challenged or not challenged with coccidial oocysts in a 4 × 2 factorial set up of treatments. Birds fed 110 µg/kg of 25-OH cholecalciferol and infected with coccidial oocyst had 41% lower (P < 0.05) fecal oocyst and 53% higher (P < 0.05) macrophage nitric oxide production than the birds fed 27.5 µg/kg of 25-OH cholecalciferol and infected with coccidial oocyst at 5 d post-coccidial infection. Birds fed 82.5 µg/kg 25-OH cholecalciferol and infected with coccidial oocyst had 5-fold higher (P < 0.05) IL-1 mRNA amounts than the birds fed 27.5 µg/kg of 25-OH cholecalciferol and infected with coccidial oocyst. Birds fed 110 µg/kg 25-OH cholecalciferol and infected with coccidial oocyst had 5.3-fold higher (P < 0.05) IL-10 mRNA amounts than the birds fed 27.5 µg/kg of 25-OH cholecalciferol and infected with coccidial oocyst at 5 d post-coccidial infection. CD4+CD25+ cells from birds fed 110 µg of 25-OH cholecalciferol and infected with coccidial oocyst had 12-fold higher (P < 0.05) IL-10 mRNA than that from the birds fed 27.5 µg/kg of 25-OH cholecalciferol and infected with coccidial oocyst. In conclusion, supplementing birds with 101 µg/kg 25-OH cholicalciferol decreases coccidial oocyst shedding in the feces and could be a nutritional strategy to reduce the coccidial infection and spread in turkeys.

Melatonin suppresses eosinophils and Th17 cells in hamsters treated with a combination of human liver fluke infection and a chemical carcinogen.

BACKGROUND: The combination of Opisthorchis viverrini (OV) infection and chemical carcinogen induces cholangiocarcinoma (CCA) in hamsters via inflammation-mediated mechanisms. Thus, suppression of inflammatory cells at the initial stages of CCA development would be of benefit. We aimed to investigate whether IL-17-producing CD4+ T cells (Th17) and CD4+ Foxp3+ T cells (Treg) are involved in the early stages of CCA genesis and can be targeted for suppression by melatonin. METHODS: Inflammation, an initial stage of CCA development, was induced in hamsters by a combination of O. viverrini infection and N-nitrosodimethylamine (NDMA) administration. Melatonin (50mg/kg) was additionally administered to one group for the 30days of the experiment. Liver tissue-resident T cells were investigated using immunostaining, western blotting, and real-time PCR. RESULTS: OV+NDMA-induced CCA tissues showed significantly higher numbers of inflammatory cells, especially eosinophils, bile duct proliferation and IL-17+ cell infiltration compared to normal livers. Expression of Foxp3 was localized in the bile duct epithelial cells, and especially in the bile duct hyperplasia. Accumulation of CD4+ and IL-17+ cells and intense staining of the Foxp3+ marker were consistent with their protein levels. Infiltration of IL-17+ inflammatory cells and Foxp3+ cells, as well as increases in their transcription expression levels, were significantly lower in the melatonin-treated group. In contrast, increased CD4+ cell infiltration and TNF-α expression were also observed through melatonin treatment. CONCLUSION: Melatonin exerts an immunomodulatory effect, suppressing eosinophils and Th17 cells and expression of Foxp3, but enhancing CD4+ cells and TNF-α. This suggests that melatonin may be used for CCA chemoprevention.

Immune responses to fungal aeroallergen in Heligmosomoides polygyrus-infected mice vary by age.

Parasite infections in the developing world have been considered to promote resistance to immune-mediated diseases such as asthma. Mouse studies have shown that helminths and their products reduce the development of allergic asthma. Since epidemiologic studies that show similar protection are in relation to geohelminth infections that occur in early life, we hypothesized that the parasite-mediated protection against asthma may differ by age. Mice infected with Heligmosomoides polygyrus at 3-weeks of age had similar asthma phenotype compared to mice infected at 28-weeks of age wherein airway eosinophilia was unaltered but tissue inflammation and GC metaplasia were reduced. In contrast, mice infected at 18-weeks of age had elevated macrophagic airway inflammation with accompanying tissue pathology. The presence of γδ T cells and Treg cells in the airways was also regulated by age at worm infection. Our findings demonstrate the importance of age in immune responses that may regulate gut and lung diseases.

Increased hepatic Th2 and Treg subsets are associated with biliary fibrosis in different strains of mice caused by Clonorchis sinensis.

Previous studies showed that CD4+T cells responses might be involved in the process of biliary fibrosis. However, the underlying mechanism resulting in biliary fibrosis caused by Clonorchis sinensis remains not yet fully elucidated. The objectives of the present study were to investigate the different profiles of hepatic CD4+T cell subsets (Th1, Th2, Th17 and Treg cells) and their possible roles in the biliary fibrosis of different strains of mice (C57BL/6, BALB/c and FVB mice) induced by C. sinensis infection. C57BL/6, BALB/c and FVB mice were orally gavaged with 45 metacercariae. All mice were sacrificed on 28 days post infection in deep anesthesia conditions. The leukocytes in the liver were separated to examine CD4+T cell subsets by flow cytometry and the left lobe of liver was used to observe pathological changes, collagen depositions and the concentrations of hydroxyproline. The most serious cystic and fibrotic changes appeared in FVB infected mice indicated by gross observation, Masson's trichrome staining and hydroxyproline content detection. In contrast to C57BL/6 infected mice, diffuse nodules and more intensive fibrosis were observed in the BALB/c infected mice. No differences of the hepatic Th1 subset and Th17 subset were found among the three strains, but the hepatic Th2 and Treg cells and their relative cytokines were dramatically increased in the BALB/c and FVB infected groups compared with the C57BL/6 infected group (P<0.01). Importantly, increased Th2 subset and Treg subset all positively correlated with hydroxyproline contents (P<0.01). This result for the first time implied that the increased hepatic Th2 and Treg cell subsets were likely to play potential roles in the formation of biliary fibrosis in C. sinensis-infected mice.

Helminth Regulation of Immunity: A Three-pronged Approach to Treat Colitis.

By reputation, the parasite is a pariah, an unwelcome guest. Infection with helminth parasites evokes stereotypic immune responses in humans and mice that are dominated by T helper (Th)-2 responses; thus, a hypothesis arises that infection with helminths would limit immunopathology in concomitant inflammatory disease. Although infection with some species of helminths can cause devastating disease and affect the course of microbial infections, analyses of rodent models of inflammatory disease reveal that infection with helminth parasites, or treatment with helminth extracts, can limit the severity of autoinflammatory disease, including colitis. Intriguing, but fewer, studies show that adoptive transfer of myeloid immune cells treated with helminth products/extracts in vitro can suppress inflammation. Herein, 3 facets of helminth therapy are reviewed and critiqued: treatment with viable ova or larvae, treatment with crude extracts of the worm or purified molecules, and cellular immunotherapy. The beneficial effect of helminth therapy often converges on the mobilization of IL-10 and regulatory/alternatively activated macrophages, while there are reports on transforming growth factor (TGF)-ß, regulatory T cells and dendritic cells, and recent data suggest that helminth-evoked changes in the microbiota should be considered when defining anticolitic mechanisms. We speculate that if the data from animal models translate to humans, noting the heterogeneity therein, then the choice between use of viable helminth ova, helminth extracts/molecules or antigen-pulsed immune cells could be matched to disease management in defined cohorts of patients with inflammatory bowel disease.

Susceptibility of Broiler Chickens to Coccidiosis When Fed Subclinical Doses of Deoxynivalenol and Fumonisins-Special Emphasis on the Immunological Response and the Mycotoxin Interaction.

Deoxynivalenol (DON) and fumonisins (FB) are the most frequently encountered mycotoxins produced by Fusarium species in livestock diets. The effect of subclinical doses of mycotoxins in chickens is largely unknown, and in particular the susceptibility of birds to pathogenic challenge when fed these fungal metabolites. Therefore, the present study reports the effects of DON and FB on chickens challenged with Eimeria spp, responsible for coccidiosis. Broilers were fed diets from hatch to day 20, containing no mycotoxins, 1.5 mg DON/kg, 20 mg FB/kg, or both toxins (12 pens/diet; 7 birds/pen). At day 14, six pens of birds per diet (half of the birds) were challenged with a 25×-recommended dose of coccidial vaccine, and all birds (challenged and unchallenged) were sampled 6 days later. As expected, performance of birds was strongly affected by the coccidial challenge. Ingestion of mycotoxins did not further affect the growth but repartitioned the rate of reduction (between the fraction due to the change in maintenance and feed efficiency), and reduced apparent nitrogen digestibility. Intestinal lesions and number of oocysts in the jejunal mucosa and feces of challenged birds were more frequent and intense in the birds fed mycotoxins than in birds fed control feed. The upregulation of cytokines (interleukin (IL) IL-1ß, IL-6, IL-8 and IL-10) following coccidial infection was higher in the jejunum of birds fed mycotoxins. Further, the higher intestinal immune response was associated with a higher percentage of T lymphocytes CD4⁺CD25⁺, also called Tregs, observed in the cecal tonsils of challenged birds fed mycotoxins. Interestingly, the increase in FB biomarker of exposure (sphinganine/sphingosine ratio in serum and liver) suggested a higher absorption and bioavailability of FB in challenged birds. The interaction of DON and FB was very dependent on the endpoint assessed, with three endpoints reporting antagonism, nine additivity, and two synergism. In conclusion, subclinical doses of DON and FB showed little effects in unchallenged chickens, but seem to result in metabolic and immunologic disturbances that amplify the severity of coccidiosis.

The role of regulatory T cells during Plasmodium chabaudi chabaudi AS infection in BALB/c mice.

An inappropriate immune response to parasite infection is one of the primary drivers of malaria pathogenesis. Regulatory T cells (Tregs), an important subset of CD4(+) T cells, can maintain self-tolerance and prevent autoimmune diseases. However, there is little consensus about their role in malaria pathogenesis. In this study, we transiently depleted Tregs (CD25(+) T cells) using an anti-CD25 mAb (7D4 clone) at different time points following Plasmodium chabaudi chabaudi AS infection in BALB/c mice and investigated the effect of depletion of Tregs in this model. In control mice, Tregs proliferated significantly and their suppressive function was enhanced after infection. IL-10 was increased drastically during infection. Depletion of Tregs at various time points can lead to divergent outcomes. When Tregs were depleted prior to or during the early phase of infection, most mice survived and had a robust Th1 immune response. In contrast, when Tregs were depleted close to peak parasitemia, all mice died as a result of inflammation. Taken together, these data suggest that in P. c. chabaudi AS-infected BALB/c mice, Tregs inhibit the Th1 response and macrophage activation, leading to increased parasite load; however, they also control inflammation-mediated pathology by secreting high levels of IL-10.

Interleukin-27-Producing CD4(+) T Cells Regulate Protective Immunity during Malaria Parasite Infection.

Interleukin-27 (IL-27) is a heterodimeric regulatory cytokine of the IL-12 family, which is produced by macrophages, dendritic cells, and B cells upon stimulation through innate immune receptors. Here, we described regulatory CD4(+) T cells that produce IL-27 in response to T cell receptor stimulation during malaria infection, inhibiting IL-2 production and clonal expansion of other T cells in an IL-27-dependent manner. IL-27-producing CD4(+) T cells were Foxp3(-)CD11a(+)CD49d(+) malaria antigen-specific CD4(+) T cells and were distinct from interferon-γ (IFN-γ) producing Th1 or IL-10 producing Tr1 cells. In mice lacking IL-27 in T cells, IL-2 production was restored and clonal expansion and IFN-γ production by specific CD4(+) T cells were improved, culminating in reduced parasite burden. This study highlights a unique population of IL-27 producing regulatory CD4(+) T cells and their critical role in the regulation of the protective immune response against malaria parasites.

GITR Activation Positively Regulates Immune Responses against Toxoplasma gondii.

Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals. Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells. However, the precise role of this receptor in the context of T. gondii infection remains elusive. Therefore, the current study investigated the role of GITR activation in the immunoregulation mechanisms induced during the experimental infection of mice with T. gondii. Our data show that T. gondii infection slightly upregulates GITR expression in Treg cells and B cells, but the most robust increment in expression was observed in macrophages and dendritic cells. Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1. Several in vivo and in vitro analysis were performed to identify the cellular mechanisms involved in GITR activation upon infection, however no clear alterations were detected in the phenotype/function of macrophages, Tregs and B cells under treatment with DTA-1. Therefore, GITR appears as a potential target for intervention during infection by the parasite Toxoplasma gondii, even though further studies are still necessary to better characterize the immune response triggered by GITR activation during T. gondii infection.