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Cytokine Milieu (cytokine + milieu)
Selected AbstractsEffector T-cell differentiation during viral and bacterial infections: Role of direct IL-12 signals for cell fate decision of CD8+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2009Selina J. Keppler Abstract To study the role of IL-12 as a third signal for T-cell activation and differentiation in vivo, direct IL-12 signaling to CD8+ T cells was analyzed in bacterial and viral infections using the P14 T-cell adoptive transfer model with CD8+ T cells that lack the IL-12 receptor. Results indicate that CD8+ T cells deficient in IL-12 signaling were impaired in clonal expansion after Listeria monocytogenes infection but not after infection with lymphocytic choriomeningitis virus, vaccinia virus or vesicular stomatitis virus. Although limited in clonal expansion after Listeria infection, CD8+ T cells deficient in IL-12 signaling exhibited normal degranulation activity, cytolytic functions, and secretion of IFN-, and TNF-,. However, CD8+ T cells lacking IL-12 signaling failed to up-regulate KLRG1 and to down-regulate CD127 in the context of Listeria but not viral infections. Thus, direct IL-12 signaling to CD8+ T cells determines the cell fate decision between short-lived effector cells and memory precursor effector cells, which is dependent on pathogen-induced local cytokine milieu. [source] Th1 cytokine,induced downregulation of PPAR, in human biliary cells relates to cholangitis in primary biliary cirrhosis,HEPATOLOGY, Issue 6 2005Kenichi Harada Peroxisome proliferator-activated receptor-, (PPAR,) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPAR, ligands can ameliorate clinical severity by downregulating the expression of proinflammatory cytokines. Primary biliary cirrhosis (PBC) is characterized by chronic destructive cholangitis with a Th1-predominant cytokine milieu. Unusual immune responses to infectious agents are suspected to underlie its etiopathogenesis. We examined the significance of PPAR, in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-,B) DNA-binding assays to clarify the intrahepatic distribution of PPAR, and the regulation of PPAR, by inflammatory cytokines and PPAR, ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPAR, protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPAR, protein and mRNA was reduced in damaged bile ducts. PPAR, expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-, (Th1-type). PPAR, ligand negatively modulated lipopolysaccharide-induced NF-,B activation. Moreover, this inhibitory effect of PPAR, ligand was attenuated by pretreatment with IFN-,. In conclusion, PPAR, may be important to maintain homeostasis in the intrahepatic biliary epithelium, and its reduction in the bile ducts of PBC liver may be associated with the Th1-predominant milieu and with the development of chronic cholangitis in PBC. Immunosuppression using PPAR, ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC. (HEPATOLOGY 2005;41.) [source] Lymphoid microenvironment in the gut for immunoglobulin A and inflammationIMMUNOLOGICAL REVIEWS, Issue 1 2003Robert Chin Summary:, Signaling through lymphotoxin , receptor (LT,R) initiates the unfolding of a host of developmental programs ranging from the organogenesis of lymph nodes and Peyer's patches (PPs) to the coordination of splenic microarchitecture. While investigating an alternative pathway to immunoglobulin A (IgA) production, it was uncovered that LT,R signaling in the lamina propria (LP) stroma orchestrates the coordinated expression of key chemokines and adhesion molecules, creation of a cytokine milieu, and stroma development that facilitates robust IgA production independent of secondary lymphoid structures. Simultaneously, this same infrastructure can be commandeered by autoreactive T cells to organize both the acute destruction of the intestinal mucosa and chronic intestinal inflammation via the ligands for LT,R. The ability to modulate LT,R signaling may alternatively permit the suppression of autoimmune responses and augmentation of gut defenses. [source] The impact of successive infections on the lung microenvironmentIMMUNOLOGY, Issue 4 2007Arnaud Didierlaurent Summary The effect of infection history on the immune response is ignored in most models of infectious disease and in preclinical vaccination studies. No one, however, is naïve and repeated microbial exposure, in particular during childhood, shapes the immune system to respond more efficiently later in life. Concurrent or sequential infections influence the immune response to secondary unrelated pathogens. The involvement of cross-reactive acquired immunity, in particular T-cell responses, is extensively documented. In this review, we discuss the impact of successive infections on the infected tissue itself, with a particular focus on the innate response of the respiratory tract, including a persistent alteration of (1) epithelial or macrophage expression of Toll-like receptors or adherence molecules used by subsequent bacteria to invade the host, (2) the responsiveness of macrophages and neutrophils and (3) the local cytokine milieu that affects the activation of local antigen-presenting cells and hence adaptive immunity to the next infection. We emphasize that such alterations not only occur during coinfection, but are maintained long after the initial pathogen is cleared. As innate responses are crucial to the fight against local pathogens but are also involved in the maintenance of the homeostasis of mucosal tissues, dysregulation of these responses by repeated infections is likely to have a major impact on the outcome of infectious or allergic disease. [source] Putting the natural killer cell in its placeIMMUNOLOGY, Issue 1 2006Geraldine M. O'Connor Summary Natural killer (NK) cells were originally described as ,null' lymphocytes, but we have increasing evidence of their role in recognizing pathogen, and our knowledge of NK cell receptors continues to expand exponentially. Human NK cells have many receptors for human leucoctye antigen (HLA) class I. These killer immunoglobulin-like receptors (KIRs) and CD94/NKG2 receptors can signal in both positive and negative ways to regulate NK cell functions. The inhibitory receptors are the best characterized, but even in these cases much of their functional biology remains elusive. In this review, some recent advances in terms of the three-immunoglobulin (3Ig)-domain KIRs are discussed. Natural cytotoxicity receptors (NCRs) are among the activatory receptors found on NK cells. While pathogen ligands for these receptors have been described, endogenous ligands remain elusive. NCRs and NKG2D, a receptor for stress-induced antigens, appear to play complementary functional roles in terms of NK cell activation. More recently described on NK cells are the Toll-like receptors. In particular, these receptors of the innate immune system allow NK cells to directly sense pathogen, and their ligation on accessory cells indirectly activates NK cells through cytokine production. It is becoming clear that none of these receptor systems functions in isolation and that it is the sum of the signals (which will reflect the pathogenic situation), in addition to the cytokine milieu, that will direct NK cell activation. The resulting cytotoxicity, cytokine production and direct cell,cell regulatory interactions with other cells of the immune system, for example dendritic cells, ultimately determine the role of the NK cell in the context of an overall immune response. [source] Analyses of serum levels of type 1, type 2 and type 3 cytokines reveal multiple abnormalities in lupus-prone (NZB × NZW) F1 miceINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 1 2004Deijanira A. De Albuquerque Abstract Aim:, Inherent in vivo cytokine milieu may help protect normal subjects from developing clinical autoimmunity, whereas changes in cytokine milieu may contribute to the development of lupus-like autoimmunity. Method:, Here, we measured circulating levels of the three prototypic cytokines, type 1 (IFN-, and IL-2), type 2 (IL-4) and type 3 (TGF,) in the NZB/NZW F1 model of lupus and MHC-matched nonautoimmune mice. Results:, Our results demonstrate that circulating IFN-, and IL-4 levels were higher and active TGF, levels were lower in lupus-prone animals than in nonautoimmune mice. Conclusion:, Such an in vivo cytokine milieu may contribute to the development of lupus in NZB/NZW F1 mice and to the nonautoimmune phenotype in normal animals. [source] Psoriasis confined strictly to vitiligo areas , a Koebner-like phenomenon?JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2 2006TG Berger Abstract Vitiligo and psoriasis are both common skin disorders. However, psoriasis strictly confined to pre-existing vitiligo areas is rare and suggests a causal relationship. We report here on two patients with a strict anatomical colocalization of vitiligo and psoriasis. The histopathological examinations showed typical changes for both diseases together with a dense infiltrate of CD4+ and CD8+ T cells. By immunohistochemistry, intracytoplasmatic granzyme B and tumour necrosis factor alpha (TNF-,) were detected within the T-cell population, suggesting the functional activity of these cells and the creation of a local T helper 1 (Th1)-cytokine milieu. Additionally, in one patient we could identify anti-melanocytic T cells by tetramer staining and enzyme-linked immunospot (ELISPOT) analysis. These skin-infiltrating lymphocytes might trigger, by the local production of Th-1 cytokines such as TNF-, and interferon-, (IFN-,), the eruption of psoriatic plaques in patients with a genetic predisposition for psoriasis. [source] Cholangiocytes as immune modulators in rotavirus-induced murine biliary atresiaLIVER INTERNATIONAL, Issue 8 2009Barrett H. Barnes Abstract Background/Aims: Biliary atresia (BA) is a progressive disease characterized by bile duct inflammation and fibrosis. The aetiology is unknown and may be due to a virus-induced, autoimmune-mediated injury of cholangiocytes. Cholangiocytes are not only targets of injury but may also modulate hepatic inflammation. The aim of this study was to determine the immune profile of murine cholangiocytes and the ability to function as antigen-presenting cells (APCs) in culture with Rhesus rotavirus (RRV), poly I:C (viral mimic) or interferon-,/tumour necrosis factor-,. Methods/Results: Both the cholangiocyte cell line (long-term culture) and fresh, ex vivo cholangiocytes expressed APC surface markers major histocompatibility complex (MHC)-class I and II and CD40, while only the cultured cell line expressed costimulatory molecules B7-1 and B7-2. Despite APC expression, cultured cholangiocytes were unable to function as competent APCs in T-cell proliferation assays. Furthermore, both cultured and ex vivo cholangiocytes expressed RNA transcripts for many pro-inflammatory cytokines and chemokines. Conclusions: Although cholangiocytes contain APC molecules, they are incompetent at antigen presentation and cannot elicit effective T-cell activation. Upregulation of MHC-class I and II found in BA mice may serve to prime the cholangiocyte as a target for immune-mediated injury. Cholangiocytes produced many pro-inflammatory cytokines and chemokines in the setting of RRV infection and T-helper type 1 cytokine milieu, suggesting a role of cholangiocytes as immune modulators promoting the ongoing inflammation that exists in RRV-induced BA. [source] Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver diseaseLIVER INTERNATIONAL, Issue 9 2006C. P. Day Abstract: While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF-,, transforming growth factor-,, and angiotensinogen may be associated with steatohepatitis and/or fibrosis. [source] Do helminth parasites protect against atopy and allergic disease?CLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2009C. Flohr Summary Allergic diseases are rare in areas with high helminth parasite exposure and common where helminth exposure is lacking or significantly reduced, such as urban areas of developing countries and industrialized nations. Studies suggest that helminths induce a systemic immuno-modulatory network, including regulatory T cells and anti-inflammatory IL-10, which might play a key role in the protection against the allergic phenotype. Here, we review the current cross-sectional, birth cohort, and intervention study evidence for a protective effect of helminth infection on allergy. There is increasing evidence for a causal relationship between helminth infection and reduced skin prick test responsiveness to allergens. Cross-sectional studies have shown a consistent negative relationship, and these results have been confirmed in several, although not all, intervention studies. The immunological basis for this protective effect is less clear. Recent studies do not support the mast-cell IgE saturation hypothesis, but suggest that protection is associated with IL-10 production. As for allergic disease, cross-sectional studies support a negative relationship between clinical asthma and infection with some helminth species, particularly hookworm, but more studies are required to draw conclusions for eczema and rhinitis. In addition, none of the few intervention studies to date have demonstrated an increase in clinical allergy after helminth treatment, and further studies are needed. Furthermore, we are only beginning to understand the host genetic factors that are potentially involved. A genetically predetermined T-helper type 2 cell-dominated cytokine milieu reduces parasite burden and may enhance host survival in an environment where helminth parasites are prevalent. Lack of parasite exposure in such hosts might lead to hypersensitivity to seemingly minor environmental allergen stimuli. Large birth cohort studies in helminth-endemic areas that use epidemiological, genetic, and immunological tools are required to further examine how helminth parasites affect the development of atopy and allergic disease. Intervention studies with hookworm in parasite-naïve allergic individuals are currently ongoing in the United Kingdom to test the above hypotheses further. [source] | ||||||||||||||||||||||