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In this paper, a deterministic model characterizing the within-host infection of Hepatitis C virus (HCV) in intrahepatic and extrahepatic tissues is presented. In addition, the model also includes the effect of the cytotoxic T lymphocyte (CTL) immunity described by a linear activation rate by infected cells. Firstly, the non-negativity and boundedness of solutions of the model are established. Secondly, the basic reproduction number R 01 and immune reproduction number R 02 are calculated, respectively. Three equilibria, namely, infection-free, CTL immune response-free and infected equilibrium with CTL immune response are discussed in terms of these two thresholds. Thirdly, the stability of these three equilibria is investigated theoretically as well as numerically. The results show that when R 01 < 1 , the virus will be cleared out eventually and the CTL immune response will also disappear; when R 02 < 1 < R 01 , the virus persists within the host, but the CTL immune response disappears eventually; when R 02 > 1 , both of the virus and the CTL immune response persist within the host. Finally, a brief discussion will be given. [ABSTRACT FROM AUTHOR]

Increased expectations from a number of regulatory agencies, e.g., Environmental Protection Agency (EPA), Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the Ministry of Health, Labour and Welfare (MHLW) of Japan, call for the evaluation of potential adverse effects on the immune system. As recently summarized in the ICH S8 guideline, the T-cell-dependent antibody response (TDAR) has been identified in a regulatory context as a main functional test of immunotoxicity. While the characterization of immunotoxic potential is pertinent to both the chemical and pharmaceutical industries, the use of immunotoxicology data for hazard identification and/or risk assessment in each case is different. Therefore, multiple approaches to immunotoxicity testing have evolved. The assays that evaluate TDAR function include both well-established tests, e.g., anti-sheep red blood cell plaque-forming cell (PFC) assay, and newer models, e.g., anti-keyhole limpet hemocyanin (KLH) antibody ELISA. These tests vary in the study design, antigen application and analytical methods. However, they all evaluate the same endpoint - a competent immune (e.g., antibody) response to an antigen. Numerous issues have been identified in the application of TDAR tests, including high animal to animal variability; differences in antigen source and potency; a lack of established "normal range" of the immune response and uncertainty about the degree of inhibition of the TDAR to be considered toxicologically important. As such, the need for a forum to discuss these issues was recognized by the immunotoxicology community, and was addressed at the 2006 Society of Toxicology (SOT) Workshop. A series of papers will summarize that forum with the ultimate objectives being to build a consensus among immunotoxicologists on the implications of these factors on using TDAR results in hazard identification and/or risk assessment, and to establish a criteria to classify compounds as immunotoxicants. [ABSTRACT FROM AUTHOR]

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of studies and endpoints. While the functional assessment of CD8+ cytotoxic T-lymphocytes (CTL) is well-characterized in the clinic, the lack of a robust macaque CTL functional assay has been an important hurdle in evaluating and accurately quantifying cell-mediated CD8+ T-cell effector responses in the nonclinical setting. This paper describes the development of an assay to measure CTL activity in peripheral blood mononuclear cells (PBMC) isolated from Cynomolgus macaques. A human EGFR/CD3 Bispecific T-cell Engager (BiTE®) was used to mount a robust CD8+ T-cell response in the presence of target-expressing cells. Upon target engagement, degranulation of CD107a and production of interferon (IFN)-γ both reliably indicated a robust functional response in CD8+ T-cells. The BiTE®-mediated stimulation method proved to be favorable when compared to other methods of stimulation in the absence of target cells. These studies demonstrated acceptable longitudinal variability of the functional assay and sensitivity to dexamethasone-mediated immunosuppression. Taken together, the results indicated an assay leveraging CD3-bispecific antibodies and target-expressing cells can provide a robust approach to the in vitro or ex vivo assessment of CTL function in Cynomolgus macaques. Because the impairment of CTL activity by immunomodulators is recognized to be an important contributor to decreased antiviral defense and increased carcinogenicity risk, we believe that this novel assay to be a valuable addition to the immunotoxicology assessment of therapeutic drug candidates. [ABSTRACT FROM AUTHOR]

In this paper, we introduce ordinary and delay differential equations to describe the interactions between a malignant tumour and the immune systemin vivoin the presence of human immunodeficiency virus (HIV) infection of CD4+T-cells. In the delay model, we take into account the time lags required by the healthy effector cell components to recognize the pathogens and tumour cells. The models consist of four populations: tumour cells, healthy effector cells (CD4+T-cells), effector cells infected by HIVs and free viral particles. The presence of delay term in the model leads to a notable increase in the complexity of the observed behaviour. We investigate the qualitative behaviour of the models and find the conditions that guarantee the asymptotic stability of the steady states. Numerical simulations are provided to illustrate and extend the theoretical results. The obtained results are consistent with the real phenomena and give a better understanding of cancer immunity and viral oncogenesis. [ABSTRACT FROM PUBLISHER]

Age-induced atrophy of the thymus results in a compromised immune system characterized by a restricted T-cell receptor repertoire, skewed towards memory T cells and a global reduction in immune responsiveness. This has important clinical implications in immune recovery from lymphopenic states, for example, after cytoablative treatment for cancer therapy, in conditioning regimes for bone marrow transplants and severe viral infections, such as HIV. The paper from Napolitano et al. evaluates the use of growth hormone (GH) to regenerate the thymus and replenish the naive T-cell population for immune recovery in adult HIV patients, albeit those carrying a low viral load. This study - an extension of an earlier paper from the same group - provides important evidence that GH, at least when administered over a long period of time, enhances thymopoiesis and therefore facilitates CD4+ T-cell recovery in HIV-1-infected adults. Provided the side effects of GH treatment can be better controlled, these results could contribute towards developing strategies for a broader clinical use of GH in immune recovery. [ABSTRACT FROM AUTHOR]

CD4+ T lymphocytes play an essential role in adaptive immune responses. In pathogen infection, naïve CD4+ T cells that strongly respond to foreign antigens robustly proliferate to differentiate into effector/memory cells, contributing to elimination of the pathogen concerned. In addition to this conventional T cell activation pathway, naïve T cells can also weakly respond to self antigens in the periphery to spontaneously acquire a memory phenotype through homeostatic proliferation in steady state. Such 'memory-phenotype' (MP) CD4+ T lymphocytes are distinguishable from foreign antigen-specific memory cells in terms of marker expression. Once generated, MP cells are maintained by rapid proliferation while differentiating into the T-bet+ 'MP1' subset, with the latter response promoted by IL-12 homeostatically produced by type 1 dendritic cells. Importantly, MP1 cells possess innate immune function; they can produce IFN-γ in response to IL-12 and IL-18 to contribute to host defense against pathogens. Similarly, the presence of RORγt+ 'MP17' and Gata3hi 'MP2' cells as well as their potential immune functions have been proposed. In this review, I will discuss our current understanding on the unique mechanisms of generation, maintenance, and differentiation of MP CD4+ T lymphocytes as well as their functional significance in various disease conditions. [ABSTRACT FROM AUTHOR]

Micro- and nanoplastics (MNP) are ubiquitously present in the environment due to their high persistence and bioaccumulative properties. Humans get exposed to MNP via various routes and consequently, they will encounter dendritic cells (DC) which are antigen-presenting cells involved in regulating immune responses. The consequences of DC exposure to MNP are an important, yet understudied, cause of concern. Therefore, this study aimed to assess the uptake and effect of MNP in vitro by exposing human monocyte-derived dendritic cells (MoDC) to virgin and environmentally weathered polystyrene (PS) particles of different sizes (0.2, 1, and 10 µm), at different concentrations ranging from 1 to 100 µg/ml. The effects of these particles were examined by measuring co-stimulatory surface marker (i.e. CD83 and CD86) expression. In addition, T-cell proliferation was measured via a mixed-leukocyte reaction (MLR) assay. The results showed that MoDC were capable of absorbing PS particles, and this was facilitated by pre-incubation in heat-inactivated (HI) plasma. Furthermore, depending on their size, weathered PS particles in particular caused increased expression of CD83 and CD86 on MoDC. Lastly, weathered 0.2 µm PS particles were able to functionally activate MoDC, leading to an increase in T-cell activation. These in vitro data suggest that, depending on their size, weathered PS particles might act as an immunostimulating adjuvant, possibly leading to T-cell sensitization. [ABSTRACT FROM AUTHOR]

Kidney transplants (KT) from hepatitis C (HCV) viremic donors to HCV negative recipients has shown promising renal outcomes, however, high incidence of cytomegalovirus (CMV) viremia were reported. We performed a prospective cohort study of 52 HCV negative KT recipients from Methodist University Hospital including 41 receiving transplants from HCV aviremic donors and 11 from HCV viremic donors. CMV specific CD4+ and CD8 + T cell immunity was measured by intracellular flow cytometry assay. Primary outcome was the development of positive CMV specific CD4+ and CD8 + T cell immune response in the entire cohort and each subgroup. The association between donor HCV status and CMV specific CD4+ and CD8 + T cell immune response was analyzed by Cox proportional hazard models. Mean recipient age was 48 ± 13 years, with 73% male and 82% African American. Positive CMV specific CD4+ and CD8 + T cell immune response was found in 53% and 47% of the cohort at 1 month, 65% and 70% at 2 months, 80% and 75% at 4 months, 89% and 87% at 6 months, and 94% and 94% at 9 months post-transplant, respectively. There was no significant difference in the incidence of positive CMV specific T cell immune response between recipients of transplants from HCV aviremic donors compared to HCV viremic donors in unadjusted (for CD8+: HR = 1.169, 95%CI: 0.521–2.623; for CD4+: HR = 1.208, 95%CI: 0.543–2.689) and adjusted (for CD8+: HR = 1.072, 95%CI: 0.458–2.507; for CD4+: HR = 1.210, 95%CI: 0.526–2.784) Cox regression analyses. HCV viremia in donors was not associated with impaired development of CMV specific T cell immunity in this cohort. [ABSTRACT FROM AUTHOR]

This study investigated the potential immunomodulatory effects of fermented soybean extract (FSE) in RAW264.7 cells and BALB/c mice. The expression of proinflammatory cytokines in RAW264.7 cells was measured after LPS stimulation in the presence or absence of FSE. Mice were orally administered 125, 250, and 500 mg/kg FSE for 21 days, and their immune response was analyzed. In RAW264.7 cells, FSE significantly reduced the expression of proinflammatory cytokines. In vivo experiments revealed significantly elevated splenocyte proliferation; neutrophil migration; phagocytic activities; expression of CD18+, CD4+, and CD8+ T cells; and expression of IL-2, IL-4, and IFN-γ. The major compounds in FSE were identified by GC–MS and by LC–MS/MS. Molecular docking analysis showed that daidzin, genistin and daidzein could potentially bind to the human high-affinity FcγRI–IgG complex to be involved in immunological responses. Taken together, FSE can be a candidate ingredient for health functional food with enhanced immunomodulating ability. [ABSTRACT FROM AUTHOR]

Cellular adjuvants, such as dendritic cells (DCs) are in the focus of tumor immunology and immunotherapy as tools to enhance immune responses in order to control cancer. Recent observations suggest that so-called tolerogenic DCs can be employed to achieve the opposite -- the control of adverse immune reactions in transplantation or autoimmunity. However, the use of DCs is limited due to their low frequency, lack of purity and expansion in cell culture. Activated B cells have previously been shown to efficiently present antigen and be expandable to almost unlimited amounts, rendering them an interesting alternative to induce antitumor immune responses. The paper under evaluation extends this concept to B cells as tolerogenic cells by providing insight in a novel mechanism -- the induction of regulatory T cells. [ABSTRACT FROM AUTHOR]

The current level of knowledge on transcriptome responses triggered by endotoxins and gluco-corticoids in immune cells in pigs is limited. Therefore, in the present study, we treated porcine peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and dexamethasone (DEX) separately or combined for 2 hours. The resultant transcriptional responses were examined by mRNA sequencing. We found that the LPS treatment triggered pronounced inflammatory responses as evidenced by upregulation of pro-inflammatory cytokines, chemokines, and related signaling pathways like NF-κB. Concurrently, a series of downregulated pro-inflammatory and upregulated anti-inflammatory molecules were identified. These are involved in the inhibition of TLR, NF- κB, and MAPK cascades and activation of signaling mediated by Tregs and STAT3, respectively. These findings suggested that LPS initiated also an anti-inflammatory process to prevent an overwhelming inflammatory response. The transcriptome responses further revealed substantial crosstalk of immune responses and glucocorticoid receptor (GR) signaling. This was apparent in four aspects: constitutive inhibition of T cell signaling by DEX through a subset of genes showing no response to LPS; inhibition of LPS-induced inflammatory genes by DEX; attenuation of DEX action by LPS paralleled by the regulation of genes implicated in cytokine and calcium signaling; and DEX-induced changes in genes associated with the activation of pro-inflammatory TLR, NF-κB, iNOS, and IL-1 signaling. Consequently, our study provides novel insights into inflammatory and GR signaling in pigs, as well as an understanding of the application of glucocorticoid drugs for the treatment of inflammatory disorders. [ABSTRACT FROM AUTHOR]

MDSCs, which are defined as a kind of negatively regulatory cells, could suppress T cell immune response in many tumor-bearing animal models and cancer patients. We supposed that MDSCs also contributed to the impaired antitumor immunity in MDS. Here we demonstrated that STAT3-ARG1 pathway could be a critical signal transduction pathway that regulated MDSCs-mediated immunosuppression. Increased MDSCs was revealed in MDS patients when compared to healthy controls. Especially, MDSCs performed higher activated STAT3 and CCR2 expression in high-risk MDS patients. The CCL2 and IL-6 levels in MDS patients were also higher than in healthy controls, which could drive recruitment and activation of MDSCs. Meanwhile, lower expression levels of CD3ζ chain, perforin and granzyme B were demonstrated in MDS patients, which were associated with downregulated activation of CD8+ T lymphocytes. The results were supported by the decreased perforin, granzyme B and IFN-γ levels in the mixed-culture system of MDSCs and CD8+ T lymphocytes in vitro. Notably, targeting STAT3 pathway by selective inhibitor could decrease ARG1 expression in MDSCs and partially reverse the lower expression levels of effector molecules on CD8+ T lymphocytes. Therefore, this study revealed the potential STAT3-ARG1 mechanism behind MDSCs and provided a promising STAT3 targeting strategy in MDS. [ABSTRACT FROM AUTHOR]

Introduction: Biological agents (BAs) target disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse. In addition, ADAs can also cause serious adverse events such as infusion hypersensitivity reactions (HRs). Areas covered: This review discusses the recent knowledge on the effector and regulatory mechanisms involved in the immune response to BAs used in patients suffering from rheumatic diseases leading to the production of ADAs and the impact on clinical outcome. Specifically, the demonstration of the involvement of specific T cell responses underlines B cells activation, and ADAs production is discussed correlating them to the different possible clinical consequences. Expert opinion: Although the mechanisms of the immune response and specifically the ADAs production to BAs have been extensively clarified in the last years, as well as their capacity to impact on clinical outcomes, among clinicians today a low awareness and in some cases a rejection persists, not only of the analysis and understanding of the immunological mechanisms behind the immunogenicity of BAs, but also the possible clinical impact that this may have. [ABSTRACT FROM AUTHOR]

The author reflects on the role of T-regulatory cells in tumor-host immune interaction in many lymphomas. According to the author, T-regulatory cells are part of the immune response which aimed at suppressing the effects of CD4+T-helper 1 (Th1) and CD8+ cytotoxic T cells. Despite some conflicting findings, the author believes that T-regulatory cells are important to chronic inflammation, autoimmunity, and tumor immunosurveillance.

Objective.The development of gliadin-specific antibody and T-cell responses were longitudinally monitored in young children with genetic risk for celiac disease (CD).Material and methods.291 newborn children positive for HLA-DQB1*02 and -DQA1*05 alleles were followed until 3–4 years of age by screening for tissue transglutaminase autoantibodies (tTGA) by using a commercial ELISA-based kit and antibodies to deamidated gliadin peptide (anti-DGP) by an immunofluorometric assay. Eighty-five of the children were also followed for peripheral blood gliadin-specific CD4+T-cell responses by using a carboxyfluorescein diacetate succinimidyl ester-basedin vitroproliferation assay.Results.The cumulative incidence of tTGA seropositivity during the follow-up was 6.5%. CD was diagnosed in nine of the tTGA-positive children (3.1%) by duodenal biopsy at a median 3.5 years of age. All of the children with confirmed CD were both IgA and IgG anti-DGP positive at the time of tTGA seroconversion and in over half of the cases IgG anti-DGP positivity even preceded tTGA seroconversion. Peripheral blood T-cell responses to deamidated and native gliadin were detected in 40.5% and 22.2% of the children at the age of 9 months and these frequencies decreased during the follow-up to the levels of 22.2% and 8.9%, respectively.Conclusions.Anti-DGP antibodies may precede tTGA seroconversion and thus frequent monitoring of both tTGA and anti-DGP antibodies may allow earlier detection of CD in genetically susceptible children. Peripheral blood gliadin-specific T-cell responses are relatively common in HLA-DQ2-positive children and are not directly associated with the development of CD. [ABSTRACT FROM PUBLISHER]

Delayed-type hypersensitivity (DTH) is a T-cell-mediated immune response that may be used for immunotoxicity testing in non-clinical species. However, in some cases DTH assays using T-dependent antigens may be confounded by the production of antibodies to the antigen. The authors have previously modified a DTH assay, initially validated in the mouse, for use in juvenile rats to assess the effect of immunosuppressive drugs on the developing rat immune system. The assay measures footpad swelling induced by subcutaneous footpad injection ofCandida albicans(C. albicans) derived-chitosan in rats previously sensitized withC. albicans. Antibodies to chitosan are not produced in this model. However, considerable inter-animal variability inherent in the footpad swelling assay can make it difficult to precisely quantify the magnitude of the immune response and inhibition by immunosuppressants, particularly if complete suppression is not observed. This report describes the development of anex vivoassay to assess DTH in rats using interferon (IFN)-γ production by splenocytes, obtained from rats sensitized withC. albicans, as the quantifiable measure of the DTH response. Adult and neonatal rats administered dexamethasone (DEX), a known immunosuppressant, exhibited immunosuppression as evidenced by a reduction inex vivoIFNγ production from splenocytes challenged withC. albicans-derived chitosan. Current data indicate that theex vivobased DTH assay is more sensitive than the conventional footpad swelling assay due to a lower background response and the ability to detect a response as early as post-natal day (PND) 12. Theex vivobased rat DTH assay offers a highly sensitive and quantitative alternative to the footpad swelling assay for the assessment of the immunotoxic potential of drugs. The increased sensitivity of theex vivoDTH assay may be useful for identifying smaller changes in response to immunotoxic drugs, as well as detecting responses earlier in animal development. [ABSTRACT FROM PUBLISHER]

Reconstitution of the immune function in chemotherapy patients will lead to decreases in post-operative complications. A preliminary investigation showed that an isoxazole derivative R-13 (3,5-dimethyl-isoxazole[5,4-e]8H-triazepin-4-one) hydrochloride, given in a single oral dose to normal mice, induced significant increases in the content of CD4+cells in the spleens and lymph nodes. That observation prompted the authors to assess the immune reconstituting effects of R-13 in mice pre-treated with cyclophosphamide (CP). Mice were given intraperitoneally (IP) a sublethal dose of CP (200 mg/kg) and then R-13 (as 20 µg IP doses, every 3 days post-CP treatment). Control mice, not treated with CP, received R-13 or the vehicle (DMSO in appropriate dilution). Blood leukocyte and splenocyte numbers, blood cell type levels, splenocyte spontaneous and ConA-induced proliferation, and delayed-type hypersensitivity (DTH) to ovalbumin (OVA) were investigated on day 15 post-CP treatment and five R-13 doses. The humoral immune response (antibody-forming cell development to sheep erythrocytes) was measured 30 days post-CP treatment and 10 R-13 doses. In CP-treated mice, five dosings with R-13 led to increases in numbers of splenocytes and blood leukocytes, as well as in spontaneous and ConA-induced splenocyte proliferation, relative to levels in mice that received only CP 15 days earlier. Blood analysis revealed decreases in neutrophil and eosinophil contents and an increased appearance of lymphocyte immature forms in all mice that received the R-13. Both cell-mediated responses to OVA and humoral immune response to sheep erythrocytes in CP-treated hosts were restored. Based on the data here, it is concluded that R-13 may be of potential value for reconstitution of the immune function of chemotherapy patients. [ABSTRACT FROM PUBLISHER]

Myeloid-derived suppressor cells (MDSCs) play a critical role in suppressing immune responses in patients with cancer or severe inflammation. Recent studies have focused on the strong relationship between MDSCs and autoimmune diseases, such as autoimmune hepatitis, inflammatory bowel disease and experimental autoimmune encephalomyelitis. Interestingly, MDSCs appear to serve multifaceted functions in autoimmunity, playing both protective and pathogenic roles. Therefore, although MDSCs may be a functional target for the therapy of autoimmune diseases, the disorders that accompany such treatments should be noted. In this manuscript, we summarize the functions and molecular regulation of MDSCs in immunity and autoimmune disease. [ABSTRACT FROM AUTHOR]

To determine whether there was a relationship between damage associated molecular pattern molecule (DAMP) expression and recruitment of suppressor cells to sites of metastasis we measured relative expression of DAMPs, regulatory T cells (Tregs), and myeloid derived suppressor cells (MDSC) in mice at various stages of breast cancer progression using the 4T1 model. Although S100A8 was expressed at relatively low levels in the tumor cells, expression was 100-fold higher in the lung and liver which are common sites of metastasis for this tumor. Despite the relatively high level of S100A8 expression in the lungs of naïve mice, the level of expression increased further and was significantly elevated after only 7 days of tumor growth. The same pattern was observed for MDSC, and both S100A8 and MDSC expression peaked in the lungs of mice following 21 days of tumor growth. Characterization of MDSC from the lungs revealed expression of RAGE, and the cells were capable of migrating in a dose-dependent manner toward S100A8. In addition, the MDSC expressed low levels of MHC Class I, MHC Class II, CD80, and secreted TGF-β. Taken together, these data suggest that expression of S100A8 in the lungs may facilitate recruitment of MDSC, which may in turn aid in establishing a metastatic niche capable of suppressing a localized immune response. [ABSTRACT FROM AUTHOR]

According to the self-nonself model of immunity, allogeneic T cells are considered as major cause of graft versus host disease (GVHD) following allogeneic stem cell transplantation (SCT). On the other hand, the danger model of immunity suggests that transplant-associated recipient tissue injury rather than donor-derived alloreactive T cells is the main cause of GVHD. What has been less appreciated are the early, both conditioning-dependent and conditioning-independent, events that impair homeostatic cellular adaptations and host-protective immune responses leading to the development of tissue-specific GVHD. The notion of gut injury precipitating in GVHD has been acknowledged by clinicians, with the shift to reduced intensity-conditioning regimens that prevent acute tissue injury and are less disruptive of tissue adaptation to T cell attack. Also, the role of host-protective immune response against pathogens in preventing GVHD has been shown by the lack of severe GVHD in germ free mice as well as an impaired anti-viral immune response during chronic GVHD. This article provides a brief review of the literature on GVHD and suggests that transplant-induced dysregulation of the protective immune response in the recipient of SCT is more important than allogeneic T cells in causing GVHD. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (DM1) is a chronic inflammatory disease, which when progresses leads to the development of late vascular complications. The disease involves impairments in regulatory and effector subsets of T lymphocytes, which suppress and maintain inflammatory response, respectively. ST2/IL-33 pathway is involved in T-cell-mediated immune response and might regulate the inflammatory process in several diseases. This review presents the latest research findings regarding effector and regulatory T cell subsets in the context of inflammation accompanying DM1 with particular focus on the ST2/IL-33 network and its possible association with T cell-mediated immunity. [ABSTRACT FROM AUTHOR]

Purpose: Vogt-Koyanagi-Harada (VKH) syndrome is a multisystem disorder presumed to be mediated by an autoimmune response. Recent studies have shown that interleukin (IL) 25 was involved in the T-cell immune response. This study analyzed the expression and potential role of IL-25 in the pathogenesis of VKH syndrome. Methods: The IL-25 serum levels were determined by enzyme-linked immunosorbent assay (ELISA). The IL-1β, IL-6, and TNF-α level in supernatants of PBMCs cultured with LPS in the absence or presence of recombinant(r) IL-25 was detected by ELISA. Results: A significantly decreased serum IL-25 level was found in VKH patients. In vitro experiments showed that rIL-25 was able to significantly inhibit the production of IL-1β, IL-6, and TNF-α by PBMCs from active VKH patients. Conclusions: IL-25 may be involved in the development of VKH syndrome, possibly by inhibiting the expression of proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) act in trans to control immune responses. The suppressive function of Tregs relies heavily on high and stable expression of the transcription factor FOXP3, which, together with other transcription factors, activates anti-inflammatory genes and represses proinflammatory genes. FOXP3 is required to shape the unique signaling mechanisms in Tregs, creating a positive-feedback pathway to further enhance its own expression. In addition, FOXP3 is thought to switch on a complex transcriptional network that leads to the stabilization of the Treg phenotype. Emerging data reveal that FOXP3 achieves this function in concert with several other transcription factors, many of which are associated with lineages of conventional T cells. In this review, we will discuss the structural features of FOXP3 and how it functions by interacting with other transcription factors. We will also summarize the role of FOXP3 in establishing the unique signaling cascades in Tregs. Finally, we will dissect the cooperative roles of FOXP3 and other T-cell lineage-defining transcription factors and discuss how these networks not only control the ability to Tregs to suppress different types of immune responses, but also enable Treg plasticity. [ABSTRACT FROM AUTHOR]

Apart from clonal deletion of self-reactive T cells in the thymus, Tregs are the major regulators of immune responses in the periphery and maintain a state of self-tolerance free from autoimmune diseases. Due to their inherent suppressive function, Tregs are being explored for their therapeutic potential in preventing autoimmunity and improving survival of allografts. This review provides recent updates on Treg biology and their use in animal as well as clinical models of transplantation. We discuss potential problems that limit the widespread clinical application of Tregs and provide future perspectives on how to optimize their medical use. Special consideration is given to methods by which Tregs should be isolated and expanded in order to facilitate clinical therapies. We also focus on recent discussions of Treg stability and plasticity, with specific insights into preventing the loss of Treg suppression by allotransplant-mediated inflammation. [ABSTRACT FROM AUTHOR]

The effective accumulation and interaction of mature dendritic cells (DCs) and naïve T cells within lymph nodes (LNs), which are driven by the CCR7-CCL19/CCL21 chemokine axis, are critical for the induction of adaptive T-cell immunity. human natural killer (NK) cells activated by interleukin (IL)-18 exhibit a unique 'helper' activity in promoting productive Dc-T cell interactions, inducing Dc maturation and shifting DC-primed T-cell responses toward a TH1 polarization. here, we demonstrate that such IL-18-activated 'helper' NK cells uniquely stimulate DCs to produce high levels of CCL19 through tumor necrosis factor α (TNFα) and interferon γ (IFNγ), a process that relies on secondary NK-cell activation by additional inflammatory signals including IFNα, IL-15, IL-12 and IL-2. DCs activated by helper NK cells not only promote the efficient CCR7-mediated recruitment of naïve cD8+ T cells, but also stimulate their expansion and expression of granzyme B. Using an ex vivo explant culture system based on LNs isolated from colorectal cancer patients, we found that CCL19 is upregulated in human tumor-associated lymphoid tissues treated with helper NK cell-stimulating factors. Our findings demonstrate the ability of 2 signal-activated helper NK cells to promote the production of the DC- and naïve/memory T cell-attracting chemokine CCL19 in LNs, and provide a rationale for the therapeutic application of IL-18-containing 'combinatorial adjuvants' to facilitate the induction of antitumor immune responses. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are a group of highly reactive chemicals containing oxygen produced either exogenously or endogenously. ROS are related to a wide variety of human disorders, such as chronic inflammation, age-related diseases and cancers. Besides, ROS are also essential for various biological functions, including cell survival, cell growth, proliferation and differentiation, and immune response. At present there are a number of excellent publications including some reviews about functions of these molecules either in normal cell biology or in pathophysiology. In this work, we reviewed available information and recent advances about ROS in the main immune cell types and gave summary about functions of these highly reactive molecules both in innate immunity as conservative defense mechanisms and in essential immune cells involved in adaptive immunity, and particularly in immune suppression. [ABSTRACT FROM AUTHOR]

Purpose: Isolated limb perfusion (ILP) with hyperthermia is an effective treatment for in-transit metastases of malignant melanoma in the extremities. Preclinical studies have shown that hyperthermia may induce an immunogenic death of tumour cells. We therefore decided to study whether ILP may induce tumour-specific immune responses in the clinical setting. Method: The number of Melan-A/Mart-1 specific CD8+ T cells, as well as other phenotypically different immune cells, was recorded in peripheral blood in 12 HLA-A2+ patients with in-transit metastases undergoing hyperthermic ILP with melphalan. Results: All patients underwent ILP without any complication and with an overall response rate of 83%. No substantial changes in the number of circulating T-cells, B-cells, NK-cells or monocytes were observed during follow-up. Four out of 12 patients showed an elevation of Melan-A+ CD8+ T-cells 4 weeks after ILP. Conclusion: We here report our preliminary observations that a small increase in tumour-specific T-cells could be seen in a subpopulation of patients after ILP. However, much more work is necessary to fully delineate the systemic immune response to hyperthermic ILP. [ABSTRACT FROM AUTHOR]

The immune system is an anatomically structured, orchestrated interaction of different cell types that communicate via a large number of receptors recognizing both soluble and cellular ligands. Recent technological advances now allow large-scale measurements for better appreciation of this complexity. Despite these advances, only a few immunological parameters are routinely measured in clinical practice. The authors believe that these measurements are insufficient to describe the immune function of individual patients and thus cannot be used to evaluate immunemediated diseases or response to therapy. Our current knowledge of immunology comes largely from work in murine model systems where the immune system has been characterized in great detail. This impressive volume of knowledge has proven to be difficult to translate into novel therapies in humans; one reason for this is the lack of large-scale immune monitoring allowing for systems-wide analysis of the human immune system. The authors propose a systems approach to immunology, where the focus is moved from analysis of individual cell types towards more integrated studies of the entire immune system. Exercising 'systems immunology' in preclinical research, during drug development and in patients undergoing therapies affecting the immune system, will enable us to improve clinical results through personalized medicine and help to define clinically relevant patterns of immune reactivity. [ABSTRACT FROM AUTHOR]

Little is known regarding the immunobiology of regulatory T (Treg) cells in hematopoietic malignancies, particularly in chronic lymphocytic leukemia (CLL). In the present study, we showed that the frequencies of CD8+ and CD4+ Treg cells were significantly increased in progressive as compared with indolent CLL patients and normal subjects. Enriched CD4+ Treg cells induced a similar level of inhibition in polyclonally activated B cells and effector T cells from CLL patients and normal subjects. Our results suggest that the increase in circulating Treg cells may result in downregulation of tumor-specific immune response, leading to tumor expansion and disease progression. [ABSTRACT FROM AUTHOR]

An assessment of antitumor immunity versus autoimmunity as provoked by the specific depletion of FOXP3+ Tregs is now possible with the development of Foxp3-diphtheria toxin receptor-like transgenic mouse models. We have used the poorly immunogenic B16F10 melanoma model to characterize a very heterogeneous antitumor effect of the immune response induced by Treg depletion. Depletion and neutralization studies demonstrated the importance of host T cells and interferon γ (IFNγ) in mediating the antitumor response developing in Treg-depleted mice. Such a response correlated with increased proliferation of granzyme B- and IFNγ-producing T cells in the tumor. Furthermore, enhanced antitumor immunity modulated the expression of MHC Class I molecules by B16F10 melanoma cells in Tregdepleted mice. Since Foxp3+ Treg depletion induced a significantly heterogeneous antitumor response, for the first time we were able to assess antitumor immunity and autoimmunity across different groups of responding mice. Strikingly, the duration of the tumor-immune system interaction provoked in individual Treg-depleted mice positively correlated with their propensity to develop vitiligo. A rapid complete tumor rejection was not associated with the development of autoimmunity, however, a proportion of mice that suppressed, but did not effectively clear, B16F10 melanoma did develop vitiligo. The significant implication is that approaches that combine with Treg depletion to rapidly reject tumors may also diminish autoimmune toxicities. [ABSTRACT FROM AUTHOR]

It has been shown that naturally occurring regulatory T-cells (CD4+CD25+ Foxp3+ T-cells) have critical roles in tumor invasion and down-regulation of immune response against established tumors. High expression of CD25 (IL-2R α) by regulatory T (Treg) cells may cause an inefficient response when using IL-2-based cancer vaccines. It seems that selective elimination of Treg cells before treatment of tumor-bearing T-cells can strongly increase the efficacy of a vaccine. The aim of this study was to set up an efficient cost-effective protocol to eliminate CD4+CD25+ T-cells-using the immunotoxin anti-tac-SAP. Peripheral blood mononuclear cells (PBMC) taken from colon cancer patients were treated with different concentrations (i.e., 0-100 µg/dl) of the immunotoxin. Flow cytometric analyses were then preformed to analyze expression of CD4, CD25, CD3, CD8, and CD45 surface markers; semi-quantitative fluorescent-PCR was used for the detection of Foxp3 expression before and after anti-tac-SAP treatment. The results indicated that anti-tac-SAP effectively eliminated CD4+CD25+ Treg cells and that 25 µg/dl was the optimal concentration of anti-tac-SAP for selective depletion of these cells. These outcomes were verified by analyses of Foxp3 expression. The results also indicated that this immunotoxin had no non-specific effects on other T-cells, including CD4+CD25− and CD8+CD45+ T-cells. Building on the work here, ongoing/future studies with the anti-tac-SAP will focus on functional assessments of the remaining (i.e., non-eliminated) T-cells (i.e., CD8, CD4; using proliferation and peptide sensitization assays) to ascertain if the immunotoxin inadvertently alters the functions of these cells-an untoward outcome. [ABSTRACT FROM AUTHOR]

Introduction. Magnesium (Mg) administration has been shown to promote bronchodilation and to improve lung function in asthma. It also plays an additional role in modulating the immune responses. This study was initiated to explore if Mg supplementation could affect the secretion of cytokines in acute asthmatic CD4+ T cells. Methods. Total serum Mg concentrations of the acute asthmatic patients and healthy controls were determined. CD4+ T cells were isolated from the blood of the acute asthmatic patients. They were cultured in various concentrations of Mg-supplemented (0.8, 5, 10, 15, and 20 mmol/1) medium. Cytokine (IL-5, IL-13, and IFN-γ) levels were determined by Enzyme-Linked Immunosorbnent Assay (ELISA). Results. Serum Mg concentration was lower in the acute asthmatic patients than that in the healthy controls (p < .05). The secretion of IL-5 and IL-13 was decreased, while the acute asthmatic CD4+ T cells were cultured in 10 and 15 mmol/1 Mg-supplemented medium, respectively, as compared to the 0.8 mmol/1 Mg group (p < .05). The secretion of IFN-γ increased in the 10 mmol/1 Mg group (p < .05). Conclusion. Mg supplementation was able to modulate the immune responses of acute asthmatic CD4+ T cells and decrease the secretion of type 2 CD4+ T lymphocytes cytokines. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are powerful activators of primary and secondary immune responses and have promising activity as anticancer vaccines. However, various populations of immune cells, including natural killer cells, regulatory T cells and especially cytotoxic T lymphocytes (CTLs), can inhibit DC function through cytotoxic clearance. Spontaneous tumor-specific CTL responses are frequently observed in patients before immunotherapy, and it is unclear how such pre-existing responses may affect DC vaccines. We used an adoptive transfer model to show that DC vaccination fails to induce the expansion of pre-existing CTLs or increase their production of interferon γ (IFNγ). The expansion and effector differentiation of naïve host CD81+ T cells was also suppressed in the presence of CTLs of the same specificity. Suppression was caused by the cytotoxic activity of the adoptively transferred CTLs, as perforin-deficient CTLs could respond to DC vaccination by expanding and increasing IFNγ production. Proliferation and effector differentiation of host CD81+ T cells as well as resistance to tumor challenge were also significantly increased. Expression of perforin by antitumor CTLs was critical in regulating the survival of vaccine DCs, while FAS /FAS L and TRAIL/DR5 had a significant, but comparatively smaller, effect. We conclude that perforin-expressing CTLs can suppress the activity of DC vaccines and prevent the expansion of naïve and memory CD81+ T cells as well as antitumor immune responses. We suggest that, paradoxically, temporarily blocking the cytotoxic functions of CTLs at the time of DC vaccination should result in improved vaccine efficiency and enhanced antitumor immunity. [ABSTRACT FROM AUTHOR]

Dendritic cells are characterized by the ability to induce primary antigen-specific immune responses in both major histocompatibility complex (MHC) Class I-restricted CD8 cells and MHC Class II-restricted CD4 cells. This professional antigen presentation function is associated with the up-regulation of co-stimulatory molecules and Class II MHC. While it has been recognized that several types of innate lymphocytes in mouse and humans can express co-stimulatory molecules and present antigen, the property of antigen presentation to elicit responses in naïve cells has been considered the exclusive domain of the dendritic cell. This concept has been challenged through the description of innate lymphocytes, capable of killing using NK receptors, but also up-regulating co-stimulatory molecules and driving the antigen-specific proliferation of naïve lymphocytes to the same extent as dendritic cells. Interferon (IFN)- γ secreting killer dendritic cells (IKDC) have been described in mice and share immunophenotypic properties of both dendritic cells and natural killer cells. Human blood γδ T-lymphocytes have innate tumor cell killing properties by both antibody-dependent and natural killer receptor-dependent mechanisms. This article reviews data from the authors' own laboratory showing a particular feature in common between the mouse IKDC and human blood γδ T-lymphocytes; namely their requirement for interaction with a target cell for specific licensing for professional antigen presentation. [ABSTRACT FROM AUTHOR]

Myeloid-Derived Suppressor Cells (MDSC) are immature myeloid cells that are potent inhibitors of immune cell function and which accumulate under conditions of inflammation, especially cancer. MDSC are suggested to promote the growth of cancer by both enhancement of tumor angiogenesis and metastasis and also inhibition of antitumor immune responses. The presence of deficient and/or defective antitumor adaptive and innate immune responses, coincident with accumulation of MDSC in lymphoid organs and tumor parenchyma, supports the notion of a causal relationship. The potent ability of MDSC to inhibit several components and phases of immune response highlights the likelihood that targeting the inhibitory functions of MDSC may maximize the therapeutic potential of antitumor immunotherapy. In order to guide the rational development of immunotherapeutic strategies that incorporate inhibition of MDSC activity and enzymatic functions, thorough understanding of the role of MDSC in antitumor immune responses is required. In this manuscript we review the multifaceted inhibitory functions of MDSC and consider the role of MDSC-induced inhibition of antitumor T cell effector phase. [ABSTRACT FROM AUTHOR]

The pathology of relapsing-remitting multiple sclerosis (RR-MS) is largely attributed to activated autoreactive effector T lymphocytes. The influence of microRNAs on the immune response has been shown to occur in different pathways of lymphocyte differentiation and function. Here, the expression of the miRNAs miR-15a/16-1 in PBMC, CD4+, and CD8+ from RR-MS patients has been investigated. BCL2, a known miR-15a/16-1 target, has also been analyzed. The results have shown that miR-15a/16-1 is downregulated in CD4+ T cells, whereas BCL2 is highly expressed in RR-MS patients only. Our data suggest that miR-15a/16-1 can also modulate the BCL2 gene expression in CD4+ T cells from RR-MS patients, thereby affecting apoptosis processes. [ABSTRACT FROM AUTHOR]

Vaccination remains the most cost-effective method for preventing infectious diseases. Key to vaccine design is the development of immunological memory, which is an essential property of the adaptive immune system. Bacterial polysaccharide conjugate vaccines are the gold standard currently used to confer protection of the host by inducing humoral immune responses against T-cell-independent antigens. Conjugate vaccines are effective, but we propose that local mucosal immune responses are likely to also play an important role in inducing immunity, and they have been less explored than systemic and adaptive immune responses. Adjuvants have been used to improve the immune response to vaccine antigens, however, no mucosal adjuvant has been licensed for human use. Here we describe the recent progress in the use of mucosal adjuvants to achieve significant immune responses against T-cell-independent antigens. We also introduce the idea that studying the mechanisms that induce cell sub-populations with strong immunological memory may facilitate the design of novel vaccine formulations, in particular in cases of B-cell unresponsiveness to thymus-independent stimuli. [ABSTRACT FROM AUTHOR]

In the present study, we evaluated the effectiveness of a levamisole-based adjuvant (ADL) to enhance the ability of the Ag85B-ESAT6 fusion protein to boost immune responses after primary vaccination with recombinant bacillus Calmette-Guerin (rBCG) in Balb/c mice. The results were compared with that of the control adjuvant formulation of dimethyl dioctadecylammonium bromide (DDA) and monophosphoryl lipid A (MPL), which has previously been shown to induce T-helper type 1 (Th1)-biased responses. Enzyme-linked immunospot (ELISPOT) assay with Ag85B and ESAT6 derived peptides corresponding to CD4++ and CD8++ T cell restricted epitopes and cell surface immunostaining indicated that Ag85B-ESAT6/ADL predominantly triggered activation of CD4++ T cells. Functional CD8++ T cells with interferon (IFN)-γ production or cytotoxicity were undetectable all vaccinated mice. The ADL adjuvant modified T-helper (Th) subtypes by up-regulating multiple signature cytokines. Furthermore, profiles of the immunoglobulin G (IgG) subtypes indicated ADL enhanced the secretion of Th1-associated IgG2a antibodies and decreased the yield of Th2-associated IgG1 subtype. These observations suggest that the ADL adjuvant formulated with a protein booster may induce Th1-biased cellular and humoral immune responses to primary vaccination with a live attenuated bacterial TB vaccine. [ABSTRACT FROM AUTHOR]

Cell-mediated immunity offers protection against virus-infected cells and tumor cells, involves activation of natural killer (NK) cells, production of antigen-specific cytotoxic T-lymphocytes, and release of various cytokines in response to an antigen. Administration of an ethanolic extract of Aerva lanata was found to stimulate cell-mediated immunological responses in normal and tumor-bearing BALB/c mice. A significant enhancement in NK cell activity in both normal and tumor-bearing hosts was observed after administration of A. lanata. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent complement-mediated cytotoxicity (ACC) were significantly enhanced as well in both sets of treated hosts. In addition, in vivo production of IL-2 and IFNg were each significantly enhanced by extract treatment. The stimulatory effect of A. lanata on cytotoxic T-lymphocyte (CTL) production was determined by Winn's neutralization assay using CTL-sensitive EL4 thymoma cells. A. lanata treatment caused a significant increase in CTL production in both in vivo and in vitro models, in each case as indicated by a significant increase in the life-spans of tumor-injected mice. Taken together, all of these results in the murine model indicate that administration of an ethanolic extract of A. lanata could enhance the cell-mediated anti-tumor response. [ABSTRACT FROM AUTHOR]

Various Invariant NKT (iNKT) cell ligands have been shown as potent adjuvants in boosting T cell reactivates to antigens on professional APC. Non-professional APC, such as T cells, also co-expressing MHC class I and CD1d, have been unattractive cell vaccine carriers due to their poor immunogenicity. Here, we report that T cells as well as T cell lymphoma can efficiently generate antigen-specific cytotoxic T lymphocytes (CTL) responses in mice in vivo, when formulated to present iNKT ligand α-galactosylceramide (αGC) on their surface CD1d. Vaccination with αGC-pulsed EG-7 T-cell lymphoma induced tumor-specific CTL response and suppressed the growth of EG-7 in a CD8 T cell-dependent manner. Injection of αGC-loaded CD4 T cells in mice efficiently activated iNKT cells in vivo. While T cells loaded with a class I-restricted peptide induced proliferation but not effector differentiation of antigen-specific CD8 T cells, injection of T cells co-pulsed with αGC strongly induced IFNc and Granzyme B expression in T cells and complete lysis of target cells in vivo. Presentation of αGC and peptide on the same cells was required for optimal CTL response and vaccinating T cells appeared to directly stimulate both iNKT and cytotoxic CD8 T cells. Of note, the generation of this cytotoxic T cell response was independent of IL-4, IFNγ, IL-12, IL-21 and costimulation. Our data indicate that iNKT cell can license a non-professional APC to directly trigger antigen-specific cytotoxic T cell responses, which provides an alternative cellular vaccine strategy against tumors. [ABSTRACT FROM AUTHOR]

Patients with sarcoidosis can be subgrouped according to organ engagement and clinical manifestations. One such subgroup is Löfgren's syndrome (LS), constituting a distinct group of sarcoidosis patients with typical clinical manifestations, separate genetic associations and an immune response that seems to differ from that of non-LS patients. In particular, LS patients have strong associations with HLA-DRB1 alleles, and the well-known association with HLA-DRB1*03 is particularly striking. This particular HLA-DRB1 allele is also a very strong marker within that particular group of patients for a prognostically favorable disease course. This article will mainly discuss genetic associations with LS, and the possible implications of such associations. [ABSTRACT FROM AUTHOR]

Understanding how nanoparticles may affect immune responses is an essential prerequisite to developing novel clinical applications. To investigate nanoparticle-dependent outcomes on immune responses, dendritic cells (DCs) were treated with model biomedical poly(vinylalcohol)-coated super-paramagnetic iron oxide nanoparticles (PVA-SPIONs). PVA-SPIONs uptake by human monocyte-derived DCs (MDDCs) was analyzed by flow cytometry (FACS) and advanced imaging techniques. Viability, activation, function, and stimulatory capacity of MDDCs were assessed by FACS and an in vitro CD4++ T cell assay. PVA-SPION uptake was dose-dependent, decreased by lipopolysaccharide (LPS)-induced MDDC maturation at higher particle concentrations, and was inhibited by cytochalasin D pre-treatment. PVA-SPIONs did not alter surface marker expression (CD80, CD83, CD86, myeloid/plasmacytoid DC markers) or antigen-uptake, but decreased the capacity of MDDCs to process antigen, stimulate CD4++ T cells, and induce cytokines. The decreased antigen processing and CD4++ T cell stimulation capability of MDDCs following PVA-SPION treatment suggests that MDDCs may revert to a more functionally immature state following particle exposure. [ABSTRACT FROM AUTHOR]

Purpose: The effects of radiation ++/− hypogravity on immunologic function were investigated using the Partial Weight Suspension (PWS) model (Wagner et al. 2010). Materials and methods: Mice were exposed to 0.5, 1, or 2 Gray (Gy) dose of gamma radiation and then placed in the PWS system for 4, 24, 48 hours, or 4 days. Spleens were excised and white blood cells were prepared for flow cytometry analyses. Results: The combination of PWS ++ radiation (1 and 2 Gy doses only) resulted in decreased cell viability at the 24 h (∼16% decrease), 48 h (∼20% decrease), and 4 day (∼20% decrease) time points, compared to the PWS (no radiation) and no treatment (non-suspended, non-irradiated) groups. The T lymphocyte (thymus-derived) population increased by ∼10% (24 h, 48 h, and 4 day time points), while the B lymphocyte (bursal or bone marrow-derived) population decreased by ∼10% (at all time points examined), when mice were exposed to PWS ++ radiation (2 Gy dose only), compared to the PWS or no treatment groups. T cell activation was observed in the PWS group and the 0.5 Gy ++/− PWS groups at the 4 and 24 h time points, compared to the no treatment group. However, T cell activation was significantly suppressed (∼85%) at the acute time points in the 2 Gy ++/− PWS groups, comparable to the no treatment group. Conclusions: Ionizing radiation in the absence and presence of simulated hypogravity results in acute lymphocyte dysfunction and compromised immune response. [ABSTRACT FROM AUTHOR]

In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (Tregs) include natural or thymic-derived Tregs, T-cells which express Foxp3+CD25+CD4+ and can suppress immune responses to autoreactive T-cells, as well as inducible Tregs, that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible Tregs include TH3 cells, Tr1 cells, and Foxp3+-inducible Tregs. Tregs have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4+CD25+ Tregs from mice resulted in the development of multi-organ autoimmune diseases. CD4+CD25+ Tregs and/or IL-10-producing Tr1 cells are capable of suppressing or attenuating TH2 responses to allergens. Moreover, adoptive transfer of CD4+CD25+ Tregs from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFβ-producing Tr1 cells as well as FoxP3- expressing IL-10 T-cells, with resulting suppression of the TH2 cytokine milieu. Activation, expansion, or suppression of CD4+CD25+ Tregs in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases. [ABSTRACT FROM AUTHOR]

The identification of a novel helper T (Th)-cell subset, the IL-17-producing Th (Th17) cells, has provided new insight into our understanding of the molecular mechanisms of reproduction. IL-17 has an important role in induction of the protective immune response against extracellular bacteria or fungal pathogens. Th17 cells seem to participate in successful pregnancy processes. Th17 cells also play a pivotal role in pathogenesis of endometriosis, miscarriage, preterm labor and preeclampsia. Recent data show the reciprocal development of pathways between Th1/Th17 subsets and between Th17/Treg subsets, and the imbalance of Th17/Treg development has been reported in recurrent pregnancy loss and preeclampsia. [ABSTRACT FROM AUTHOR]

Background: Ingested immunoactive proteins type I interferon, soluble immune response suppressor peptide 1-21 and melanocyte-stimulating hormone inhibit clinical attacks and inflammation in acute experimental autoimmune encephalomyelitis (EAE). Objective: We examined whether another immunoactive protein, somatostatin (SST), would have similar anti-inflammatory effects on EAE after oral administration. Design/methods: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or SST during ongoing disease. Splenocytes from mock-fed or SST-fed mice were adoptively transferred into active MOG peptide 35-55-immunized recipient mice during ongoing disease. Results: In actively fed mice, increased Th2-like cytokines in both the spleen and the central nervous system (CNS) inhibited active disease. In recipients of donor cells from SST-fed donors, reduction of Th1 and Th17 and induction of Th2-like IL-4 cytokines in both the spleen and CNS inhibited disease. Treg cells were increased threefold in actively fed spleen cells that are responsible for protection against disease after adoptive transfer. Conclusions: Ingested (orally administered) SST can inhibit clinical disease, inhibit CNS inflammation by decreasing Th17 and Th1-like cytokines and increasing Th2-like cytokines in the CNS via induction of Treg cells. [ABSTRACT FROM AUTHOR]

Heterologous immunity is a common phenomenon present in all infections. Most of the time it is beneficial, mediating protective immunity, but in some individuals that have the wrong crossreactive response it leads to a cascade of events that result in severe immunopathology. Infections have been associated with autoimmune diseases such as diabetes, multiple sclerosis and lupus erythematosis, but also with unusual autoimmune like pathologies where the immune system appears dysregulated, such as, sarcoidosis, colitis, panniculitis, bronchiolitis obliterans, infectious mononucleosis and even chronic fatigue syndrome. Here we review the evidence that to better understand these autoreactive pathologies it requires an evaluation of how T cells are regulated and evolve during sequential infections with different pathogens under the influence of heterologous immunity. [ABSTRACT FROM AUTHOR]

SJL mice represent a mouse model in which young adult females are susceptible to autoimmune disease, while age-matched males are relatively resistant. T cells primed in female SJL mice secrete cytokines associated with a Th1 phenotype. By contrast, T cells primed in males secrete cytokines associated with a Th2 phenotype. Activation of Th2-type T cells in males vs. Th1 cells in females correlates with increased CD4++CD25++ T regulatory cells (Treg) in males. T cells primed in males depleted of CD4++CD25++ T cells preferentially secrete IFN-γγ and decreased IL-4 and IL-10 compared to CD4++CD25++ T-cell-sufficient males, suggesting that Treg influence subsequent antigen-specific cytokine secretion. Treg from males and females exhibit equivalent in vitro T-cell suppression. Treg from males express increased CTLA-4 and CD62L and preferentially secrete IL-10. These data suggest that an increased frequency of IL-10 secreting Treg in male SJL mice may contribute resistance to autoimmune disease by favoring the development of Th2 immune responses. [ABSTRACT FROM AUTHOR]

Nanomaterial of titanium dioxide (TiO2) is manufactured in large-scale production plants, resulting in risks for accidental high exposures of humans. Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects. By using the Dark Agouti (DA) rat, a strain disposed to develop chronic inflammation following exposure to immunoactivating adjuvants, we investigated local and systemic inflammatory responses after lung exposure of nanosized TiO2 particles up to 90 days after intratracheal instillation. TiO2 induced a transient response of proinflammatory and T-cell-activating cytokines (interleukin [IL]-1αα, IL-1ββ, IL-6, cytokine-induced neutrophil chemoattractant [CINC]-1, granulocyte--macrophage colony-stimulating factor [GM-CSF], and IL-2) in airways 1--2 days after exposure, accompanied by an influx of eosinophils and neutrophils. Neutrophil numbers remained elevated for 30 days, whereas the eosinophils declined to baseline levels at Day 8, simultaneously with an increase of dendritic cells and natural killer (NK) cells. The innate immune activation was followed by a lymphocyte expansion that persisted throughout the 90-day study. Lymphocytes recruited to the lungs were predominantly CD4++ helper T-cells, but we also demonstrated presence of CD8++ T-cells, B-cells, and CD25++ T-cells. In serum, we detected both an early cytokine expression at Days 1--2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon-gamma [IFN-γγ] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-αα), indicating systemic late-phase effects in addition to the local response in airways. In summary, these data demonstrate a dynamic response to TiO2 nanoparticles in the lungs of DA rats, beginning with an innate immune activation of eosinophils, neutrophils, dendritic cells, and NK cells, followed by a long-lasting activation of lymphocytes involved in adaptive immunity. The results have implications for the assessment of risks for adverse and persistent immune stimulation following nanoparticle exposures in sensitive populations. [ABSTRACT FROM AUTHOR]

T helper type 17 (Th17) cells, a newly identified effector T-cell subset, have recently been shown to play a role in numerous autoimmune diseases, including iodine-induced autoimmune thyroiditis in non-obese diabetic (NOD)-H2h4 mice, which had previously been thought Th1-dominant. We here studied the role of Th17 in Graves' hyperthyroidism, another thyroid-specific autoimmune disease, in a mouse model. Two genetically distinct BALB/c and NOD-H2h4 strains with intact or disrupted IL-17 genes (IL-17++/++ or IL-17−−  /  −−  ) were immunized with adenovirus (Ad) expressing the thyrotropin receptor (TSHR) A-subunit (Ad-TSHR289). Both IL-17++/++ and IL-17−−  /  −−  mice developed anti-TSHR antibodies and hyperthyroidism at equally high frequencies on the BALB/c genetic background. In contrast, some IL-17++/++, but none of IL-17−−  /  −−  , mice became hyperthyroid on the NOD-H2h4 genetic background, indicating the crucial role of IL-17 for development of Graves' hyperthyroidism in non-susceptible NOD-H2h4, but not in susceptible BALB/c mice. In the T-cell recall assay, splenocytes and lymphocytes from the draining lymph nodes from either mouse strains, irrespective of IL-17 gene status, produced IFN-γγ and IL-10 but not other cytokines including IL-17 in response to TSHR antigen. Thus, the functional significance of Th17 may not necessarily be predictable from cytokine expression patterns in splenocytes or inflammatory lesions. In conclusion, this is, to our knowledge, the first report showing that the role of Th17 cells for the pathogenesis of a certain autoimmune disease depends on the mouse genetic backgrounds. [ABSTRACT FROM AUTHOR]