Maternal and postnatal dietary probiotic supplementation enhances splenic regulatory T helper cell population and reduces peanut allergen-induced hypersensitivity responses in mice

Neonatal to early childhood is the critical period for establishing a balance of T helper 1 (Th1) versus T helper 2 (Th2) cellular immunity within the gut, which is strongly influenced by the source and establishment of gut microflora. Probiotic administration has been shown to attenuate Th2-biased cellular immunity and predisposition to food allergies. To test this hypothesis we provided ad libitum a probiotic-supplemented (Primalac 454 Feed Grade Microbials) or control diet to lactating dams with suckling pups and weaned pups until 10 weeks of age. Weaned mice were sensitized/challenged with peanut extract, saline or adjuvant at 6, 8 and 10 weeks of age. At 3, 6, 8 and 10 weeks, fecal samples were collected for microbial analysis, while blood samples were analyzed for total plasma IgE levels. At termination (10 weeks of age), splenic T lymphocyte population subtypes were determined using FACS analysis and Th1/Th2/Th17 gene expression by PCR array. Mice given the probiotic-supplemented diet had significantly enhanced probiotic fecal counts compared to controls at 3, 6, 8 and 10 weeks. Moreover, mice fed the probiotic-supplemented diet had enhanced splenic naturally occurring T regulatory cell populations, and reduced splenic gene expression of allergic mediator IL-13 compared to controls. These results provide evidence that early probiotic supplementation may provide host protection to hypersensitivity reactions to food allergens by attenuating food allergen inflammatory responses.     

Impairment of T helper and T regulatory cell responses at birth

Background: There is strong evidence that reduced exposures to microbial compounds triggering innate immune responses early in life are critical for the development of allergic illnesses. The underlying mechanisms remain unknown, but will include T‐cell responses either along T helper type 1 (Th1)/Th2 pathways or via T regulatory and Th17 cells. Yet, little is known about innate immune responses and the function of T regulatory/Th17 cells at birth. The aim of this study was to investigate T‐cell responses to innate (Lipid A/LpA, peptidoglycan/Ppg) and adaptive (phytohemagglutinin) stimuli at birth and to compare these findings with adult immune responses. Methods: Cord and peripheral blood mononuclear cells including T regulatory and Th17 cells from 25 neonates and 25 adults were examined for proliferation, cytokine secretion, surface, mRNA expression and functional suppression assays. Results: Proliferation and cytokine responses to innate stimuli were less mature at birth than in adulthood. T regulatory and Th17 cells were less expressed in cord than in adult blood (Ppg‐induced Foxp3, P = 0.001, LpA‐induced CD4⁺ CD25⁺ high, P = 0.02; Th17 : P < 0.0001). Mitogen‐induced suppression of T‐regulatory cells on T‐effector cell function was less efficient in cord than in adult blood (P = 0.01). At both ages, Th17 cells were correlated with Th1/Th2 cells (P < 0.01), but not with interleukin‐10 secretion following innate‐stimulation. Conclusion: Innate immune responses are immature at birth. Furthermore, the function of T regulatory and Th17 cells is impaired. Th17 cells in association with Th1/Th2 cells may be involved in early immuno‐modulation. Potent innate immune stimulation early in life can potentially contribute to protection from allergic diseases.     

Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes

Many elderly subjects are at increased risk of infectious and noninfectious diseases due to an age-related decline in lymphoid cell activity (immunosenescence). Noninvasive means of enhancing cellular immunity are therefore desirable in the elderly. Previous reports have suggested that dietary supplementation could represent an effective means of enhancing the activity of circulating natural killer (NK) cells in the elderly. In the present study, we have conducted a pre–post intervention trial to determine the impact of dietary supplementation with probiotic lactic acid bacteria (LAB) on peripheral blood NK cell activity in healthy elderly subjects. Twenty-seven volunteers consumed low-fat/low-lactose milk supplemented with known immunostimulatory LAB strains (Lactobacillus rhamnosus HN001 or Bifidobacterium lactis HN019) for a period of 3 weeks. A dietary run-in of milk alone was shown to have no significant effect on NK cells. In contrast, the proportion of CD56-positive lymphocytes in peripheral circulation was higher following consumption of either LAB strain, and ex vivo PBMC tumoricidal activity against K562 cells was also increased. Supplementation with HN001 or HN019 increased tumoricidal activity by an average of 101 and 62%, respectively; these increases were significantly correlated with age, with subjects older than 70 years experiencing significantly greater improvements than those under 70 years. These results demonstrate that dietary consumption of probiotic LAB in a milk-based diet may offer benefit to elderly consumers to combat some of the deleterious effects of immunosenescence on cellular immunity.     

Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization

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Vitamin E and immune response: I. Enhancement of helper T cell activity by dietary supplementation of vitamin E in mice

The effects of vitamin E on the humoral immune response to hamster erythrocytes (HRBC) and 2,4,6-trinitrophenyl (TNP) were studied in mice. Inbred SL mice were fed on a diet supplemented with 0, 20 or 200 mg of vitamin E per kg of food throughout the course of experiments. These mice were immunized primarily with HRBC 50 days after the beginning of treatment with vitamin E supplementation. Secondary immunization with TNP—HRBC, a hapten-carrier conjugate, was given 28 days after primary immunization with HRBC. Anti-HRBC and anti-TNP haemagglutinin titres were increased by supplementing mice with vitamin E. Moreover, the effect of previous priming of mice with HRBC on the hapten-specific antibody response to immunization with TNP-HRBC was also enhanced by vitamin E supplementation. These effects of vitamin E were dose-dependent, and vitamin E as tocopheryl acetate exerted more effect than vitamin E as tocopheryl nicotinate. In experiments with the mouse inbred strain DDD, vitamin E seemed to facilitate the shift of antibody production from IgM to IgG. Initial IgM response and late IgG response were not augmented by treating mice with vitamin E supplementation. These findings suggested that vitamin E stimulated the helper activity of T lymphocytes. This was confirmed using an adoptive transfer system involving stimulation of hapten-primed cells by a hapten-carrier conjugate in the presence of carrier-primed helper cells.     

Antigen dose defines T helper 1 and T helper 2 responses in the lungs of C57BL/6 and BALB/c mice independently of splenic responses

To investigate the effect of antigen dose on immune response, C57BL/6 and BALB/c mice were sensitized with aluminum hydroxide gel (alum)-precipitated ovalbumin (OVA) then challenged with aerosolized OVA. Low-dose sensitization (less than 8 microg of OVA) elicited T helper 2 (Th2)-type immunoglobulins (Igs) secretion from C57BL/6 mice, including high levels of serum IgE, IgG1 and low levels of IgG2a, while BALB/c mice secreted T helper 1 (Th1)-type Igs, including low levels of IgE, IgG1 and high levels of IgG2a. In contrast, high-dose sensitization (more than 50 microgram) elicited Th1-type Igs secretion in C57BL/6mice, while BALB/c mice exhibited Th2-type Igs secretion. Furthermore, the number of eosinophils infiltrating into the lungs of low-dose OVA-sensitized C57BL/6 mice was significantly greater than in BALB/c mice sensitized with the same amount of OVA. Only a very high dose of OVA (1 mg) could induce greater eosinophil infiltration into the lungs of BALB/c mice compared with C57BL/6 mice. Additionally, low-dose sensitization generated Th2-type cytokines, including high levels of interleukin (IL) -4, IL-5 and a low level of interferon-gamma (IFN-gamma) in the lungs of C57BL/6 mice, while BALB/c mice generated Th1-type cytokines in their lungs, including low levels of IL-4, IL-5 and a high level of IFN-gamma. In contrast, high-dose sensitization elicited Th1-type cytokines production in the lungs of C57BL/6 mice, while BALB/c mice generated Th2-type cytokines in their lungs. Interestingly, splenocyte cultures from C57BL/6 mice produced Th1-type cytokines, while cultures from BALB/c mice produced Th2-type cytokines regardless of OVA sensitization dose (100 ng-1 mg). These results indicate that C57BL/6 and BALB/c mice have different susceptibilities to OVA-sensitization and OVA-induced pulmonary eosinophilia regulated by Th1- and Th2-type cytokines, independent of splenic Th1- and Th2-type cytokines production.     

T cell proliferation and cytokine responses to ovalbumin and ovomucoid detected in children with and without egg allergy

BACKGROUND: The specific T cell responses in egg allergy and resolution have not been fully elucidated. OBJECTIVE: To characterize egg allergen-specific T cells of children with active and resolved egg allergy, in comparison with non-allergic controls. METHOD: We studied children with active (n=35) or resolved (n=20) egg allergy determined by oral challenge, and non-allergic controls (n=15). Peripheral blood mononuclear cells were labelled with carboxyfluorescein succinimidyl ester (CFSE) and stimulated with ovalbumin (OVA), ovomucoid (OM) or tetanus toxoid. Flow cytometry was used to detect divided CD3+ CFSE(lo) cells that expressed intra-cytoplasmic IL-4 or IFN-gamma. The cell division index (CDI) was calculated as a measure of allergen-specific proliferation. Peanut-specific T cells of a subgroup of children who also had peanut allergy were also studied. RESULTS: OVA-specific T cells were found in subjects with active (87%) or resolved (75%) egg allergy and in controls (67%), with a trend towards increased T cell proliferation in allergy. OM-induced weaker T cell responses than OVA, stimulating fewer responders (46% allergic, 50% resolved, 60% controls) and 10-fold less proliferation [CDI(OVA) 2.0 (median), 25.6 (maximum) vs. CDI(OM) 0.2 (median), 15.1 (maximum); P<0.01]. Both egg allergens induced significant IL-4+ (median 10%, range 1.4-58%) and IFN-gamma+ (median 28%, range 4.5-63%) cells in responders, including non-allergics. There were no significant differences in IFN-gamma+ or IL-4+ cells or in IFN-gamma/IL-4 ratios between groups. Peanut-specific T cell proliferation was significantly higher in peanut allergy [CDI(CPE) 16.5 (median), 24.8 (maximum)] compared with controls [CDI(CPE) 2.1 (median), 16.1 (maximum)] but cytokine profiles were not different. Tetanus-specific T cells were seen in 90% of the subjects, with no significant inter-group differences in responses. CONCLUSION: Egg allergen-specific T cells are readily detected in all groups and not restricted to egg allergy. In contrast, peanut-specific proliferation was significantly higher in peanut allergy. This suggests that T cell responses in peanut and egg allergy may differ. We did not find T helper type 2-deviated cytokine responses in egg or peanut allergy.     

Cell-mediated and humoral immune responses in mice. IV. Difference of the functional cell population between helper activity and delayed-type hypersensitivity.

Helper activity in the anti-hapten antibody response was studied in mice in reference to the induction of delayed-type hypersensitivity (DTH) to the carrier protein. Mice were immunized either by an i.v. injection of alum-precipitated bovine serum albumin (AP-BSA) plus bacterial endotoxin or by a s.c. injection of BSA in Freund's complete adjuvant, the latter being effective in inducing DTH. The helper activity was estimated by the antibody response to the challenge with dinitrophenylated BSA (DNP-BSA) given at varying intervals after the injection of BSA. The results indicated that the helper activity was independent of DTH to the carrier protein, suggesting that these two activities, are mediated by different populations of functional cells. A low dose of tolerogenic soluble BSA (sBSA) was sufficient to abrogate the helper activity in the response to DNP-BSA. In contrast, DTH to BSA was only partially depressed by the pretreatment with a low dose of sBSA and was completely depressed by a high dose. DTH reactivity in mice pretreated with a low dose of tolerogen and followed by the immunization with BSA in Freund's complete adjuvant was substantiated by the microscopic observation of mononuclear cell infiltration at the site of the test antigen injection. These results suggest that cells involved in the helper function and DTH may be derived from different precursors.     

A dietary probiotic (Bifidobacterium lactis HN019) reduces the severity of Escherichia coli O157:H7 infection in mice

The protective effects of the probiotic Bifidobacterium lactis HN019 against Escherichia coli O157:H7 were investigated in murine challenge infection models. BALB/c or C57BL/6 mice were fed milk-based diets supplemented with B. lactis HN019 (3 × 10⁸ cfu/g) for 7 days prior to and following oral challenge with E. coli O157:H7. Behavioral parameters (morbidity, feed intake) were measured for 7 days following challenge; immunological responses (phagocytosis, antibody) and pathogen translocation were measured in a sub-sample of ostensibly healthy animals 1 week post-challenge. Results showed that HN019-fed mice maintained significantly higher post-challenge feed intake and exhibited a lower cumulative morbidity rate, compared to control mice which did not receive the probiotic. Significantly higher proportions of phagocytically active cells in the blood and peritoneum, and higher intestinal tract IgA anti-E. coli antibody responses, were recorded among HN019-fed mice compared to controls. Among HN019-fed mice, pathogen translocation was identified in one of five BALB/c and one of five C57 mice; the comparative figures in control mice were two of five and three of five, respectively, and the mean bacterial burdens in these mice were over 100-fold higher than in HN019-fed mice. These results demonstrate that HN019 can reduce the severity of infection due to the enterohemolytic pathogen E. coli O157:H7, and suggest that this reduction may be associated with enhanced immune protection conferred by the probiotic. Received: 24 October 2000     

Seoul virus enhances regulatory and reduces proinflammatory responses in male Norway rats

Zoonotic pathogens, including hantaviruses, are maintained in the environment by causing persistent infection in the absence of disease in their reservoir hosts. Spillover of hantaviruses to humans can cause severe disease that is mediated by excessive proinflammatory responses. The mechanisms mediating hantaviral persistence in rodent reservoirs remain largely unknown. Male Norway rats were inoculated with their species-specific hantavirus, Seoul virus (SEOV), and viral RNA, cytokine, and chemokine responses were evaluated in spleen and lung tissue. More viral RNA was detectable in the lungs than spleen, with copies of SEOV peaking 15-30 days post-inoculation (p.i.) and persisting for 60 days p.i. In the lungs, the expression and production of proinflammatory mediators (i.e., IL-1beta, IL-6, TNF-alpha, IFN-gamma, CCL5, CCL2, CX3CL1, CXCL10, VCAM, VEGF, and NOS2) remained at or below baseline throughout SEOV infection; whereas, regulatory factors, including TGF-beta and FoxP3 were elevated. Conversely, in the spleen, proinflammatory responses were induced while regulatory responses remained unchanged during infection. To determine whether reduced proinflammatory responses mediate hantavirus persistence in the lungs, male rats were administered rIL-1beta or vehicle for 30 days during SEOV infection. SEOV persistence and shedding were not affected by IL-1beta treatment. Proinflammatory responses were elevated in rIL-1beta-treated rats, but remained within physiological levels, suggesting that supra-physiological concentrations may be necessary for viral clearance at the cost of causing disease. Elevated regulatory responses may suppress excessively high proinflammatory responses at a site of elevated SEOV replication to contribute to viral persistence and prevent proinflammatory-mediated disease in reservoir hosts.     

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (T_FH) cells, rather than type 2 T-helper (T_H2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (T_FR) cells, a specialized subset of regulatory T (T_REG) cells resident in B-cell follicles, restricts T_FH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5⁺ T_FH cells, not CXCR5⁻ conventional T_H2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5⁺ T_FR cell deletion. Upregulation of T_FH cell activities, including a skewing toward type 2 T_FH (T_FH2) and IL-13 producing T_FH (T_FH13) phenotypes, and defects in T_FR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between T_FH and T_FR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of T_FH and T_FR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.     

Centella asiatica treatment during postnatal period enhances learning and memory in mice

Present investigation was planned to evaluate the nootropic effect of Centella asiatica. Three months old male Swiss albino mice were injected orally with graded doses (200, 500, 700, 1000 mg/kg body weight) of C. asiatica aqueous extract for 15 days to select an effective dose for nootropic studies. Animals were tested in radial arm maze to assess the learning and memory performance. Based on these results, mice were treated orally with 200 mg/kg of C. asiatica for 15 days from day 15 to day 30 post partum (p.p.) and the nootropic effect was evaluated on the 31st day and 6 months p.p. The behavioral (open field, dark/bright arena, hole board and radial arm maze tests), biochemical (acetylcholine esterase activity) and histological studies (dendritic arborization) were carried out. Performance of juvenile and young adult mice was significantly improved in radial arm maze and hole board tests, but locomotor activity did not show any change compared to control. Treatment resulted in increased acetylcholine esterase activity in the hippocampus. Dendritic arborization of hippocampal CA3 neurons was also increased in terms of intersections and branching points, both at one month and 6 months. Results of the present investigation show that treatment during postnatal developmental stage with C. asiatica extract can influence the neuronal morphology and promote the higher brain function of juvenile and young adult mice.     

Prenatal exposure to bisphenol A up-regulates immune responses, including T helper 1 and T helper 2 responses, in mice

The effect of prenatal exposure to bisphenol A (BPA) on the immune system in mice was investigated. Virgin female mice were fed varying doses of BPA, on a daily basis, over a period of 18 days commencing on the day of pairing with stud males (day 0). On day 77, their male offspring of 8 weeks were immunized with hen egg lysozyme (HEL). Three weeks later, anti-HEL immunoglobulin G (IgG) in sera, and proliferative responses of spleen cells to the antigen, were measured. Anti-HEL IgG2a and interferon-gamma (IFN-gamma), secreted from splenic lymphocytes, were measured as indicators of T helper 1 (Th1) immune responses, while anti-HEL IgG1 and interleukin-4 (IL-4) were measured as indicators of Th2 responses. The results showed that fetal exposure to BPA was followed by significant increases in anti-HEL IgG as well as antigen-specific cell proliferation. Both Th1 responses (including anti-HEL IgG2a and IFN-gamma production) and Th2 responses (including anti-HEL IgG1 and IL-4 production) were augmented by prenatal exposure to BPA, although the augmentation of Th1 responses appeared to be greater than that of Th2 responses. Two-colour flow cytometric analysis showed that mice exposed prenatally to BPA had 29% and 100% more splenic CD3(+) CD4(+) and CD3(+) CD8(+) cells, respectively, than control animals. Similar results were obtained from females whose mothers had consumed BPA during pregnancy. These results suggest that prenatal exposure to BPA may result in the up-regulation of immune responses, especially Th1 responses, in adulthood.     

Running reduces stress and enhances cell genesis in aged mice

Cell proliferation and neurogenesis are diminished in the aging mouse dentate gyrus. However, it is not known whether isolated or social living affects cell genesis and stress levels in old animals. To address this question, aged (17–18 months old) female C57Bl/6 mice were single or group housed, under sedentary or running conditions. We demonstrate that both individual and socially housed aged C57Bl/6 mice have comparable basal cell proliferation levels and demonstrate increased running-induced cell genesis. To assess stress levels in young and aged mice, corticosterone (CORT) was measured at the onset of the active/dark cycle and 4 h later. In young mice, no differences in CORT levels were observed as a result of physical activity or housing conditions. However, a significant increase in stress in socially housed, aged sedentary animals was observed at the onset of the dark cycle; CORT returned to basal levels 4 h later. Together, these results indicate that voluntary exercise reduces stress in group housed aged animals and enhances hippocampal cell proliferation.     

Dendritic cell and T cell responses in children with food allergy

Background Food allergy (FA) and eosinophilic oesophagitis (EE) are increasingly common clinical problems. Dendritic cells (DCs) are key regulators of the sensitization and effector phases of allergic immune responses, but their role in these diseases is largely unknown. Objective To evaluate for alterations in the phenotype and function of DCs in children with IgE‐mediated milk allergy or EE compared with their non‐affected siblings. Methods Plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were prepared from peripheral blood of children with milk allergy (FA), EE, and non‐affected siblings (CON). Purified pDCs and mDCs were cultured alone or with autologous CD4⁺ lymphocytes. Cytokine levels in plasma, or culture supernatants following stimulation, were measured using multiplex array immunoassay. Cell‐surface molecule expression was determined by flow cytometry. Results DCs from FA subjects produced greater levels of pro‐inflammatory cytokines (IL‐6, TNF‐α), granulocyte macrophage‐colony forming factor, and mDC‐derived IL‐10 compared with controls following allergen exposure. T_H2 but not T_H1 cytokines were spontaneously produced in DC‐CD4⁺ T cell co‐cultures from children with FA and were not significantly increased after stimulation with milk extract, suggesting an ongoing activation in vivo. This hypothesis was further supported by evidence for elevated IL‐5 and IL‐13 protein in the plasma of children with both FA and EE. The only significant DC phenotypic differences were: (1) reduced levels of CD80 in EE subjects and (2) Fc?RI expression that correlated with serum IgE levels in both groups of subjects. Conclusion This study suggests that DCs from children with FA and EE produce more pro‐inflammatory cytokines, and that their CD4⁺ T cells are spontaneously activated to produce T_H2 cytokines in the presence of Fc?RI‐bearing DCs. Cite this as: P. A. Frischmeyer‐Guerrerio, A. L. Guerrerio, K. L. Chichester, A. P. Bieneman, R. A. Hamilton, R. A. Wood and J. T. Schroeder, Clinical & Experimental Allergy, 2011 (41) 61–71.     

Effects of lysed Enterococcus faecalis FK-23 on allergen-induced serum antibody responses and active cutaneous anaphylaxis in mice

BACKGROUND: Our previous studies have presented evidence that lysed Enterococcus faecalis FK-23 (LFK), a lysozyme and heat-treated probiotic product, can inhibit allergen-induced local accumulation of eosinophils in mice. OBJECTIVE: The purpose of this experimental study was to evaluate the influence of orally administrated LFK on the host immune responses. METHODS: BALB/c mice were sensitized subcutaneously, and challenged intraperitoneally by cedar pollen allergen. Blood and spleen samples were collected after oral administration of LFK 60 mg/day for 21 days. The serum levels of total and allergen-specific IgE and IgG2a antibodies and the production of IL-4, IL-5 and IFN-gamma generated by allergen-stimulated cultured splenocytes were determined. Additionally, the effect of LFK on active cutaneous anaphylaxis (ACA) induced by ovalbumin (OVA) challenge in mice was measured after 28 days LFK treatment. RESULTS: No significant differences in serum immunoglobulin levels, as well as in cytokine production of splenocytes were observed between LFK-treated and control mice (P>0.05). There was, however, an increasing tendency of allergen-specific IgG2a level in mice after LFK treatment for 21 days compared with controls (P=0.060). Furthermore, the serum ratio of specific IgE to IgG2a was found to be significantly decreased in the LFK group (P=0.005). In addition, a significant inhibition of OVA-induced ACA reaction was observed in mice that had been fed for 28 days with LFK compared with control mice (P=0.008). CONCLUSION: These results suggest that LFK shows an anti-inflammatory effect, which may be part of the mechanism for protection against IgE-mediated allergy.     

Infusion of UVB-treated splenic stromal cells induces suppression of beta cell antigen-specific T cell responses in NOD mice

Our previous study has demonstrated that transfusion of UVB-irradiation-induced apoptotic beta cells effectively prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. However, the limitation of beta cell source would preclude the clinical application of this approach. Therefore, in the present study, we have attempted to establish a more practical approach by utilizing apoptotic non-beta cells to prevent T1D. We find that apoptotic splenic stromal cells significantly suppress beta cell antigen-reactive T cell proliferation in vitro and in vivo. Moreover, beta cell antigen-specific T cells primed by beta cell antigens in the presence of apoptotic stromal cells have markedly reduced responsiveness to the re-stimulation of the same beta cell antigen. We also find that beta cell antigen-specific IL-10-producing CD4+ T cells are induced in the presence of apoptotic splenic stromal cells. As expected, transfusion of apoptotic stromal cells effectively protected NOD mice from developing T1D. Furthermore, the proliferation of adoptively transferred beta cell antigen-specific TCR-transgenic T cells in pancreatic draining lymph nodes is markedly suppressed in UVB-stroma-treated mice, indicating that UVB-stroma treatment induces immune tolerance to multiple beta cell antigens. This study provides an effective and convenient approach for managing T1D by utilizing apoptotic non-beta cells.     

DNA-Salmonella enterica serovar Typhimurium primer-booster vaccination biases towards T helper 1 responses and enhances protection against Leishmania major infection in mice

Successful resolution of infections by intracellular pathogens requires gamma interferon (IFN-gamma). DNA vaccines promote T helper 1 (Th1) responses by triggering interleukin-12 (IL-12) release by dendritic cells (DC) through Toll-like receptor 9 (TLR9). In humans TLR9 is restricted to plasmacytoid DC. Here we show that DNA-Salmonella enterica serovar Typhimurium primer-booster vaccination, which provides alternative ligands to bind TLR4 on myeloid DC, strongly biases towards Th1 responses compared to vaccination with DNA alone. This results in higher immunoglobulin G2a (IgG2a) responses compared to IgG1 responses, higher IFN-gamma responses compared to IL-10 CD4(+)-T-cell responses, and enhanced protection against Leishmania major infection in susceptible BALB/c mice.     

IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses

As IL-1 expression is augmented in delayed-type hypersensitivity (DTH) responses, we analyzed the role of IL-1 in this response. DTH responses against methyl BSA (mBSA) were significantly suppressed in IL-1beta-deficient (IL-1beta-/-) and IL-1alpha/beta-/- mice, but not in IL-1alpha-/- mice. In contrast, responses in IL-1R antagonist-/- (IL-1Ra-/-) mice were exacerbated. Lymph node cells derived from mBSA-sensitized IL-1beta-/-, IL-1alpha/beta-/- and IL-1R type I (IL-1RI)-/- mice, but not from IL-1alpha-/- mice, exhibited reduced proliferative responses against mBSA, while these from IL-1Ra-/- mice demonstrated augmented responses. DTH responses in wild-type mice following adoptive transfer of CD4+ T cells from mBSA-sensitized IL-1alpha/beta-/- mice were also reduced, while those in mice given cells derived from IL-Ra-/- mice were increased. DTH responses in IL-1RI-/-, but not IL-1alpha/beta-/-, mice were reduced upon transplantation of mBSA-sensitized CD4+ T cells from wild-type mice. The recall response of mBSA-sensitized CD4+ T cells against mBSA decreased upon co-culture with dendritic cells (DCs) from IL-1RI-/- mice, while the responses were normal with DCs from IL-1alpha/beta-/- mice. DTH responses in tumor necrosis factor alpha-/- (TNF-/-) mice were also suppressed; the magnitude of the suppression in IL-1alpha/beta-/-TNF-/- mice, however, was similar to that observed in IL-1alpha/beta-/- mice. These observations indicate that IL-1 possesses dual functions during the DTH response. IL-1beta is necessary for the efficient priming of T cells. In addition, CD4+ T cell-derived IL-1 plays an important role in the activation of DCs during the elicitation phase, resulting in the production of TNF, that activate allergen-specific T cells.     

Involvement of T helper type 17 and regulatory T cell activity in tumour immunology of bladder carcinoma

T helper type 17 (Th17) and regulatory T cells (T_reg) play an important role in the pathogenesis of inflammation and autoimmune disorders. Recent studies have suggested that they also had an impact on tumour immunology. However, the relationship between Th17 and T_reg cells in the pathogenesis of bladder carcinoma is still unclear. Flow cytometry was used to analyse the numbers, phenotype and cytokine production of Th17 cells in peripheral blood and tumour tissue from bladder carcinoma patients, in parallel with analysis of T_reg cells. The suppressor capacity of T_reg and the potential effects of interleukin (IL)‐2 on the differentiation of Th17 and T_reg cells in vitro were studied in a T cell stimulation and suppression assays. The results were as follows: Th17 cells were enriched in the tumours of patients with bladder carcinoma compared with the peripheral blood of patients and controls; patients with bladder carcinoma had a higher proportion of T_reg cells in peripheral blood compared with healthy controls and nearly all patients examined showed a relative enrichment of tumour‐infiltrating T_reg with respect to peripheral blood; there appeared to be an inverse relationship between tumour‐infiltrating Th17 and T_reg cells; IL‐2 could convert tumour‐infiltrating T_reg cells cultured in the presence of the autologous irradiated CD3^– fraction into Th17 cells, down‐regulate forkhead box P2 expression and suppressive capacity of T_reg cells. This study is the first to define the frequency and characteristics of Th17 cells in bladder carcinoma. We suggest that the balance between Th17 and T_reg cells may be involved in the development or progression of bladder carcinoma.