Fluoxetine treatment to rats modifies serotonin transporter and cAMP in lymphocytes,CD4+ and CD8+ subpopulations and interleukins 2 and 4

Several lines of evidences indicate that antidepressants produce various immunomodulatory effects. Fluoxetine, an antidepressant and selective serotonin reuptake inhibitor, modulates immune cells in vitro. To explore the in vivo influence of fluoxetine on lymphocytes, male Sprague–Dawley rats were treated daily, 10 mg/kg, or with saline solution for 1, 2 and 3 weeks. The presence of serotonin transporter in CD3+, CD4+ and CD8+ subpopulations of T lymphocytes was determined by immunofluorescence. Serotonin transporter was also labeled with [³H]paroxetine, specific binding defined with imipramine. Plasma levels of pro-inflammatory interleukin 2 (IL-2), and anti-inflammatory interleukin 4 (IL-4), were measured by ELISA; and cAMP concentration by radioimmunoassay. Fluoxetine significantly increased the number of lymphocytes expressing serotonin transporter and elevated the binding of [³H]paroxetine. The percentage of CD4+ cells decreased, that of CD8+ increased, and CD3+ did not change. The ratio CD4+/CD8+ was significantly lowered. Fluoxetine administration elevated the levels of IL-4 at 1, 2 and 3 weeks; and of IL-2, at 2 and 3 weeks. IL-4/IL-2 ratio was significantly increased in fluoxetine group respecting the controls and was similar during the 3 weeks of treatment. Fluoxetine produced a significant decrease in cAMP concentrations in lymphocytes, probably by secondary activation of serotonin receptors. Treatment with fluoxetine modified immune parameters in plasma and lymphocytes of rats, which might be relevant for its systemic therapeutic action as an antidepressant.     

Differential immune modulation by deoxynivalenol (vomitoxin) in mice

Mycotoxin deoxynivalenol (DON), a secondary metabolite produced by Fusarium fungi, is a contaminant in wheat, barley, and corn worldwide. It has been suggested that DON exhibits toxicity in various organs. Due to the lack of immunotoxicity data for DON, we investigated the differential immunomodulatory effects of DON in mice. DON was orally administered to female BALB/c mice at a dose of 0, 0.5, or 2 mg/kg body weight for 14 days and various immunotoxicity tests were performed with standard protocols. The population of CD19⁺ and CD11c⁺ cells in the spleen and mesenteric lymph node (MLN) and of F4/80⁺ cells in the spleen was significantly decreased in DON-treated mice, whereas the level of CD8⁺ and CD4⁺CD25⁺Foxp3⁺ cells in the spleen and CD4⁺ T cells in MLN was significantly increased. In intra-epithelial lymphocytes (IELs) of the small intestine, the population of CD4 ⁺ and CD19⁺ cells was increased but that of CD8⁺ cells was decreased. Levels of CD4 ⁺ and CD8⁺ cells were decreased in lamina propria lymphocytes (LPLs) of small intestine; however, the level of CD4⁺ and CD8⁺ lymphocytes was increased but that of CD19⁺ cells was decreased in Peyer's patches lymphocytes (PPLs). Normalized expression of TLR4 in spleen, TLR9 in PPs, and TLR2, TLR3 and TLR4 in MLNs was significantly decreased, whereas expression of TLR5 and TLR9 was increased in spleen. The concentration of IgA and IgE was decreased and increased, respectively, in serum; however, the mucosal IgA level was significantly increased in the duodenum. Levels of IFN-γ, IL-2, IL-4, and IL-6 were significantly increased in serum. Furthermore, DON induced apoptosis in spleen, MLNs, and PPs, and DON-induced apoptosis was promoted by increased expression of Bax and decreased expression of Bcl-2. The autophagy genes Atg5 and Beclin-1 were up-regulated in spleen but down-regulated in MLN. After priming of the RAW 264.7 macrophage cell line with different TLR ligands, DON exposure differentially modulated IL-1β, IL-10, and TNF-α production. These results indicate that DON can cause various immunomodulatory effects in mice, creating a milieu that might allow invasion by other microorganisms.     

Obaculactone suppresses Th1 effector cell function through down-regulation of T-bet and prolongs skin graft survival in mice

Allograft rejection is a predominantly Th1 immune response. In this study, we showed that obaculactone, a natural compound derived from citrus fruit, prolonged skin graft survival in mice when treated after but not before transplantation. Furthermore, obaculactone inhibited alloantigen-specific production of Th1 cytokine IFN-γ as well as proinflammatory cytokine IL-2, TNFα and IL-6. In parallel, IL-10 production was markedly up-regulated. Obaculactone significantly enhanced the percentage of CD4⁺CD25⁺Foxp3⁺ Treg cells in the CD4⁺ splenocytes without any effect on their inhibitory function. In vitro and in vivo tests showed obaculactone down-regulated T-bet expression in Th1 effector cells. Taken together, the unique immunomodulatory properties might qualify obaculactone as a putative, therapeutic compound for the treatment of Th1-driven diseases, including transplant rejection.     

Immunomodulatory effects of cinobufagin isolated from Chan Su on activation and cytokines secretion of immunocyte in vitro

The objective of this study was to evaluate the immunomodulatory effects of cinobufagin (CBG) isolated from Chan Su (Venenum Bufonis) in vitro. In this paper, our results show that CBG signi?cantly stimulated cell proliferation of splenocytes and peritoneal macrophages (PMΦ) and markedly enhanced the phagocytic activation of PMΦ. CBG also significantly increased CD4⁺CD8⁺ double-positive T-cell populations and the percentage of S-phase cells of splenic lymphocytes. The levels of several Th1 cytokines, including interferon-γ and tumor necrosis factor-α, are signi?cantly increased after CBG treatment, whereas the levels of the Th2 cytokine interleukin-4 and interleukin-10 are signi?cantly decreased. As a result, the ratio of Th1/Th2 also increased. Taken together, these results indicated that CBG had potential immune system regulatory effects and suggested that this compound could be developed as a novel immunotherapeutic agent to treat immune-mediated diseases such as cancer.     

RETRACTED: Pierisformoside B exhibits neuroprotective and anti-inflammatory effects in murine hippocampal and microglial cells via the HO-1/Nrf2-mediated pathway

Ideal potential vaccine adjuvants to stimulate a Th1 immune response are urgently needed to control intracellular infections in clinical applications. Telocinobufagin (TBG), an active component of Venenum bufonis, exhibits immunomodulatory activity. Therefore, we investigated whether TBG enhances the Th1 immune response to ovalbumin (OVA) and formalin-inactivated Salmonella typhimurium (FIST) in mice. TBG augmented serum OVA- and FIST-specific IgG and IgG2a and the production of IFNγ by antigen-restimulated splenocytes. TBG also dramatically enhanced splenocyte proliferative responses to concanavalin A, lipopolysaccharide, and OVA and substantially increased T-bet mRNA levels and the CD3⁺/CD3⁺CD4⁺/CD3⁺CD8⁺ phenotype in splenocytes from OVA-immunized mice. In in vivo protection studies, TBG significantly decreased the bacterial burdens in the spleen and prolonged the survival time of FIST-immunized mice challenged with live S. typhimurium. In vivo neutralization of IFNγ with anti-IFNγ mAbs led to a significant reduction in FIST-specific IgG2a and IFNγ levels and in anti-Salmonella effect in TBG/FIST-immunized mice. In conclusion, these results suggest that TBG enhances a Th1 immune response to control intracellular infections.     

Thymol as a reciprocal regulator of T cell differentiation: Promotion of regulatory T cells and suppression of Th1/Th17 cells

Regulatory T cells (Tregs) are critical for maintaining immune response and enhancing their differentiation has therapeutic implications for autoimmune diseases. In this study, we investigated the effects of thymol a well-known monoterpene from Thyme on differentiation and function of Tregs. In vitro generation of Tregs from purified naïve CD4⁺CD25⁻ T cells in the presence of thymol was carried out. Suppressor activity of generated Tregs was examined by changes in the proliferation of CFSE-labeled conventional T cells. Thymol promotes differentiation of naïve CD4⁺CD25⁻ T cells to CD4⁺CD25⁺Foxp3⁺ Tregs [66.9–71.8% vs. control (47%)] and increased intensity of Foxp3 expression on Tregs (p < 0.01). In functional assay, an increased immune suppression by thymol-induced Tregs (≈2.5 times of untreated Tregs) was detected. For in vivo study, thymol was intraperitoneally administered to ovalbumin (Ova)-immunized mice. Flow cytometry assessment of spleens from thymol-treated Ova-immunized mice showed increased number of CD4⁺ Foxp3⁺ Tregs (>8%, p < 0.01(and decreased levels of CD4⁺T-bet⁺ Th1 and CD4⁺RORγt⁺ Th17 cells resulted in significant decreased Th1/Treg and Th17/Treg ratios. In ex vivo Ova challenge of splenocytes from thymol-treated Ova-immunized mice, similarly higher levels of CD4⁺ Foxp3⁺ Tregs, and also elevated TGF-β expression in CD4⁺Foxp3⁺ population (48.1% vs. 18.9% in untreated Ova-immunized group) and reduced IFN-γ-producing CD4⁺T-bet⁺ T cells and IL-17-producing CD4⁺RORγt⁺ T cells were detected. This led to marked decreased ratios of IFNγ/TGF-β and IL-17/TGF-β expressions. In conclusion, this study revealed thymol as a compound with enhancing effects on Treg differentiation and function, which may have potential benefits in treatment of immune-mediated diseases with Th1/Th17 over-activation.     

Effects of Al on the splenic immune function and NE in rats

Norepinephrine (NE) regulates the splenic immune function and it may be related to the effects of Aluminum (Al) on the splenic immune function. Here, the aim of this study was to further explore the effects of aluminum trichloride (AlCl₃) on the splenic immune function and its relationship with NE. Forty male Wistar rats were orally exposed to AlCl₃ (0, 64.18, 128.36 and 256.72 mg/kg BW) through drinking water for 120 days. The CD3⁺, CD4⁺, CD8⁺ T lymphocytes, the T and B lymphocytes proliferation rates and serum NE concentration were examined. The correlation analysis between splenic immune function and NE were done. The results showed that the CD3⁺, CD4⁺, CD8⁺ T lymphocytes and the T and B lymphocytes proliferation rates decreased and NE concentration increased in AlCl₃-treated rats. NE was negatively correlated with proportions of CD3⁺, CD4⁺ T lymphocytes and T and B lymphocytes proliferation rates, but not correlated with CD8⁺ T lymphocytes. The results suggest that AlCl₃ suppresses the splenic immune function and NE plays important role in this process.     

Disodium cromoglycate treatment reduces TH2 immune response and immunohistopathological features in a murine model of Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is an emergent chronic disease of the esophagus. The immunopathological process in EoE is characterized by Th2 immune response and prominent eosinophilic influx, in response to common food allergens. The classical treatment consists of allergen elimination diet and systemic/topical corticosteroid therapy. Nevertheless, patients do not always comply to treatment, and the prolonged corticosteroid therapy can cause side effects, therefore, there is an immediate need for new therapeutic approach for EoE. Disodium cromoglicate (DSCG) is a substance broadly used in allergic asthma treatment, and a well-known mast cell activation stabilizer. However, its effect in EoE have not been evaluated yet. This study aimed to assess the effects of DSCG treatment in an EoE experimental model. Male Balb/C mice were subcutaneously sensitized for five days with OVA, and subsequently orally OVA-challenged, DSCG administration was performed between the OVA-challenges. DSCG treatment not only reduced eosinophilic and mast cell influx, as well as reduced fibrosis. In addition, tslp, GATA_3, IL-5, FoxP₃ and IL-10 mRNA expression were reduced in esophageal mucosa, associated with lower Th2 (CD3⁺CD4⁺GATA3⁺IL4⁺) and B cells (CD19⁺CD40⁺) number in peripheral lymphoid organs. In conclusion, the data demonstrate DSCG treatment was effective in reducing mast cell activation and Th2 immune response, important immunopathological EoE features. Therefore, the use of DSCG as an EoE treatment can be considered a promising therapeutic approach to treat this disease.     

Augmentation of immune response by chicoric acid through the modulation of CD28/CTLA-4 and Th1 pathway in chronically stressed mice

This study demonstrates the protective effect of chicoric acid (CA) on chronic restraint stress-induced altered T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental Swiss albino mice. CA has the potential to restore diminished immune response and Th1/Th2 homeostasis in chronically stressed mice as evident by significant increase in lymphocyte proliferation and CD3⁺, CD4⁺ and CD8⁺ T cell population. Interestingly, chicoric acid imparted immunostimulation mainly by upregulating the expression of CD28 and CD80 and downregulating CTLA-4. It exerted stimulatory effect on IL-12, IFN-gamma and IL-2 and suppressed the increased IL-10 levels in chronically stressed mice. It also exhibited a significant lowering effect on raised corticosterone levels and reversed the chronic stress-induced hypertrophy of adrenal glands and atrophy of thymus and spleen, thereby showing its normalizing effect on HPA axis. Our results reveal that CA has the potential to reverse the impact of chronic restraint stress on immune status by normalizing corticosterone levels and augmenting Th1 cytokine profile along with the co-stimulatory molecules particularly CD28/CTLA-4 pathway that plays a very important role in generation of an effective immune response in immune compromised situations.     

Therapeutic anti-psoriatic effects of myeloid-derived suppressor cells in combination with systemic tacrolimus (FK-506) in an imiquimod-induced mouse model of psoriasis

Although tacrolimus (FK-506) has been shown to be an effective monotherapy for psoriasis, it does not always work well. Currently, combination therapy is frequently used to manage psoriasis because clinical trials have shown it may provide additive or synergistic benefits and reduce risks of adverse effects. Myeloid-derived suppressor cells (MDSCs) have potent immunomodulatory and anti-inflammatory properties in autoimmune diseases. We previously reported that MDSCs had protective effects in a murine model of imiquimod (IMQ)-induced psoriasis. The present study was undertaken to investigate the systemic immunomodulatory and therapeutic efficacy effects of MDSC plus FK-506 in an IMQ-induced mouse model of psoriasis and to investigate the immunomodulatory mechanisms involved. Systemic MDSC plus FK-506 therapy was found to have a significant anti-psoriatic effect in the murine model, to reduce levels of pro-inflammatory cytokines Th1 cytokines (TNF-α and IFN-γ) and Th17 cytokines (IL-17A and IL-23) in serum and skin. However, treatment with MDSCs or FK-506 alone had little impact. Furthermore, the anti-psoriatic effects of MDSC plus FK-506 were associated with histopathological reductions in inflammatory infiltration, epidermal hyperplasia, and hyperkeratosis. In addition, this combined treatment also attenuated IMQ-induced splenomegaly, and increased the proportion of CD4⁺CD25⁺FoxP3⁺ regulatory T (Treg) cells and decreased the proportions of CD4⁺IFN-γ⁺ Th1 cells and CD4⁺IL-17⁺ Th17 cells in spleen. Taken together, our results show systemic combination therapy with MDSCs and FK-506 had a better therapeutic effect in our IMQ-induced psoriasis model than either agent alone, and suggest that this combinatorial therapy might be useful for the management of autoimmune skin diseases like psoriasis.     

Alcoholic extract of Cicer microphyllum augments Th1 immune response in normal and chronically stressed Swiss albino mice

Objective The purpose of this study was to observe the effect of an alcoholic extract of Cicer microphyllum (I³M/38/A001) (whole plant without seeds and flowers) on the immunological parameters of sheep red blood cell immunized normal and chronically stressed Swiss albino mice. Methods Estimation of T‐cell subsets (CD3⁺, CD4⁺/CD8⁺), CD80/CD86, CD28, CD 69, costimulatory molecules and Th1/Th2 cytokines was carried out using a flow cytometer. This was followed by study of the delayed type hypersensitivity response, in‐vitro lymphocyte proliferation assay and measurement of Th1/Th2 cytokines in isolated peripheral blood mononuclear cells by flow cytometry. An enzyme immune assay was used to analyse corticosterone levels in the serum of chronically stressed animals. Key findings We found that oral administration of I³M/38/A001once daily at the graded doses of 6.25, 12.5, 25, 50, 100 and 200 mg/kg p.o. enhanced the proliferation and differentiation of T lymphocytes in sheep red blood cell normal and chronically stressed mice, as shown by flow cytometric analysis. The extract selectively induced type 1 immunity: it guided enhanced expression of Th1 cytokines, interferon‐γ and interleukin‐2, while no significant change in interleukin‐4 (Th2 cytokine) levels was observed. Confirmation of Th1 polarization was confirmed by the augmented levels of interferon‐γ and interleukin‐2 in isolated peripheral blood mononuclear cells. A significant suppression of raised corticosterone levels was also observed in stressed animals, which suggests the extract's normalizing effect on the hypothalamic–pituitary–adrenal axis. Co‐stimulatory molecules, CD28, CD69, CD80 and CD86, which are important secondary signals for the activation of the immune system, elicited significant expression in I³M/38/A001 treated mice. Conclusion Our studies show the immune potentiating and immune recuperative effect of the test drug in sheep red blood cell‐immunized normal and chronically stressed mice.     

Prenatal cadmium exposure alters postnatal immune cell development and function

Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl₂ (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4⁺FoxP3⁺CD25⁺ (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8⁺CD223⁺ T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific.     

Th9 cells are subjected to PD-1/PD-L1-mediated inhibition and are capable of promoting CD8 T cell expansion through IL-9R in colorectal cancer

Th9 cells are named after their expression of IL-9. Studies in recent years demonstrated that Th9 cells could contribute to antitumor immunity by enhancing the recruitment and activation of mast cells, natural killer cells, CD8 T cells, and dendritic cells in the tumor microenvironment. To determine whether Th9 cells participate in colorectal cancer (CRC), we collected resected tumor samples from 20 CRC patients. In the tumor-infiltrating lymphocytes (TILs), IL-9⁺IL-4⁻ CD4⁺ T cells could be observed and were present at higher frequencies than the IL-9⁺IL-4⁺ and the IL-9⁻IL-4⁺ cells, suggesting that the majority of IL-9-producing TILs were bona fide Th9 cells. IL-9-secreting TILs presented particularly high PD-1 expression directly ex vivo. The expression of IL-9 was significantly reduced with PD-L1-mediated inhibition, which in turn was suppressed by anti-PD-1 blocking. Interestingly, the circulating CD4⁺ T cell compartment in CRC patients also presented Th9 enrichment, characterized by higher IL-9⁺IL-4⁻ and IL-9⁺IL-4⁺ cell frequencies in the CXCR3⁻CCR6⁻ compartment as compared to that in non-cancer controls. Using exogenous TGF-β and IL-4, we were capable of enriching Th9 cells without concurrent enrichment of Th2 cells. Th9-enriched CD4⁺ T cells, but not Th9-non-enriched cells, significantly increased the expansion of activated CD8⁺ T cells, in a manner that was dependent on the expression of IL-9R. In addition, the frequencies of Th9 cells in the tumor were positively correlated with the frequencies of CD8⁺ TILs. Together, we demonstrated that Th9 cells infiltrated CRC tumor, could be regulated via the PD-1/PD-L1 pathway, and could contribute the CD8⁺ T cell expansion.     

Immunomodulatory Activity of Ginsan, a Polysaccharide of Panax Ginseng, on Dendritic Cells

Ginsan, a Panax ginseng polysaccharide that contains glucopyranoside and fructofuranoside, has immunomodulatory effects. Although several biologic studies of ginsan have been performed, its effects on dendritic cells (DCs), which are antigen-presenting cells of the immune system, have not been studied. We investigated the immunomodulatory effects of ginsan on DCs. Ginsan had little effect on DC viability, even when used at high concentrations. Ginsan markedly increased the levels of production by DCs of IL-12 and TNF-α, as measured by ELISA. To examine the maturation-inducing activity of ginsan, we measured the surface expression levels of the maturation markers MHC class II and CD86 (B7.2) on DCs. It is interesting that ginsan profoundly enhanced the expression of CD86 on DC surfaces, whereas it increased that of MHC class II only marginally. In ³H-thymidine incorporation assays, ginsan-treated DCs stimulated significantly higher proliferation of allogeneic CD4⁺ T lymphocytes than did medium-treated DCs. Taken together, our data demonstrate that ginsan stimulates DCs by inducing maturation. Because DCs are critical antigen-presenting cells in immune responses, this study provides valuable information on the activities of ginsan.     

Anti-inflammatory effects of DA-9601, an extract of Artemisia asiatica,on aceclofenac-induced acute enteritis

DA-9601 is an extract obtained from Artemisia asiatica, which has been reported to have anti-inflammatory effects on gastrointestinal lesions; however, its possible anti-inflammatory effects on the small intestine have not been studied yet. Therefore, in this study, we investigated the protective effects of DA-9601 against the ACF-induced small intestinal inflammation. Inflammation of the small intestine was confirmed by histological studies and the changes in the CD4⁺ T cell fraction induced by the inflammation-related cytokines, and the inflammatory reactions were analyzed. Multifocal discrete small necrotic ulcers with intervening normal mucosa were frequently observed after treatment with ACF. The expression of IL-6, IL-17, and TNF-α genes was increased in the ACF group; however, it was found to have been significantly decreased in the DA-9601 treated group. In addition, DA-9601 significantly decreased the levels of proinflammatory mediators such as IL-1β, GM-CSF, IFN-γ, and TNF-α; the anti-inflammatory cytokine IL-10, on the other hand, was observed to have increased. It is known that inflammatory mediators related to T cell imbalance and dysfunction continuously activate the inflammatory response, causing chronic tissue damage. The fractions of IFN-γ⁺ Th1 cells, IL-4⁺ Th2 cells, IL-9⁺ Th9 cells, IL-17⁺ Th17 cells, and Foxp3⁺ Treg cells were significantly decreased upon DA-9601 treatment. These data suggest that the inflammatory response induced by ACF is reduced by DA-9601 via lowering of the expression of genes encoding the inflammatory cytokines and the concentration of inflammatory mediators. Furthermore, DA-9601 inhibited the acute inflammatory response mediated by T cells, resulting in an improvement in ACF-induced enteritis.     

Paeoniflorin inhibits skin lesions in imiquimod-induced psoriasis-like mice by downregulating inflammation

Psoriasis is a common chronic immune-mediated inflammatory disease. It is well known that macrophages, neutrophils and T-helper 1 (Th1)/T-helper 17 (Th17) cells play important roles in skin lesions by provoking inflammation. Paeoniflorin (PF) is the major effective component extracted from the root of Paeonia lactiflora, which has been widely used in China to treat inflammatory and autoimmune diseases, including psoriasis. Although PF shows a clinical therapeutic effect on psoriasis patients, how PF affects infiltrated immune cells in psoriasis skin lesions is still unknown. In this study, using a generated imiquimod (IMQ)-induced psoriasis-like mouse model, we found that PF ameliorates inflammation and skin lesions. Subsequent analyses showed that PF decreases the number of F4/80⁺CD68⁺ macrophages and their related cytokine production (TNF-α, IL-1β, IL-6, IL-12 and inducible nitric oxide synthase (iNOS)) in the skin of IMQ-challenged mice. Moreover, PF suppresses the number of CD11b⁺Gr-1⁺ neutrophils and the expression of macrophage inflammatory protein-2 (MIP-2; a counterpart of human IL-8, which is responsible for the recruitment of neutrophils in mice). Finally, PF also down-regulates Th1- and Th17-related cytokine expression. Therefore, our new findings reveal that PF alleviates psoriatic skin lesions by inhibiting inflammation, which provides new insights into the immunomodulatory effect of PF in psoriasis treatment.     

Induced apoptosis of Th2 lymphocytes and inhibition of airway hyperresponsiveness and inflammation by combined lactic acid bacteria treatment

Several lactic acid bacteria (LAB) demonstrably regulate the immune system and inhibit allergic disease. This study examined whether oral feeding of either Lactobacillus paracasei (L. paracasei) BB5 and/or Lactobacillus rhamnosus (L. rhamnosus) BB1 suppresses ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in a murine model. OVA-specific immune responses, cell profile of bronchoalveolar lavage fluid (BALF), and airway AHR were assessed following OVA and methacholine challenge. We investigated whether LAB can enhance CD4⁺FoxP3⁺ and CD8⁺FoxP3⁺ regulatory T (Treg) cells in splenic cells and apoptosis of CD4⁺IL-4⁺ T cells. Results found oral administration of combined LAB better than single L. paracasei or L. rhamnosus strain, improving Penh ratio after challenge with methacholine. High-dose combined LAB starkly decreased synthesis of OVA-specific IgE and IgG2a levels, as well as eosinophils infiltration in BALF. In addition, CD4⁺IL-4⁺ T cells decreased while CD4⁺FoxP3⁺ and CD8⁺FoxP3⁺ Treg cells increased significantly in splenic mononuclear cells of high-dose combined LAB group. Findings indicate allergen-induced AHR and airway allergic inflammation suppressed by enhances CD4⁺FoxP3⁺ and CD8⁺FoxP3⁺ Treg populations as well as Th1 cell response after treating with combined LAB. This study may provide a basis for developing a novel therapeutic or protective method for airway allergic disease.     

Alloantigen specific T regulatory cells in transplant tolerance

CD4⁺CD25⁺Foxp3⁺T cells are regulatory/suppressor cells (Treg) that include non-antigen(Ag)-specific as well as Ag-specific Tregs. How non-Ag-specific naïve CD4⁺CD25⁺Treg develop into specific Tregs is unknown. We have studied DA rats tolerant to fully allogeneic PVG cardiac grafts that survived with out immunosuppression for over 100 days and identified the cellular basis of alloantigen specific tolerance. Key observations from our studies will be reviewed including how CD4⁺CD25⁺Tregs were first identified and the cytokine dependence of CD4⁺T cells that transfer alloantigen specific transplant tolerance which died in culture unless stimulated with both cytokine rich ConA supernatant and specific donor alloantigen. Both the tolerant CD4⁺CD25⁺ and CD4⁺CD25⁻ T cell populations are required to transfer tolerance, yet alone the CD4⁺CD25⁻ T cell effect rejection. Tolerance transfer occurs with a low ratio of CD4⁺CD25⁺T cells (< 1:10), whereas to induce tolerance with naive CD4⁺CD25⁺T cells requires both a ratio of > 1:1 and is not alloantigen specific.Recent findings on how naïve CD4⁺CD25⁺T cells developed into two separated pathways of alloantigen specific Tregs, by culturing them with alloAg with either IL-2 or IL-4 and donor alloantigen are described. IL-2 enhances IFN-γR and IL-5 mRNA while IL-4 induced a reciprocal profile with de novo IL-5Rα and increased IFN-γ mRNA expression. Both IL-2 and IL-4 alloactivated CD4⁺CD25⁺Tregs within 3–4 days of culture can induce alloantigen specific tolerance at ratios of 1:10. Long term, CD4⁺CD25⁺T cells from tolerant hosts given IL-2 cultured cells have increased IL-5 and IFN-γR mRNA; whereas hosts given IL-4 cultured cells had enhanced IL-5Rα mRNA expression and IL-5 enhanced their proliferation to donor but not third party alloAg.These findings suggest that Th1 and Th2 responses activate two pathways of alloantigen specific Tregs that can mediate transplant tolerance but are dependent upon cytokines produced by ongoing Th1 and/or Th2 immune responses.     

The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses

Lentinan, a (1-3)-beta glucan from Lentinus edodes, is an effective immunostimulatory drug. We tested the effects of lentinan during blood-stage infection by Plasmodium yoelii 17XL (P.y17XL). Pre-treatment of mice with lentinan significantly decreased the parasitemia and increased their survival after infection. Enhanced IL-12, IFN-γ and NO production induced by lentinan in spleen cells of infected mice revealed that the Th1 immune response was stimulated against malaria infection. In vitro and in vivo, lentinan can result in enhanced expression of MHC II, CD80/CD86, and Toll-like receptors (TLR2/TLR4), and increased production of IL-12 in spleen dendritic cells (DCs) co-cultured with parasitized red blood cells (pRBCs). Moreover, both the number of CD4⁺CD25⁺ regulatory T cells (Tregs) and the levels of IL-10 secreted by Tregs were reduced by pre-treatment with lentinan in the spleen of malaria-infected mice. Meanwhile, apoptosis of CD4⁺ T cell in spleens of mice pretreated with lentinan was significantly reduced. In summary, lentinan can induce protective Th1 immune responses to control the proliferation of malaria parasites during the blood-stage of P.y17XL infection by stimulating maturation of DCs to inhibit negative regulation of the Th1 immune response by Tregs. Taken together, our findings suggest that lentinan has prophylactic potential for the treatment of malaria.