Home About us Contact
|
Home About us Contact | ||
|
|
||
Immune Regulation (immune + regulation)
Selected AbstractsDonor-specific Immune Regulation by CD8+ Lymphocytes Expanded from Rejecting Human Cardiac AllograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2009I. E. Dijke To assess whether regulatory T cells are present in rejecting human cardiac allografts, we performed functional analyses of graft lymphocytes (GLs) expanded from endomyocardial biopsies (EMB; n = 5) with histological signs of acute cellular rejection. The GL cultures were tested for their proliferative capacity and regulatory activity on allogeneic-stimulated peripheral blood mononuclear cells (PBMC) of the patient (ratio PBMC:GLs = 5:1). Three of these GL cultures were hyporesponsive to donor antigens and suppressed the antidonor proliferative T-cell response of PBMC, but not the anti-third-party response. Interestingly, it was the CD8+ GL subset of these cultures that inhibited the antidonor response (65,91% inhibition of the proportion of proliferating cells); the CD4+ GLs of the expanded GL cultures were not suppressive. In conclusion, CD8+ GLs expanded from rejecting human cardiac allografts can exhibit donor-specific immune regulatory activities in vitro. We suggest that during acute cellular rejection, GLs may not only consist of graft-destructing effector T cells, but also of cells of the CD8+ type with the potential to specifically inhibit antidonor immune reactivity. [source] Immune regulation by 4-1BB and 4-1BBL: complexities and challengesIMMUNOLOGICAL REVIEWS, Issue 1 2009Chao Wang Summary:, The tumor necrosis factor receptor family member 4-1BB plays a key role in the survival of activated and memory CD8+ T cells. Depending on the disease model, 4-1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4-1BB to prolong the immune response when pathogens take longer to clear. The expression of 4-1BB on diverse cell types, evidence for bidirectional as well as receptor-independent signaling by 4-1BBL, the unexpected hyperproliferation of 4-1BB-deficient T cells, and complex effects of agonistic anti-4-1BB therapy have revealed additional roles for the 4-1BB/4-1BBL receptor/ligand pair in the immune system. In this review, we discuss these diverse roles of 4-1BB and its ligand in the immune response, exploring possible mechanisms for the observed complexities and implications for therapeutic applications of 4-1BB/4-1BBL. [source] LIGHTing up dendritic cell activation: Immune regulation and viral exploitationJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2005Gabriele Pollara The maturation state of dendritic cells (DC) is regulated by a variety of factors. These include ligands expressed by T cells, such as members of the TNF superfamily. Recent studies have highlighted the role of one such molecule, LIGHT, as a positive regulator of DC biology, promoting the maturation of these cells through the activation of NF-,B pathways. In addition, HSV-1 envelope glycoproteins can also bind the LIGHT receptor, herpes virus entry mediator (HVEM), and activate similar downstream signalling pathways in DC. The consequence of this host-viral interaction may be a novel pathway of viral immune evasion. © 2005 Wiley-Liss, Inc. [source] Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates,ANNALS OF NEUROLOGY, Issue 3 2009Stefano Pluchino MD Objective Transplanted neural stem/precursor cells (NPCs) display peculiar therapeutic plasticity in vivo. Although the replacement of cells was first expected as the prime therapeutic mechanism of stem cells in regenerative medicine, it is now clear that transplanted NPCs simultaneously instruct several therapeutic mechanisms, among which replacement of cells might not necessarily prevail. A comprehensive understanding of the mechanism(s) by which NPCs exert their therapeutic plasticity is lacking. This study was designed as a preclinical approach to test the feasibility of human NPC transplantation in an outbreed nonhuman primate experimental autoimmune encephalomyelitis (EAE) model approximating the clinical and complex neuropathological situation of human multiple sclerosis (MS) more closely than EAE in the standard laboratory rodent. Methods We examined the safety and efficacy of the intravenous (IV) and intrathecal (IT) administration of human NPCs in common marmosets affected by human myelin oligodendrocyte glycoprotein 1-125,induced EAE. Treatment commenced upon the occurrence of detectable brain lesions on a 4.7T spectrometer. Results EAE marmosets injected IV or IT with NPCs accumulated lower disability and displayed increased survival, as compared with sham-treated controls. Transplanted NPCs persisted within the host central nervous system (CNS), but were also found in draining lymph nodes, for up to 3 months after transplantation and exhibited remarkable immune regulatory capacity in vitro. Interpretation Herein, we provide the first evidence that human CNS stem cells ameliorate EAE in nonhuman primates without overt side effects. Immune regulation (rather than neural differentiation) is suggested as the major putative mechanism by which NPCs ameliorate EAE in vivo. Our findings represent a critical step toward the clinical use of human NPCs in MS. Ann Neurol 2009;66:343,354 [source] Acquisition of regulatory function by human CD8+ T cells treated with anti-CD3 antibody requires TNFEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Vitaly Ablamunits Abstract Anti-CD3 mAb can modulate graft rejection and attenuate autoimmune diseases but their mechanism(s) of action remain unclear. CD8+ T cells with regulatory function are induced in vitro by Teplizumab, a humanized anti-CD3 antibody and inhibit responses of autologous and allogeneic T cells. They inhibit CD4+ T-cell proliferation by mechanisms involving TNF and CCL4, and by blocking target cell entry into G2/M phase of cell cycle but neither kill them, nor compete for IL-2. CD8+ Treg can be isolated from peripheral blood following treatment of patients with Type 1 diabetes with Teplizumab, but not from untreated patients. The induction of CD8+ Treg by anti-CD3 mAb requires TNF and signaling through the NF-,B cascade. The CD8+ Treg express CD25, glucocorticoid-induced TNF receptor family, CTLA-4, Foxp3, and TNFR2, and the combined expression of TNFR2 and CD25 identifies a potent subpopulation of CD8+ Treg. These studies have identified a novel mechanism of immune regulation by anti-CD3 mAb and markers that may be used to track inducible CD8+ Treg in settings such as chronic inflammation or immune therapy. [source] Revisiting the role of IL-2 in autoimmunityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Hans Dooms Abstract IL-2 was discovered as a T-cell growth factor that promoted T-cell-dependent immune responses; however, more recent studies suggest that the essential role of IL-2 is to maintain functional Treg and thus control immune responses. These results are leading to new ideas about the potential of IL-2 as a therapeutic strategy in autoimmune diseases. In this issue of the European Journal of Immunology, a study further examines the role of IL-2 in immune regulation and shows for the first time that IL-2 complexes can ameliorate autoantibody-mediated autoimmunity. This commentary examines the current findings in relation to what we already know about IL-2 complexes. [source] Stress for maintaining memory: HSP70 as a mobile messenger for innate and adaptive immunityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Taoyong Chen Abstract HSP are abundant and conserved proteins present in all cells. Upon temperature shock or other stress stimuli, HSP are synthesized intracellularly, which may protect cells from protein denaturation or from death. Although HSP are synthesized intracellularly, HSP can also be mobilized to the plasma membrane or even be released under stress conditions. Elucidating the roles of cell surface and extracellular HSP in immune regulation has attracted much attention in recent years. Extracellularly, HSP can serve a cytokine function to initiate both innate and adaptive immunity through activation of APC. HSP serves also a chaperone function and facilitates presentation of antigen peptide to T cells. Similarly, cell surface HSP may activate APC and promote antigen presentation through cell,cell contact. A study in this issue of the European Journal of Immunology demonstrates that cell surface HSP70 on DC induced by stress can upregulate membrane-associated IL-15, which in turn promotes the proliferation of CD4+CD45RA memory T cells. Moreover, a DC-CD4+ T-cell interacting circuit formed by CD40L on T cells and CD40 on DC is proposed to play a role in the maintenance of memory homeostasis. This study has widened our view of HSP in adaptive immunity as well as their classical functions such as APC activator and antigen carrier. [source] Regulatory T cells and immune computationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2008Francisco J. Quintana Dr. Abstract The role of Treg in immune regulation is the topic of this Viewpoint series in the European Journal of Immunology (EJI); the question to be discussed in this section is the effector function of Treg in immune regulation. In this manuscript, we take on the following three postulates outlined by Rolf Zinkernagel on the role of Treg in the control of immunity. First, the immune response is regulated primarily by the antigen and not by Treg. Second, immune non-responsiveness results from the deletion of specific receptor-bearing T cells. Third, there is no definitive proof of the existence of specialized Treg that know what is needed for an equilibrated immune response. Herein, we discuss data demonstrating the existence of specialized Treg and therefore arguing against the validity of the first two postulates. However, based on the reactive nature of the immune system, we agree with Rolf's third postulate in that Treg cannot know ahead of time an ideal set-point for immune homeostasis. See accompanying commentary: http://dx.doi.org/10.1002/eji.200738114 [source] Autoantibodies in alcoholic liver diseaseADDICTION BIOLOGY, Issue 2 2000Ian G. McFarlane Despite many decades of research, the reasons why only a relatively small proportion of individuals who consume excessive quantities of alcohol develop clinically significant liver disease remain unknown. The association with features of autoimmune diseases, including hypergammaglobulinaemia, circulating autoantibodies, inheritance of certain immunogenetic (HLA) markers and response to corticosteroid therapy in some patients has led to a persistent impression that altered immune regulation with a relative loss of self-tolerance underlies susceptibility to the development of the more severe forms of alcoholic liver disease (alcoholic hepatitis and/or cirrhosis). However, review of the data from the numerous studies that have been conducted over the past 30 years fails to reveal sufficiently convincing evidence that autoimmunity plays a primary role in alcohol-related liver damage. In particular, most of the wide range of circulating autoantibodies that have been reported in patients are found mainly at low titres, are not confined to those with severe liver injury, and are probably more likely to be a response to the hepatic insult than causally related to liver damage. Additionally, an association with various HLA phenotypes has not been confirmed by meta-analysis. Interpretation is complicated by evidence that alcohol may have direct effects on some components of the immune system but, if there is an immunogenetic basis for alcoholic liver disease, the present evidence suggests that this might be related more to cytokine gene polymorphisms than to a predisposition to autoimmunity per se. [source] Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytesGLIA, Issue 15 2008Thomas Calzascia Abstract T cell mediated immunotherapies are proposed for many cancers including malignant astrocytoma. As such therapies become more potent, but not necessarily more tumor-specific, the risk of collateral autoimmune damage to normal tissue increases. Tumors of the brain present significant challenges in this respect, as autoimmune destruction of brain tissue could have severe consequences. To investigate local immune reactivity toward a tumor-associated antigen in the brain, transgenic mice were generated that express a defined antigen (CW3170,179) in astroglial cells. The resulting six transgenic mouse lines expressed the transgenic self-antigen in cells of the gastrointestinal tract and CNS compartments, or in the CNS alone. By challenging transgenic mice with tumor cells that express CW3, self/tumor-specific immune responses were visualized within a normal polyclonal T cell repertoire. A large expansion of the endogenous CW3170,179 -specific CD8 T cell population was observed in nontransgenic mice after both subcutaneous and intracerebral implantation of tumor cells. In contrast, CW3170,179 -specific immune responses were not observed in transgenic mice that exhibited extracerebral transgene expression. Importantly, in certain groups of mice in which transgene expression was restricted to the CNS, antigen-specific immune responses occurred when tumor was implanted subcutaneously, but not intracerebrally. This local immune tolerance in the brain was induced via peripheral (extrathymic) rather than central (thymic) tolerance mechanisms. Thus, this study highlights the role of regional immune regulation in the prevention of autoimmunity in the brain, and the potential impact of these mechanisms for brain tumor immunotherapy. © 2008 Wiley-Liss, Inc. [source] Bioluminescence imaging allows measuring CD8 T cell function in the liver,HEPATOLOGY, Issue 4 2010Dirk Stabenow In vivo evaluation of CD8 T cell effector (cytotoxic T lymphocyte [CTL]) function in peripheral organs such as the liver is currently not possible but would greatly improve our understanding of local immune regulation, because simple determination of antigen-specific CTL numbers does not predict the outcome of immune responses. In particular, measurement of alanine aminotransferase serum levels is not sensitive enough to detect T cell immunity against low numbers of target hepatocytes. We developed a procedure that detects virus-specific effector function of CTLs in the liver after simultaneous adenoviral transfer of reporter and immune target genes into hepatocytes, followed by bioluminescence imaging of reporter genes. Bioluminescence imaging enabled detection of as few as 10,000 infected hepatocytes in vivo, and even more importantly, quantification of antiviral effector function of as few as 50,000 CTLs. Conclusion: Our results provide evidence that low numbers of antigen-specific CTLs are sufficient to control viral gene expression and eliminate viral infection from hepatocytes. The experimental system established here is a highly sensitive method to simultaneously detect viral infection of hepatocytes and to quantify antiviral CTL function in the liver in vivo and will help in characterizing principles of hepatic immune regulation. (HEPATOLOGY 2010;51:1430,1437) [source] Activating and inhibitory nature of the murine paired immunoglobulin-like receptor familyIMMUNOLOGICAL REVIEWS, Issue 1 2001Toshiyuki Takai Summary: Clones for murine paired immunoglobulin-like receptors (PIR) were first isolated as those coding for type I transmembrane glycoproteins with six immunoglobulin-like domains homologous to human Fc,R, bovine Fc,2R, and other related receptors. However, they turned out to bind neither IgA nor other immunoglobulins in the case of the ectopic expression on COS-1 fibroblastic cells. PIR-A and B are expressed on a wide variety of cells in the murine immune system, such as in B cells, mast cells, macrophages, and dendritic cells, mostly in a pairwise fashion. PIR-A requires homodimeric Fc receptor common , chain, which harbors an immunoreceptor tyrosine-based activation motif, for its efficient cell surface expression and for the delivery of activation signaling. In contrast, PIR-B contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic portion and inhibits receptor-mediated activation signaling in vitro upon engagement with other activating-type receptors such as the antigen receptor on B cells and the high affinity Fc receptor for IgE on mast cells. ITIMs of PIR-B on macrophages and B cells have been shown to be constitutively phosphorylated in their tyrosine residues. Although the ligand for PIR still remains unknown, the transgenics and the gene-targeted mice will provide us with valuable information on their physiological roles in the immune regulation. We thank Hiromi Kubagawa for discussion. This work is supported by CREST Program of JST, Virtual Research Institute of Aging funded by Boehringer Ingelheim, and by research grants from the Ministry of Education, Science, Sports and Culture of Japan to T. Takai. [source] Local control of the immune response in the liverIMMUNOLOGICAL REVIEWS, Issue 1 2000Percy A. Knolle Summary: The physiological function of the liver , such as removal of pathogens and antigens from the blood, protein synthesis and metabolism , requires an immune response that is adapted to these tasks and is locally regulated. Pathogenic microorganisms must be efficiently eliminated while the large number of antigens derived from the gastrointestinal tract must be tolerized. From experimental observations it is evident that the liver favours the induction of tolerance rather than the induction of immunity. The liver probably not only is involved in transplantation tolerance but contributes as well to tolerance to orally ingested antigens (entering the liver with portal-venous blood) and to containment of systemic immune responses (antigen from the systemic circulation entering the liver with arterial blood). This review summarizes the experimental data that shed light on the molecular mechanisms and the cell populations of the liver involved in local immune regulation in the liver. Although hepatocytes constitute the major cell population of the liver, direct interaction of hepatocytes with leukocytes in the blood is unlikely. Sinusoidal endothelial cells, which line the hepatic sinusoids and separate hepatocytes from leukocytes in the sinusoidal lumen, and Kupffer cells, the resident macrophage population of the liver, can directly interact with passenger leukocytes. In the liver, clearance of antigen from the blood occurs mainly by sinusoidal endothelial cells through very efficient receptor-mediated endocytosis. Liver sinusoidal endothelial cells constitutively express all molecules necessary for antigen presentation (CD54, CD80, CD86, MHC class I and class II and CD40) and can function as antigen-presenting cells for CD4+ and CD8+ T cells. Thus, these cells probably contribute to hepatic immune surveillance by activation of effector T cells. Antigen-specific T-cell activation is influenced by the local microenvironment. This microenvironment is characterized by the physiological presence of bacterial constituents such as endotoxin and by the local release of immunosuppressive mediators such as interleukin-10, prostaglandin E2 and transforming growth factor-b. Different hepatic cell populations may contribute in different ways to tolerance induction in the liver. In vitro experiments revealed that naive T cells are activated by resident sinusoidal endothelial cells but do not differentiate into effector T cells. These T cells show a cytokine profile and a functional phenotype that is compatible with the induction of tolerance. Besides sinusoidal endothelial cells, other cell populations of the liver, such as dendritic cells, Kupffer cells and perhaps also hepatocytes, may contribute to tolerance induction by deletion of T cells through induction of apoptosis. [source] Multi-tasking of helper T cellsIMMUNOLOGY, Issue 2 2010Yisong Y. Wan Summary CD4 T helper cells (Th) are critical in combating pathogens and maintaining immune homeostasis. Since the establishment of the Th1,Th2 paradigm in the 1980s, many types of specialized Th cells, including Th1, Th2, Th17, Th9, follicular helper T and regulatory T, have been identified. We have become accustomed to the idea that different Th cells are ,committed' to their paths but recent emerging evidence suggests that under certain conditions, seemingly committed Th cells possess plasticity and may convert into other types of effector cells. In this review, we will first introduce the major sub-types of Th cells that are involved in immune regulation. Then, we will describe in detail the inter-convertibility of Th cells among different sub-types under in vitro and in vivo conditions. Finally, we will discuss our current understanding of the underlying mechanisms on how a particular type of Th cells may convert into other types of Th cells. [source] Mechanisms of regulatory T-cell suppression , a diverse arsenal for a moving targetIMMUNOLOGY, Issue 1 2008Dorothy K. Sojka Summary Naturally-occurring regulatory T cells (Tregs) are emerging as key regulators of immune responses to self-tissues and infectious agents. Insight has been gained into the cell types and the cellular events that are regulated by Tregs. Indeed, Tregs have been implicated in the control of initial activation events, proliferation, differentiation and effector function. However, the mechanisms by which Tregs disable their cellular targets are not well understood. Here we review recent advances in the identification of distinct mechanisms of Treg action and of signals that enable cellular targets to escape regulation. Roles for inhibitory cytokines, cytotoxic molecules, modulators of cAMP and cytokine competition have all been demonstrated. The growing number of inhibitory mechanisms ascribed to Tregs suggests that Tregs take a multi-pronged approach to immune regulation. It is likely that the relative importance of each inhibitory mechanism is context dependent and modulated by the inflammatory milieu and the magnitude of the immune response. In addition, the target cell may be differentially susceptible or resistant to distinct Treg mechanisms depending on their activation or functional status at the time of the Treg encounter. Understanding when and where each suppressive tool is most effective will help to fine tune therapeutic strategies to promote or constrain specific arms of Treg suppression. [source] H2-Dd -mediated upregulation of interleukin-4 production by natural killer T-cell and dendritic cell interactionIMMUNOLOGY, Issue 1 2008Kazuomi Mizuuchi Summary Natural killer T (NKT) cells are capable of subserving apparently opposite functions, the interferon-, (IFN-,)-mediated enhancement of host defence and interleukin-4 (IL-4) -mediated immune regulation. Although dendritic cells (DCs) potently activate NKT cells, DC regulation of the IL-4,IFN-, balance via NKT-cell activation is not well characterized. In the present study, we examined the effect of DC treatment with CpG oligodeoxynucleotide (ODN), a Toll-like receptor 9 ligand, on the induction of NKT-cell cytokine production. CpG-ODN-conditioned and ,-galactosylceramide (,-GalCer)-loaded myeloid DCs (CpG-DCs) from BALB/c mice showed enhanced ability to induce NKT-cell production of IL-4, but not IFN-,, compared to ,-GalCer-loaded control DCs (not treated with CpG-ODN). The CpG-DCs expressed significantly higher levels of H2-Dd than control DCs, and blocking of the H2-Dd and Ly49 receptor interaction during antigen presentation completely abolished the enhanced ability of the CpG-DCs to induce NKT-cell production of IL-4. These findings demonstrate that DC recognition of the CpG motif leads to induction of enhanced IL-4 production by NKT cells via interaction of the augmented H2-Dd with Ly49 receptors on NKT cells. [source] Toll-like receptors and immune regulation: their direct and indirect modulation on regulatory CD4+ CD25+ T cellsIMMUNOLOGY, Issue 2 2007Guangwei Liu Summary Regulatory CD4+ CD25+ T (Treg) cells with the ability to suppress host immune responses against self- or non-self antigens play important roles in the processes of autoimmunity, transplant rejection, infectious diseases and cancers. The proper regulation of CD4+ CD25+ Treg cells is thus critical for optimal immune responses. Toll-like receptor (TLR)-mediated recognition of specific structures of invading pathogens initiates innate as well as adaptive immune responses via antigen-presenting cells (APCs). Interestingly, new evidence suggests that TLR signalling may directly or indirectly regulate the immunosuppressive function of CD4+ CD25+ Treg cells in immune responses. TLR signalling may shift the balance between CD4+ T-helper cells and Treg cells, and subsequently influence the outcome of the immune response. This immunomodulation pathway may therefore have potential applications in the treatment of graft rejection, autoimmune diseases, infection diseases and cancers. [source] A novel association between clustered NF-,B and C/EBP binding sites is required for immune regulation of mosquito Defensin genesINSECT MOLECULAR BIOLOGY, Issue 4 2006J. M. Meredith Abstract A comparative analysis identified key cis -acting regulatory elements responsible for the temporal control of mosquito Defensin gene expression. The promoters of Anopheles gambiae Defensin 1 and two isoforms of Aedes aegypti Defensin A are up-regulated by immune challenge. This stimulated activity depends upon a cluster of three NF-,B binding sites and closely associated C/EBP-like motifs, which function as a unit for optimal promoter activity. Binding of NF-,B and C/EBP like transcription factors is confirmed by electrophoretic mobility shift assay, including supershifts with antibodies to C/EBP. ,B-like motifs are abundant within antimicrobial peptide gene promoters and most are very closely associated with putative C/EBP binding sites. This novel association between NF-,B and C/EBP binding sites may, therefore, be of widespread significance. [source] Mating triggers dynamic immune regulations in wood ant queensJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 3 2009G. CASTELLA Abstract Mating can affect female immunity in multiple ways. On the one hand, the immune system may be activated by pathogens transmitted during mating, sperm and seminal proteins, or wounds inflicted by males. On the other hand, immune defences may also be down-regulated to reallocate resources to reproduction. Ants are interesting models to study post-mating immune regulation because queens mate early in life, store sperm for many years, and use it until their death many years later, while males typically die after mating. This long-term commitment between queens and their mates limits the opportunity for sexual conflict but raises the new constraint of long-term sperm survival. In this study, we examine experimentally the effect of mating on immunity in wood ant queens. Specifically, we compared the phenoloxidase and antibacterial activities of mated and virgin Formica paralugubris queens. Queens had reduced levels of active phenoloxidase after mating, but elevated antibacterial activity 7 days after mating. These results indicate that the process of mating, dealation and ovary activation triggers dynamic patterns of immune regulation in ant queens that probably reflect functional responses to mating and pathogen exposure that are independent of sexual conflict. [source] ICAM-1 expressed on hepatic stellate cells plays an important role in immune regulationMICROSURGERY, Issue 4 2007Zhenyu Yin M.D. The authors have demonstrated a strong T-cell inhibitory activity of hepatic stellate cells (HSC), which may participate in the establishment of hepatic tolerance. The underlying mechanism is not completely understood. This study showed that intercellular adhesion molecule 1 (ICAM-1) was constitutively expressed on HSC, and up-regulated upon activation. ICAM-1 knockout mice was used to analyze the role of ICAM-1 expressed on HSC, and showed that deficiency in ICAM-1 expression partially reverses HSC immune inhibitory activity both in vitro and in vivo, but did not significantly affect their capacity to induce T-cell apoptosis. © 2007 Wiley-Liss, Inc. Microsurgery 2007. [source] Immunology highlights at high altitude: review of the fourth EAACI-GA2LEN Davos MeetingALLERGY, Issue 10 2006J. Gutermuth The field of allergy is moving fast. To keep pace with the underlying immunologic mechanisms, the 4th EAACI-GA2LEN Davos meeting on ,Basic Immunology Research in Allergy and Clinical Immunology' was organized in Grainau, Germany, February 16th,19th, 2006 by the Immunology Section of the European Academy of Allergy and Clinical Immunology and the ZAUM , Center for Allergy and Environment, Technical University Munich, with generous support from GA2LEN. Recent advances and new insights on innate and adaptive immunity, environmental factors influencing immune responses, immune regulation and allergic inflammation were presented by keynote speakers and selected participants. [source] Selenium attenuates pro-inflammatory gene expression in macrophagesMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 11 2008Hema Vunta Abstract Selenium (Se) is an important element required for the optimal functioning of the immune system. Particularly in macrophages, which play a pivotal role in immune regulation, Se acts as a major antioxidant in the form of selenoproteins to mitigate the cytotoxic effects of reactive oxygen species. Here we describe the role of Se as an anti-inflammatory agent and its effect on the macrophage signal transduction pathways elicited by bacterial endotoxin, LPS. Our studies demonstrate that supplementation of Se to macrophages (Se-deficient) leads to a significant decrease in the LPS-induced expression of two important pro-inflammatory genes, cyclooxygenase-2 (COX-2) and tumor necrosis factor-, (TNF-,) via the inhibition of MAP kinase pathways. Furthermore, Se-deficiency in mice exacerbated the LPS-mediated infiltration of macrophages into the lungs suggesting that Se status is a crucial host factor that regulates inflammation. In summary, our results indicate that Se plays an important role as an anti-inflammatory agent by tightly regulating the expression of pro-inflammatory genes in immune cells. [source] Neuromyelitis optica/Devic's disease: Gene expression profiling of brain lesionsNEUROPATHOLOGY, Issue 6 2008Jun-ichi Satoh Neuromyelitis optica (NMO), also known as Devic's disease, is an inflammatory demyelinating disease that affects selectively the optic nerves and the spinal cord, possibly mediated by an immune mechanism distinct from that of multiple sclerosis (MS). Recent studies indicate that NMO also involves the brain. Here, we studied gene expression profile of brain lesions of a patient with NMO by using DNA microarray, along with gene expression profile of the brains of Parkinson disease and amyotrophic lateral sclerosis patients. We identified more than 200 genes up-regulated in NMO brain lesions. The top 20 genes were composed of the molecules closely associated with immune regulation, among which marked up-regulation of interferon gamma-inducible protein 30 (IFI30), CD163, and secreted phosphoprotein 1 (SPP1, osteopontin) was validated by real time RT-PCR, Northern blot and Western blot analysis. Pathologically, CD68+ macrophages and microglia expressed intense immunoreactivities for IFI30 and CD163 in NMO lesions, consisting of inflammatory demyelination, axonal loss, necrosis, cavity formation, and vascular fibrosis. KeyMolnet, a bioinformatics tool for analyzing molecular interaction on the curated knowledge database, suggested that the molecular network of up-regulated genes in NMO brain lesions involves transcriptional regulation by the nuclear factor-kappaB (NF-,B) and B-lymphocyte-induced maturation protein-1 (Blimp-1). These results suggest that profound activation of the macrophage-mediated proinflammatory immune mechanism plays a pivotal role in development of NMO brain lesions. [source] Relation between stressful life events, neuropeptides and cytokines: results from the LISA birth cohort studyPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 8 2008Gunda Herberth Stressful life events evidently have an impact on development of allergic diseases, but the mechanism linking stress to pathological changes of immune system function is still not fully understood. The aim of our study was to investigate the relationship between stressful life events, neuropeptide and cytokine concentrations in children. Within the LISAplus (Life style-Immune system-Allergy) study, blood samples from children of 6 yr of age were analysed for concentration of the neuropeptides vasoactive intestinal peptide (VIP), somatostatin (SOM), substance P (SP) and the Th1/Th2 cytokines interferon-, (IFN-,) and interleukin (IL)-4. Life events such as severe disease or death of a family member, unemployment or divorce of the parents were assessed with a questionnaire filled in by the parents. For 234 children, blood analysis and questionnaire data regarding life events were available. Children with separated/divorced parents showed high VIP levels and high concentrations of the Th2 cytokine IL-4 in their blood. Severe diseases and death of a family member were neither associated with neuropeptide levels nor with cytokine concentrations. Unemployment of the parents was associated with decreased IFN-, concentrations in children's blood but not with neuropeptide levels, whereas children experiencing concomitant severe disease and death of a family member had reduced SP blood levels. The neuropeptide VIP might be a mediator between stressful life events and immune regulation contributing to the Th2 shifted immune response in children with separated/divorced parents. Unemployment of the parents was associated with immune regulation in children on the basis of a still unknown mechanism whereas reduced SP levels seem to have no effect on immune regulation. [source] Idiosyncratic drug-induced agranulocytosis: Possible mechanisms and management,AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2009Daniel Tesfa The incidence of drug-induced neutropenia has not changed in the western hemisphere over the last 30 years. Yet, the drug panorama has changed considerably. This implies that host factors may play an intriguing role for this idiosyncratic reaction. The knowledge as to mechanisms for the reaction has advanced with emerging understanding of neutropoiesis and immune regulation. Nonetheless, it is still remarkably difficult to pinpoint why and how a drug causes this unexpected, severe adverse event in a patient. Patient characteristics, e.g. genetics, appear to be keys for better understanding, predictions and prevention. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] MS analysis of rheumatoid arthritic synovial tissue identifies specific citrullination sites on fibrinogenPROTEOMICS - CLINICAL APPLICATIONS, Issue 5 2010Monika Hermansson Abstract Purpose: Citrullination is a post-translational modification of arginine residues to citrulline catalyzed by peptidyl arginine deiminases. Induced expression of citrullinated proteins are frequently detected in various inflammatory states including arthritis; however, direct detection of citrullination in arthritic samples has not been successfully performed in the past. Experimental design: Citrullination of human fibrinogen, a candidate autoantigen in arthritis, was studied. Accurate identification of citrullinated fibrinogen peptides from rheumatoid arthritis synovial tissue specimens was performed using accurate mass and retention time analysis. Results: A peptide with the sequence ESSSHHPGIAEFPSRGK corresponding to amino acids 559,575 of fibrinogen ,-chain was identified to be citrullinated with an occupancy rate between 1.4 and 2.5%. Citrullination of the peptide KREEAPSLRPAPPPISGGGYRARPAK corresponding to amino acids 52,77 of the fibrinogen ,-chain was identified with an occupancy rate of 1.2%. Conclusions and clinical relevance: We report a proof of principle study for the identification of citrullinated proteins and within them, identification of citrullination sites and quantification of their occupancies in synovial tissue from rheumatoid arthritis patients using high-resolution MS. Detailed studies on which molecules are citrullinated in arthritis can provide information about their role in immune regulation and serve as novel biomarkers and potentially even as therapeutic targets. [source] ORIGINAL ARTICLE: Profile of Peripheral Blood Neutrophil Cytokines in Diabetes Type 1 Pregnant Women and its Correlation with Selected Parameters in the NewbornsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2010Magdalena Perty, ska-Marczewska Citation Perty,ska-Marczewska M, G,owacka E, Grodzicka A, Sobczak M, Cypryk K, Wilczy,ski JR., Wilczy,ski J. Profile of peripheral blood neutrophil cytokines in diabetes type 1 pregnant women and its correlation with selected parameters in the newborns. Am J Reprod Immunol 2010; 63: 150,160 Problem, Interleukin (IL)-12, IL-10, tumor necrosis factor-, (TNF-,), IL-6 and IL-8 alter as pregnancy progresses, implying continuous immune regulation associated with the maintenance of pregnancy. We aimed to evaluate the peripheral blood neutrophil-derived production of these cytokines in the course of pregnancy complicated by type 1 diabetes. Method of study, These parameters were measured in samples from healthy non-pregnant (C), diabetic non-pregnant (D), healthy pregnant (P) and pregnant diabetic (PD) women. Results, Neutrophil-derived secretion of TNF-, and IL-12 increased along with progression of pregnancy in PD and P groups. The concentration of IL-10 from lipopolysaccharide (LPS)-stimulated neutrophils increased during the course of uncomplicated pregnancy but decreased in diabetic pregnancy. Concentration of IL-8 decreased with the advancing gestational age in P and PD groups. LPS-stimulated neutrophil-derived IL-6 concentration increased only in PD patients. Conclusion, Our results show that diabetes creates pro-inflammatory environment thus potentially influencing the outcome of pregnancy. We conclude that neutrophil-derived cytokine production could contribute to the complications seen in pregnant women with type 1 diabetes. [source] 1141424444 Detection of a2V-ATPase in T regulatory cells of women with recurrent spontaneous abortions or implantation failuresAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2006EI Ntrivalas Problem:, T regulatory cells (Tregs) have recently been shown to play a critical role in maternal tolerance to the fetus. Tregs are decreased in women with recurrent miscarriages. a2V-ATPase (previously referred to as Regeneration and Tolerance Factor) is expressed in activated lymphocytes and plays a role in immune regulation. The aim of this study was to investigate the expression of a2V-ATPase on CD4+/CD25bright Tregs. Method of Study:, Whole blood from women with RSA or implantation failures was reacted with anti-CD4 and anti-CD25 mAbs for the identification of CD4+/CD25bright and CD4+/CD25neg T cells by flow cytometric analysis. Subsequently, these two T-cell populations were analyzed for the expression of a2V-ATPase using PE-conjugated 2C1 mAb (specific for the membrane portion of a2V-ATPase). These two cell populations were also analyzed for the expression of CD71, CD62L, CD45RO and CD58 (Treg markers). Results:, a2V-ATPase was more highly expressed on CD4+/CD25bright Tregs (22.8 ± 16.4%) than on CD4+/CD25neg T cells (2.4 ± 3.8%) in women with RSA (P < 0.0001). Additionally, a2V-ATPase was more highly expressed on CD4+/CD25bright Tregs (18.0 ± 18.2%) than on CD4+/CD25neg T cells (1.5 ± 1.4%) in women with implantation failures (P < 0.0001). a2V-ATPase expression also coincided with the expression of CD71, CD62L, CD45RO and CD58 in Tregs, as opposed to the conventional CD4+/CD25neg T cells. Conclusions:, The expression of a2V-ATPase in Tregs of women with RSA or implantation failures is a novel finding and suggests that this vacuolar ATPase plays an important role in suppression. a2V-ATPase may be a unique molecule in the identification of Tregs among peripheral blood lymphocytes and may also explain the tolerogenic activity of these cells. [source] An Unexpected Counter-Regulatory Role of IL-10 in B-Lymphocyte-Mediated Transplantation ToleranceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010G. Zhao Monoclonal antibody against the CD45RB protein induces stable transplantation tolerance to multiple types of allograft. We have previously established that this tolerance protocol relies on the regulatory function of B lymphocytes for its effect. B lymphocytes have also been reported to participate in immune regulation in several other settings. In most of these systems, the regulatory function of B lymphocytes depends on the production of IL-10. Therefore, we investigated the role of IL-10 in the anti-CD45RB model of B-cell-mediated transplantation tolerance. Surprisingly, using antibody-mediated neutralization of IL-10, IL-10-deficient recipients and adoptive transfer of IL-10-deficient B lymphocytes, we found that IL-10 actually counter-regulates tolerance induced by anti-CD45RB. Furthermore, neutralization of IL-10 reduced the development of chronic allograft vasculopathy compared to anti-CD45RB alone and reduced the production of graft reactive alloantibodies. These data suggest that the participation of regulatory B lymphocytes in transplantation tolerance may be distinct from how they operate in other systems. Identifying the specific B lymphocytes that mediate transplantation tolerance and defining their mechanism of action may yield new insights into the complex cellular network through which antigen-specific tolerance is established and maintained. [source] Allograft-Specific Cytokine Profiles Associate with Clinical Outcome After Islet Cell TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2009V. A. L. Huurman Islet cell transplantation can cure type 1 diabetes, but allograft rejection and recurrent autoimmunity may contribute to decreasing insulin independence over time. In this study we report the association of allograft-specific proliferative and cytokine profiles with clinical outcome. Peripheral blood mononuclear cells were obtained of 20 islet recipients. Cytokine values in mixed lymphocyte cultures (MLC) were determined using stimulator cells with graft-specific HLA class II. Qualitative and quantitative cytokine profiles were determined before and after islet transplantation, blinded from clinical outcome. Cytotoxic T Lymphocyte precursor (CTLp) assays were performed to determine HLA class I alloreactivity. Allograft-specific cytokine profiles were skewed toward a Th2 or regulatory (Treg) phenotype after transplantation in insulin-independent, but not in insulin-requiring recipients. IFN,/IL10 ratio and MLC proliferation decreased after transplantation in insulin-independent recipients (p = 0.006 and p = 0.01, respectively). Production of the Treg cytokine IL10 inversely correlated with proliferation in alloreactive MLC (p = 0.008) and CTLp (p = 0.005). Production of IL10 combined with low-MLC reactivity associated significantly with insulin independence. The significant correlation between allograft-specific cytokine profiles and clinical outcome may reflect the induction of immune regulation in successfully transplanted recipients. Islet donor-specific IL10 production correlates with low alloreactivity and superior islet function. [source] | ||||||||||||||||||||||||||||