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Immune Activation (immune + activation)
Kinds of Immune Activation Selected AbstractsImmune activation and inflammatory system in chronic heart failure: novel pathophysiological hypotheses generate new therapeutic optionsINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2007Massimo F. Piepoli No abstract is available for this article. [source] Vaccines modulating lipoprotein autoimmunity as a possible future therapy for cardiovascular diseaseJOURNAL OF INTERNAL MEDICINE, Issue 3 2009J. Nilsson Abstract. Current strategies for prevention of cardiovascular disease focus on risk factor intervention. Although these have been proven both safe and effective results from randomized clinical trials suggest that it is difficult to achieve relative risk reductions exceeding 40% with this approach. To further improve efficacy future therapies must aim at targeting the actual disease process in the arterial wall. Emerging evidence have identified an important role of the immune system in atherosclerosis and suggest that modulation of autoimmune responses against oxidized LDL and other antigens in the atherosclerotic plaque represent one possible new approach to disease prevention. Oxidized LDL is targeted by both antibody-mediated and cellular immune responses and as much as 10% of the T cells in atherosclerotic plaques are oxidized LDL-specific. Immune activation in the atherosclerotic plaque is primarily of the pro-inflammatory Th1-type and inhibition Th1 immunity reduces atherosclerosis in experimental animals. Atherosclerosis vaccines based on antigens derived from LDL have been developed to modulate these processes. Their mechanisms of action remain to be full characterized but may involve expression of protective antibodies that facilitate the removal of oxidized LDL and antigen-specific regulatory T cells that counteract Th1 autoimmunity against oxidized LDL. In this review we will discuss the possibilities and challenges encountering the translation of immune-modulatory therapy for atherosclerosis from the experimental stage into the clinic. [source] Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppressive therapyLIVER TRANSPLANTATION, Issue 3 2001G. Alex Bishop Liver transplants in many animal models are unusual because often they are not rejected even when transplanted across complete major histocompatibility complex barriers without immunosuppression. Their paradoxical behavior is even more obvious when the immune mechanism of acceptance is examined. Instead of acceptance resulting from a lack of immune response to the graft, the opposite occurs, and there is an unusual extensive increase in immune activation in acceptance compared with rejection. This abnormal extensive immune activation is driven by donor leukocytes transferred with the liver and results in death of the recipient cells that would normally reject the transplant. Some forms of immunosuppression inhibit this activation-associated liver transplant tolerance. The significance of these findings and possible means to design future treatment protocols for clinical transplantation that optimize management of liver transplant recipients are discussed. [source] Immune activation and inflammation in HIV-1 infection: causes and consequences,THE JOURNAL OF PATHOLOGY, Issue 2 2008V Appay Abstract Thorough research on HIV is progressively enabling us to understand the intricate mechanisms that link HIV-1 infection to the onset of immunodeficiency. The infection and depletion of CD4+ T cells represent the most fundamental events in HIV-1 infection. However, in recent years, the role played by chronic immune activation and inflammation in HIV pathogenesis has become increasingly apparent: quite paradoxically, immune activation levels are directly associated with HIV-1 disease progression. In addition, HIV-1-infected patients present intriguing similarities with individuals of old age: their immune systems are characterized by a loss of regenerative capacity and an accumulation of ageing T cells. In this review, we discuss the potential reasons for the establishment of sustained immune activation and inflammation from the early stages of HIV-1 infection, as well as the long-term consequences of this process on the host immune system and health. A simplified model of HIV pathogenesis is proposed, which links together the three major facets of HIV-1 infection: the massive depletion of CD4+ T cells, the paradoxical immune activation and the exhaustion of regenerative capacity. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Effect of comorbidity on urinary neopterin in patients with breast carcinomaEUROPEAN JOURNAL OF CANCER CARE, Issue 3 2010K. MELICHAROVÁ md K. MELICHAROVÁ, H. KALÁBOVÁ, L. KR,MOVÁ, L. URBÁNEK, D. SOLICHOVÁ, B. MELICHAR (2010) European Journal of Cancer Care19, 340,345 Effect of comorbidity on urinary neopterin in patients with breast carcinoma Urinary neopterin is increased in less than 20% of patients with breast carcinoma. Moderately increased neopterin concentrations are also known to accompany comorbid conditions commonly observed in patients with breast carcinoma, for example, diabetes mellitus or complications of atherosclerosis. In the present study, we evaluated the effect of the presence of comorbid conditions on urinary neopterin. A trend for higher neopterin concentrations was observed in patients with most of the comorbid conditions, but significantly higher neopterin was observed only in patients aged 70 years or older and in a heterogeneous group of patients with comorbidity other than diabetes mellitus, thyroid disorder, hyperlipidaemia, cardiac disorder or other malignancy. Significantly higher neopterin levels were noted in patients with two or more comorbid conditions. In conclusion, present data demonstrate an association between systemic immune activation reflected in increased urinary neopterin concentrations and age or presence of comorbid diseases in patients with breast carcinoma. A cumulative effect was observed with the presence of two or more comorbid conditions resulting in significantly increased urinary neopterin. These observations should be taken into account when interpreting the changes of parameters of systemic immune and inflammatory response in patients with breast carcinoma. [source] Highly avid, oligoclonal, early-differentiated antigen-specific CD8+ T cells in chronic HIV-2 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Aleksandra Leligdowicz Abstract HIV-1-specific CD8+ T cells are present in most HIV-1-infected people and play an important role in controlling viral replication, but the characteristics of an effective HIV-specific T-cell response are largely unknown. The majority of HIV-2-infected people behave as long-term non-progressors while those who progress to AIDS do so in a manner indistinguishable from HIV-1. A detailed study of HIV-2 infection may identify protective immune responses. Robust gag p26-specific T-cell responses are elicited during HIV-2 infection and correlate with control of viremia. In this study, we analyzed features of an HLA-B*3501-restricted T-cell response to HIV-2 p26 that may contribute to virus control. In contrast to HIV-1, HIV-2-specific T cells are at an early stage of differentiation (CD27+CD28+), a finding that relates directly to CD4+ T-cell levels and inversely to immune activation. The cells demonstrate IFN-, secretion, oligoclonal T-cell receptor V, gene segment usage, exceptional avidity and secretion of pro-inflammatory cytokines. Despite the potentially strong selection pressure imposed on the virus by these cells, there was no evidence of HIV-2 sequence evolution. We propose that in chronic HIV-2 infection, the maintenance of early-differentiated, highly avid CD8+ T cells could account for the non-progressive course of disease. Such responses may be desirable from an HIV vaccine. [source] Activation drives PD-1 expression during vaccine-specific proliferation and following lentiviral infection in macaquesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2008David Abstract Recent data supports that increased expression of PD-1, a negative regulator of immune function, is associated with T cell exhaustion during chronic viral infection. However, PD-1 expression during acute infection and vaccination has not been studied in great detail in primates. Here, we examine PD-1 expression on CD3+ T cells following DNA vaccination or lentiviral infection of macaques. Ex vivo peptide stimulation of PBMC from DNA-vaccinated uninfected macaques revealed a temporal increase in PD-1 expression in proliferating antigen-specific CD8+ T cells. Following the initial increase, PD-1 expression steadily declined as proliferation continued, with a concomitant increase in IFN-, secretion. Subsequent examination of PD-1 expression on T cells from uninfected and lentivirus-infected non-vaccinated macaques revealed a significant increase in PD-1 expression with lentiviral infection, consistent with previous reports. PD-1 expression was highest on cells with activated memory and effector phenotypes. Despite their decreased telomere length, PD-1hi T cell populations do not appear to have statistically significant uncapped telomeres, typically indicative of proliferative exhaustion, suggesting a different mechanistic regulation of proliferation by PD-1. Our data indicate that PD-1 expression is increased as a result of T cell activation during a primary immune response as well as during persistent immune activation in macaques. Supporting Information for this article is available at www.wiley-vch.de/contents/jc_2040/2008/37857_s.pdf [source] Comparative evaluation of intranasal and subcutaneous route of immunization for development of mucosal vaccine against experimental tuberculosisFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 1 2005Pramod K. Giri Abstract Activation of mucosal immunity in the respiratory tract is crucial for protection against respiratory infections. Whether the intranasal route of vaccination imparts better protection against pulmonary tuberculosis than that of subcutaneous vaccination remains a debatable issue. In this study, we have investigated the effect of the routes of immunization on the induction of immunoprotection against experimental tuberculosis employing mycobacterial culture filtrate proteins complexed with dimethyldioctadecylammonium bromide. Vaccination via intranasal and subcutaneous routes triggered immune activation in the spleen and cervical lymph node, while the former route of vaccination lead to higher antigen-specific lymphocyte proliferation, interferon-,, interleukin-12 and interleukin-4 responses in cervical lymph node and induction of antigen-specific IgA responses at mucosal level of the respiratory tract. Mice vaccinated via the intranasal route were found to be better protected against experimental tuberculosis particularly in lung compared to subcutaneous-immunized mice. These results emphasize the importance of the intranasal route vaccination in tuberculosis. [source] Soluble Interleukin-2 Receptors Increase During the Active Periods in Cluster HeadacheHEADACHE, Issue 1 2003M. Empl MD Objective.,To investigate whether cytokines are altered during the active period of cluster headache. Background.,Patients with cluster headache show activation of the hypothalamus in PET studies and via endocrinologic parameters. Data also suggest an inflammatory process occurs in cluster headache. A connection between the presumed inflammatory cause, an immunological activation, and the hypothalamus could be generated by certain cytokines. Design and Methods.,ELISA was used to determine the serum levels of soluble interleukin-2 receptors, interleukin-1, interleukin-6, and 2 soluble interleukin-6 receptors (sIL-6R and soluble gp130) in 18 patients with cluster headache (6 women and 12 men) during the cluster period and in 17 healthy controls who were headache-free (3 women and 14 men). Results.,Patients with cluster headache had significantly increased soluble interleukin-2 receptors (413.6±223 U/mL vs. 290.0±112 U/mL; P < .05) compared with controls. Serum levels of interleukin-1 (0.29±0.30 pg/mL vs. 0.13±0.13 pg/mL, n.s.), interleukin-6 (0.87±0.6 pg/mL vs. 0.91±0.7 pg/ml; n.s.), soluble interleukin-6 receptors (33,131±8,349 pg/mL vs. 35,063±7,606 pg/mL; n.s.), or soluble gp130 (289±59 pg/mL vs. 283±20 pg/mL; n.s.) did not differ between the 2 groups, although patients with cluster tended to have higher interleukin-1 values. Conclusions.,Because elevated soluble interleukin-2 receptors indicate T cell activation, our findings suggest immune activation during cluster headache. Because interleukin-2 can activate the hypothalamus and stimulate the release of Corticotropin-releasing Factor (CRF), interleukin-2 could link a putative immunological cause of cluster headache with the observed hypothalamic activation. Systemic changes of interleukin-1 or the interleukin-6 system do not seem to play a role in cluster headache, as no alterations of serum levels were observed. Even so, unchanged serum levels do not exclude limited local production. [source] Timing and tuning of CD27,CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathologyIMMUNOLOGICAL REVIEWS, Issue 1 2009Martijn A. Nolte Summary:, After binding its natural ligand cluster of differentiation 70 (CD70), CD27, a tumor necrosis factor receptor (TNFR)-associated factor-binding member of the TNFR family, regulates cellular activity in subsets of T, B, and natural killer cells as well as hematopoietic progenitor cells. In normal immune responses, CD27 signaling appears to be limited predominantly by the restricted expression of CD70, which is only transiently expressed by cells of the immune system upon activation. Studies performed in CD27-deficient and CD70-transgenic mice have defined a non-redundant role of this receptor,ligand pair in shaping adaptive T-cell responses. Moreover, adjuvant properties of CD70 have been exploited for the design of anti-cancer vaccines. However, continuous CD27,CD70 interactions may cause immune dysregulation and immunopathology in conditions of chronic immune activation such as during persistent virus infection and autoimmune disease. We conclude that optimal tuning of CD27,CD70 interaction is crucial for the regulation of the cellular immune response. We provide a detailed comparison of costimulation through CD27 with its closely related family members 4-1BB (CD137), CD30, herpes virus entry mediator, OX40 (CD134), and glucocorticoid-induced TNFR family-related gene, and we argue that these receptors do not have a unique function per se but that rather the timing, context, and intensity of these costimulatory signals determine the functional consequence of their activity. [source] Circuitry of nuclear factor ,B signalingIMMUNOLOGICAL REVIEWS, Issue 1 2006Alexander Hoffmann Summary:, Over the past few years, the transcription factor nuclear factor (NF)-,B and the proteins that regulate it have emerged as a signaling system of pre-eminent importance in human physiology and in an increasing number of pathologies. While NF-,B is present in all differentiated cell types, its discovery and early characterization were rooted in understanding B-cell biology. Significant research efforts over two decades have yielded a large body of literature devoted to understanding NF-,B's functioning in the immune system. NF-,B has been found to play roles in many different compartments of the immune system during differentiation of immune cells and development of lymphoid organs and during immune activation. NF-,B is the nuclear effector of signaling pathways emanating from many receptors, including those of the inflammatory tumor necrosis factor and Toll-like receptor superfamilies. With this review, we hope to provide historical context and summarize the diverse physiological functions of NF-,B in the immune system before focusing on recent advances in elucidating the molecular mechanisms that mediate cell type-specific and stimulus-specific functions of this pleiotropic signaling system. Understanding the genetic regulatory circuitry of NF-,B functionalities involves system-wide measurements, biophysical studies, and computational modeling. [source] Chemokine receptor-dependent alloresponsesIMMUNOLOGICAL REVIEWS, Issue 1 2003Wayne W. Hancock Summary:, Immunologists have typically viewed alloreactivity schematically as a function of antigen presentation, expansion of alloreactive T and B cells within regional lymphoid tissues, and cellular infiltration and destruction of an allograft. Actual details of the steps between immune activation and accumulation of effector cells within a graft typically have not received much attention. However, just how cells ,know' to move to and migrate within a graft or not is proving to be of increasing interest, as the chemokine-dependent mechanisms underlying leukocyte recruitment to a transplant are dissected. Experimentally, chemokine receptor targeting can prolong or induce permanent allograft survival, despite preservation of alloresponses within secondary lymphoid tissues, whereas current immunosuppressive protocols have only modest effects on chemokine production and leukocyte homing. Recent knowledge of the chemokine-dependent nature of allograft rejection, acceptance, and tolerance induction are presented as a basis for understanding the rationale for preclinical trials of chemokine receptor-targeted therapies currently underway in primate recipients of solid organ allografts. [source] Cytokine-mediated control of lipopolysaccharide-induced activation of small intestinal epithelial cellsIMMUNOLOGY, Issue 3 2007Michael Lotz Summary Cytokines with anti-inflammatory properties have been implicated in the prevention of inappropriate immune activation by commensal bacteria in the intestinal tract. Here, we analysed receptor expression, cellular signalling, and the inhibitory activity of interleukin (IL)-4, -10, -11, and -13 as well as of transforming growth factor-, on lipopolysaccharide-mediated small intestinal epithelial cell activation. Only IL-4 and IL-13 had a significant inhibitory effect on chemokine secretion and nitric oxide (NO) production in differentiated and polarized cells. Reverse transcription,polymerase chain reaction of primary intestinal epithelial cells obtained by laser-microdissection confirmed expression of the type II IL-4 receptor consisting of the IL-4 receptor , and the IL-13 receptor ,1. Also, IL-4 or IL-13 led to rapid signal transducer and activator of transcription 6 phosphorylation, diminished inducible NO synthase expression, and enhanced the antagonistic arginase 1 activity. In conclusion, cytokines such as IL-4 and IL-13 affect intestinal epithelial cells and exhibit a modulating activity on Toll-like receptor-4-mediated epithelial cell activation. [source] Acute experimental colitis and human chronic inflammatory diseases share expression of inflammation-related genes with conserved Ets2 binding sitesINFLAMMATORY BOWEL DISEASES, Issue 2 2009Tineke C.T.M. van der Pouw Kraan PhD Abstract Background: Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by chronic inflammation of the gastrointestinal tract, with overlapping clinical characteristics and unknown etiology. We reasoned that in intestinal inflammation the initial activation of the innate immune response fails to resolve, finally resulting in uncontrolled chronic inflammatory bowel disease. Methods: To identify the early inflammatory events in colitis that remain active in human chronic colitis, we analyzed the changes of the colonic transcriptome during acute experimental colitis and compared the outcome with previously published profiles of affected tissues from patients with UC and CD, and as a control for intestinal inflammation in general, tissues from celiac disease patients. Rheumatoid arthritis synovial tissues were included as a nonintestinal inflammatory disease. The expression profiles of each disease were analyzed separately, in which diseased tissues were compared to unaffected tissues from the same anatomical location. Results: Gene ontology analysis of significantly regulated genes revealed a marked activation of immunity and defense processes in all diseases, except celiac disease, where immune activation is less prominent. The control region of upregulated genes contained an increase in Ets2 binding sites in experimental colitis, UC, and rheumatoid arthritis, and were associated with upregulated immune activity. In contrast, upregulated genes in celiac disease harbored the transcription factor binding site GLI, which binds to the Gli family of transcription factors involved in hedgehog signaling, affecting development and morphogenesis. Conclusion: Ets2 may be an important transcription factor driving inflammation in acute as well as chronic inflammatory disease. (Inflamm Bowel Dis 2008) [source] IL-23/IL-17 immunity as a hallmark of Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2008Veera Hölttä MD Abstract Background: We studied the balance between ileal T-effector cells versus T-regulatory cells in active and inactive Crohn's disease (CD). Methods: We compared effector and regulatory T-cell-related markers such as interleukin (IL),17, interferon (IFN)-,, IL-4, and Foxp3 transforming growth factor (TGF),, CTLA-4 and markers for innate immune activation such as IL-6, IL-10, IL-18, IL-23, tumor necrosis factor (TNF),,, and IL-12p70, studied with immunohistochemistry and RT-PCR in ileal biopsies from patients with active or inactive CD and from control subjects. IL-17 in fecal samples was detected by ELISA. The effect of IL-17 on IL-8 and TNF-, mRNA expression in epithelial cell line Caco-2 was studied. Results: The numbers of IL-4-, IL-17-, and IL-23(p19)-positive cells in the lamina propria were higher in patients with CD, both active and inactive, than in the controls. mRNA expression of IL-17A, IL-6, and Foxp3 was increased in the biopsies both from patients with active disease and those in remission, whereas mRNA expression of IL-23 was increased only in active disease. Fecal IL-17 concentration was increased in patients with active disease. IL-17 enhanced the IL-8 and TNF-, response of the epithelial cell line to lipopolysaccharide (LPS) in vitro. Conclusions: Our findings suggest that activation of the IL-23/IL-17 axis is fundamentally connected to the etiology of CD and may represent the basis for the relapsing nature of the disease by increasing the sensitivity of epithelium to microbial LPS. (Inflamm Bowel Dis 2008) [source] Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient miceINFLAMMATORY BOWEL DISEASES, Issue 2 2002Michael Schultz Abstract Interleukin (IL)-10-deficient (IL-10,/,) mice develop colitis under specific pathogen-free (SPF) conditions and remain disease free if kept sterile (germ free [GF]). We used four different protocols that varied the time-points of oral administration of Lactobacillus plantarum 299v (L. plantarum) relative to colonization with SPF bacteria to determine whether L. plantarum could prevent and treat colitis induced by SPF bacteria in IL-10,/, mice and evaluated the effect of this probiotic organism on mucosal immune activation. Assessment of colitis included blinded histologic scores, measurements of secreted colonic immunoglobulin isotypes, IL-12 (p40 subunit), and interferon (IFN)-, production by anti-CD3-stimulated mesenteric lymph node cells. Treating SPF IL-10,/, mice with L. plantarum attenuated previously established colonic inflammation as manifested by decreased mucosal IL-12, IFN-,, and immunoglobulin G2a levels. Colonizing GF animals with L. plantarum and SPF flora simultaneously had no protective effects. Gnotobiotic IL-10,/, mice monoassociated with L. plantarum exhibited mild immune system activation but no colitis. Pretreatment of GF mice by colonization with L. plantarum, then exposure to SPF flora and continued probiotic therapy significantly decreased histologic colitis scores. These results demonstrate that L. plantarum can attenuate immune-mediated colitis and suggest a potential therapeutic role for this agent in clinical inflammatory bowel diseases. [source] Polymeric Materials for Gene Delivery and DNA VaccinationADVANCED MATERIALS, Issue 8 2009David N. Nguyen Abstract Gene delivery holds great potential for the treatment of many different diseases. Vaccination with DNA holds particular promise, and may provide a solution to many technical challenges that hinder traditional vaccine systems including rapid development and production and induction of robust cell-mediated immune responses. However, few candidate DNA vaccines have progressed past preclinical development and none have been approved for human use. This Review focuses on the recent progress and challenges facing materials design for nonviral DNA vaccine drug delivery systems. In particular, we highlight work on new polymeric materials and their effects on protective immune activation, gene delivery, and current efforts to optimize polymeric delivery systems for DNA vaccination. [source] Gene and immune therapy for renal cell carcinomaINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2001Allan J Pantuck Abstract Conventional therapy for metastatic renal cell carcinoma is associated with a poor response rate and few patients are long-term survivors. The occurrence of spontaneous regression and the prolonged latency period between primary tumor removal and the appearance of metastases in some patients suggest the existence of important host immune responses to autologous tumor cells. With the advent of molecular gene transfer techniques and increased knowledge of the basic pathways of immune activation, the field of cancer immunotherapy has finally begun to develop novel and effective approaches for harnessing the immune system as a therapeutic agent. Current immunotherapy and gene therapy strategies, including methods of cytokine delivery and tumor-cell-based vaccines, are presented. [source] Methods for the identi,cation of chemical respiratory allergens in rodents: comparisons of cytokine pro,ling with induced changes in serum IgEJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2003R. J. Dearman Abstract No validated or widely recognized test methods are currently available for the prospective identi,cation of chemicals with the potential to cause respiratory allergy. The cellular and molecular mechanisms that result in the induction of chemical sensitization of the respiratory tract are unclear, although there is evidence for the selective development of T helper 2 (Th2)-type responses and, in some cases, the production of IgE antibody. We have therefore examined the utility of cytokine pro,ling using BALB/c mice, together with the measurement of induced increases in the total serum concentration of IgE in the Brown Norway (BN) rat, as markers for the prospective identi,cation of chemical respiratory allergens. Responses provoked by the reference respiratory allergen trimellitic anhydride (TMA) have been compared with those stimulated by the respiratory sensitizing diisocyanates toluene diisocyanate (TDI) and hexamethylene diisocyanate (HDI) and by the acid anhydride hexahydrophthalic anhydride (HHPA). Topical exposure of BN rats to TMA, TDI and HHPA each provoked marked immune activation (increases in lymph node cellularity and proliferation). However, only treatment with TMA stimulated vigorous increases in the total serum concentration of IgE. In contrast, exposure to HHPA, TDI or HDI failed to provoke signi,cant changes in serum IgE concentration or induced only transient and relatively weak increases in serum IgE levels. In parallel experiments using BALB/c strain mice, however, topical application of all four chemical respiratory allergens provoked a marked Th2-type cytokine secretion pro,le in draining lymph node cells. These data suggest that the measurement of induced changes in serum IgE is not suf,ciently sensitive for the robust identi,cation of chemical respiratory allergens. Furthermore, irrespective of the reasons for variations in TMA-induced IgE production among BN rats, doubts remain regarding the utility of these animals for the characterization of immune responses to chemical allergens. Cytokine pro,ling using the BALB/c strain mouse apparently provides a more robust method for the hazard assessment of chemical respiratory allergens. Copyright © 2003 John Wiley & Sons, Ltd. [source] Induced changes in total serum IgE concentration in the Brown Norway rat: potential for identification of chemical respiratory allergensJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2002E. V. Warbrick Abstract A variety of chemicals can cause sensitization of the respiratory tract and occupational asthma that may be associated with IgE antibody production. Topical exposure to chemical respiratory allergens such as trimellitic anhydride (TMA) has been shown previously to induce increases in the total serum concentration of IgE in BALB/c strain mice. Contact allergens such as 2,4-dinitrochlorobenzene (DNCB), which apparently lack respiratory sensitizing potential, fail to provoke similar changes. However, it became apparent with time that there was some inter-animal variation in constitutive and inducible IgE levels. We have now examined the influence of topical exposure to TMA and DNCB on serum IgE levels in the Brown Norway (BN) rat. Such animals can be bled serially and thus it is possible to perform longitudinal analyses of changes in serum IgE concentration. The kinetics of IgE responses therefore can be followed on an individual animal basis, allowing discrimination between transient and sustained increases in serum IgE concentration. Rats (n = 5) were exposed on shaved flanks to 50% TMA, to 1% DNCB (concentrations that elicit comparable immune activation with respect to draining lymph node cellularity and proliferation) or to vehicle alone. Total IgE was measured by enzyme-linked immunosorbent assay in serum samples taken prior to and 14,42 days following initial exposure. Those animals having high pre-existing IgE levels (>1.0 µg ml,1) were excluded from subsequent analyses. The levels of serum IgE in the majority of rats exposed to DNCB or vehicle alone remained relatively stable throughout the duration of all the experiments conducted, although some animals displayed transient increases in serum IgE. Only TMA treatment was associated with a significant and sustained increase in the level of serum IgE in the majority of experiments. The elevated concentrations of IgE induced by topical exposure to TMA are persistent, the results reported here demonstrating that induced changes in IgE are maximal or near maximal at approximately 35 days, with a significant increase in IgE demonstrable for at least 42 days following the initiation of exposure. Interestingly, although TMA and DNCB at the test concentrations used were found to be of comparable overall immunogenicity with regard to lymph node activation and the induction of lymph node cell proliferation, there were apparent differences in humoral immune responses. Thus, not only did exposure to TMA stimulate increases in total serum IgE concentration and the production of specific IgE antibody, but also a more vigorous IgG antibody response was provoked by TMA compared with DNCB. These data suggest that the measurement of induced changes in serum IgE concentration in the BN strain of rat is able to differentiate between different classes of chemical allergen. Given the inter-animal variation in IgE production, it would be prudent to incorporate a concurrent assessment of responses induced by treatment with TMA as a positive control against which to assess the activity of other test materials. Copyright © 2002 John Wiley & Sons, Ltd. [source] Improved outcome of EAN, an animal model of GBS, through amelioration of peripheral and central inflammation by minocyclineJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2009Zhi-Yuan Zhang Abstract Experimental autoimmune neuritis (EAN) is a widely used animal model of the human acute inflammatory demyelinating polyradiculoneuropathy, which is the most common subtype of Guillain-Barré Syndrome. EAN is pathologically characterized by breakdown of the blood-nerve barrier, infiltration of reactive immune cells, local inflammation, demyelination in the peripheral nervous system and mechanical allodynia. Minocycline is known to have neuroprotective and anti-inflammatory effects. Furthermore, relieve of neuropathic pain following minocycline administration was observed in a variety of animal models. Here, we investigated the effects of minocycline on rat EAN. Suppressive treatment with minocycline (50 mg/kg body weight daily immediately after immunization) significantly attenuated the severity and duration of EAN. Macrophage and T-cell infiltration and demyelination in sciatic nerves of EAN rats treated with minocycline were significantly reduced compared to phosphate-buffered saline (PBS)-treated EAN rats. mRNA expressions of matrix metallopeptidase-9, inducible nitric oxide synthase and pro-inflammatory cytokines interleukin-1 , and tumour necrosis factor-, in EAN sciatic nerves were greatly decreased by administration of minocycline as well. Furthermore, minocycline attenuated mechanical allodynia in EAN rats and greatly suppressed spinal microglial activation. All together, our data showed that minocycline could effectively suppress the peripheral and spinal inflammation (immune activation) to improve outcome in EAN rats, which suggests that minocycline may be considered as a potential candidate of pharmacological treatment for autoimmune-mediated neuropathies. [source] Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/,PD-L1 pathwayAGING CELL, Issue 5 2010Celine S. Lages Summary Programmed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to age-associated T-cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD-1-expressing T cells and the level of expression of PD-Ls was increased on dendritic cell subsets and T cells; (ii) PD-1+ T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine-producing capacity; (iii) the expression of PD-1 was up-regulated after T-cell receptor-mediated activation of CD8+ T cells, but not of CD4+ T cells; (iv) blockade of the PD-1/PD-L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD-1/PD-L1 pathway did not restore function of PD-1+ T cells; its effect appeared to be exclusively mediated by increased functionality of the PD-1, T cells. Our data thus suggest that blockade of the PD-1/PD-L1 is not likely to be efficient at restoring exhausted T-cell responses in aged hosts, although improving the responses of PD-1, T cells may prove to be a helpful strategy in enhancing primary responses. [source] Bacterial flora in irritable bowel syndrome: role in pathophysiology, implications for managementJOURNAL OF DIGESTIVE DISEASES, Issue 1 2007Eamonn M M QUIGLEY Irritable bowel syndrome (IBS) may, in part at least, result from a dysfunctional interaction between the indigenous flora and the intestinal mucosa which, in turn, leads to immune activation in the colonic mucosa. Some propose a role for bacterial overgrowth as a common causative factor in the pathogenesis of symptoms in IBS; other evidence points to more subtle qualitative changes in the colonic flora; both hypotheses remain to be confirmed but the likelihood that bacterial overgrowth will prove to be a major factor in IBS now seems remote. Nevertheless, short-term therapy with either antibiotics or probiotics does seem to reduce symptoms among IBS patients. It seems most likely that the benefits of antibiotic therapy are mediated through subtle and, perhaps, localized, quantitative and/or qualitative changes in the colonic flora. How probiotics exert their effects remain to be defined but an anti-inflammatory effect seems likely. While this approach to the management of IBS is in its infancy, it is evident that manipulation of the flora, whether through the administration of antibiotics or probiotics, deserves further attention in IBS. [source] Review: Energy regulation and neuroendocrine,immune control in chronic inflammatory diseasesJOURNAL OF INTERNAL MEDICINE, Issue 6 2010R. H. Straub Abstract., Straub RH, Cutolo M, Buttgereit F, Pongratz G (University Hospital Regensburg, Regensburg, Germany; University of Genova, Genova, Italy; and Charité University Medicine Berlin, Berlin, Germany). Energy regulation and neuroendocrine,immune control in chronic inflammatory diseases (Review). J Intern Med 2010; 267:543,560. Energy regulation (EnR) is most important for homoeostatic regulation of physiological processes. Neuroendocrine pathways are involved in EnR. We can separate factors that provide energy-rich fuels to stores [parasympathetic nervous system (PSNS), insulin, insulin-like growth factor-1, oestrogens, androgens and osteocalcin] and those that provide energy-rich substrates to consumers [sympathetic nervous system (SNS), hypothalamic,pituitary,adrenal axis, thyroid hormones, glucagon and growth hormone]. In chronic inflammatory diseases (CIDs), balanced energy-rich fuel allocation to stores and consumers, normally aligned with circadian rhythms, is largely disturbed due to the vast fuel consumption of an activated immune system (up to 2000 kJ day,1). Proinflammatory cytokines such as tumour necrosis factor or interleukins 1, and 6, circulating activated immune cells and sensory nerve fibres signal immune activation to the rest of the body. This signal is an appeal for energy-rich fuels as regulators are switched on to supply energy-rich fuels (,energy appeal reaction'). During evolution, adequate EnR evolved to cope with nonlife-threatening diseases, not with CIDs (huge negative selection pressure and reduced reproduction). Thus, EnR is inadequate in CIDs leading to many abnormalities, including sickness behaviour, anorexia, hypovitaminosis D, cachexia, cachectic obesity, insulin resistance, hyperinsulinaemia, dyslipidaemia, fat deposits near inflamed tissue, hypoandrogenaemia, mild hypercortisolaemia, activation of the SNS (hypertension), CID-related anaemia and osteopenia. Many of these conditions can contribute to the metabolic syndrome. These signs and symptoms become comprehensible in the context of an exaggerated call for energy-rich fuels by the immune system. We propose that the presented pathophysiological framework may lead to new therapeutical approaches and to a better understanding of CID sequence. [source] Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer?JOURNAL OF INTERNAL MEDICINE, Issue 3 2006C. SÖDERBERG-NAUCLÉR Abstract. Human cytomegalovirus (HCMV) is a herpes virus that infects and is carried by 70,100% of the world's population. During its evolution, this virus has developed mechanisms that allow it to survive in an immunocompetent host. For many years, HCMV was not considered to be a major human pathogen, as it appeared to cause only rare cases of HCMV inclusion disease in neonates. However, HCMV is poorly adapted for survival in the immunosuppressed host and has emerged as an important human pathogen in AIDS patients and in patients undergoing immunosuppressive therapy following organ or bone marrow transplantation. HCMV-mediated disease in such patients has highlighted the possible role of this virus in the development of other diseases, in particular inflammatory diseases such as vascular diseases, autoimmune diseases and, more recently, with certain forms of cancers. Current research is focused on determining whether HCMV plays a causative role in these diseases or is merely an epiphenomenon of inflammation. Inflammation plays a central role in the pathogenesis of HCMV. This virus has developed a number of mechanisms that enable it to hide from the cells of the immune system and, at the same time, reactivation of a latent infection requires immune activation. Numerous products of the HCMV genome are devoted to control central functions of the innate and adaptive immune responses. By influencing the regulation of various cellular processes including the cell cycle, apoptosis and migration as well as tumour invasiveness and angiogenesis, HCMV may participate in disease development. Thus, the various drugs now available for treatment of HCMV disease (e.g. ganciclovir, acyclovir and foscarnet), may also prove to be useful in the treatment of other, more widespread diseases. [source] SLE, atherosclerosis and cardiovascular diseaseJOURNAL OF INTERNAL MEDICINE, Issue 6 2005J. FROSTEGĹRD Abstract. Atherosclerosis is an inflammatory disease and the major cause of cardiovascular disease (CVD) in general. Atherosclerotic plaques are characterized by the presence of activated immune competent cells, but antigens and underlying mechanisms causing this immune activation are not well defined. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE). SLE-related CVD and atherosclerosis are important clinical problems but may in addition also shed light on how immune reactions are related to premature atherosclerosis and atherothrombosis. A combination of traditional and nontraditional risk factors, including dyslipidaemia (and to a varying degree hypertension, diabetes and smoking), inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. Premature atherosclerosis in some form leading to atherothrombosis is likely to be a major underlying mechanism, though distinctive features if any, of SLE-related atherosclerosis when compared with ,normal' atherosclerosis are not clear. One interesting possibility is that factors such as inflammation or aPL make atherosclerotic lesions in autoimmune disease more prone to rupture than in ,normal' atherosclerosis. Whether premature atherosclerosis is a general feature of SLE or only affects a subgroup of patients remains to be demonstrated. Treatment of SLE patients should also include a close monitoring of traditional risk factors for CVD. In addition, attention should also be paid to nontraditional risk factors such as inflammation and SLE-related factors such as aPL. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation and immune reactions present in atherosclerotic lesions. [source] Immunomodulation of atherosclerosis: myth and realityJOURNAL OF INTERNAL MEDICINE, Issue 3 2000A. Nicoletti Abstract. Nicoletti A, Caligiuri G & Hansson GK (Hôpital Broussais, Paris, and Karolinska Institute, Stockholm). Immunomodulation of atherosclerosis: myth and reality (Minisymposium). J Intern Med 2000; 247: 397,405. Atherosclerosis is an inflammatory disease which displays features of immune activation both locally and systemically. In the present review, we discuss the evidence for immune activation in human disease and experimental models, and survey candidate antigens associated with atherosclerosis. Studies of atherosclerosis in genetic models of immunodeficiency are analysed, as well as immunomodulating therapies and immunization protocols. Based on recent research, it is concluded that immunomodulation represents an interesting approach to the development of new prevention and treatment methods for atherosclerosis. [source] Gene expression profiling of gut mucosa and mesenteric lymph nodes in simian immunodeficiency virus-infected macaques with divergent disease courseJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4-5 2006M.D. George Abstract Background, Although the majority of drug-naďve HIV-infected patients develop acquired immunodeficiency syndrome (AIDS), a small percentage remains asymptomatic without therapeutic intervention. Methods, We have utilized the simian immunodeficiency virus (SIV)-infected rhesus macaque model to gain insights into the molecular mechanisms of long-term protection against simian AIDS. Results, Chronically SIV-infected macaques with disease progression had high viral loads and CD4+ T-cell depletion in mucosal tissue and peripheral blood. These animals displayed pathologic changes in gut-associated lymphoid tissue (GALT) and mesenteric lymph node that coincided with increased expression of genes associated with interferon induction, inflammation and immune activation. In contrast, the animal with long-term asymptomatic infection suppressed viral replication and maintained CD4+ T cells in both GALT and peripheral blood while decreasing expression of genes involved in inflammation and immune activation. Conclusions, Our findings suggest that reduced immune activation and effective repair and regeneration of mucosal tissues correlate with long-term survival in SIV-infected macaques. [source] Impact of changes in antigen level on CD38/PD-1 co-expression on HIV-specific CD8 T cells in chronic, untreated HIV-1 infection,,JOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Thomas Vollbrecht Abstract Excessive immune activation is a hallmark of chronic uncontrolled HIV infection. During the past years, growing evidence suggests that immune inhibitory signals also play an important role in progressive disease. However, the relationship between positive and negative immune signals on HIV-specific CD8 T cells has not been studied in detail so far in chronic HIV-1 infection. In this study, the expression of markers of positive (CD38) and negative (PD-1) immune signals on virus-specific CD8 T cells in chronic, untreated HIV-1 infection was evaluated using intracellular cytokine staining. Viral escape mutations were assessed by autologous virus sequence analysis and subsequent peptide titration assays. Single-epitope CD8 T-cell responses toward Gag, Pol, and Nef were compared in 12 HIV-1 controllers (viral load <5,000,cp/ml) and 12 HIV-1 progressors (viral load >50,000,cp/ml) and a highly significant increase of CD38/PD-1 co-expression on virus-specific CD8 T cells in progressors was found (P,<,0.0001). The level of CD38/PD-1 co-expression was independent of epitope specificity. Longitudinal follow-up revealed a clear drop in CD38/PD-1 co-expression on virus-specific CD8 T cells after the suppression of antigen following either viral escape mutation or the initiation of HAART (P,=,0.004). Antigen persistence with a fluctuating viral load revealed stable levels of CD38/PD-1 co-expression whereas significant rises in viral load were accompanied or even preceded by substantial increases in CD38/PD-1 co-expression. The CD38/PD-1 phenotype clearly distinguishes HIV-specific CD8 T-cell responses between controllers and progressors. Whether it plays a causative role in disease progression remains debatable. J. Med. Virol. 82:358,370, 2010. © 2010 Wiley-Liss, Inc. [source] Changes in HIV RNA viral load, CD4+ T-cell counts, and levels of immune activation markers associated with anti-tuberculosis therapy and cotrimoxazole prophylaxis among HIV-infected tuberculosis patients in Abidjan, Côte d'IvoireJOURNAL OF MEDICAL VIROLOGY, Issue 2 2005Mireille Kalou We analyzed changes in plasma human immunodeficiency virus (HIV)-1 viral load, CD4+ T-cell count, and markers of immune activation markers at start of treatment of tuberculosis and 12 months after among 44 HIV-1-infected patients with newly diagnosed, sputum-smear positive for Mycobacterium tuberculosis pulmonary in fection. All patients received a standard regimen of 6 months of rifampicin and isoniazid with first 2 months of pyrazinamid with or without cotrimoxazole. Compared with values at start of treatment, median viral load increased by a median of 0.64 log10 copies/ml after 12 months of follow-up (P,=,0.0002). Median CD4+ T-cell counts were 393 cells/L at start of treatment and 370 cells/L after 12 months of follow-up (P,=,0.61). Levels of serum activation markers decreased significantly at 12 months of follow-up of the patients for both patients on standard and cotrimoxazole treatment. Levels of viral load, CD4+ T-cell counts, and markers of immune activation were not different for patients on standard treatment of tuberculosis compared with those on standard and cotrimoxazole treatment. Levels of serum activation markers decreased significantly at 12 months of follow-up of the patients for both patients on standard and cotrimoxazole treatment. Because viral load is a predictor of disease progression, its persistent elevated levels in blood of HIV-infected patients co-infected with tuberculosis, who successfully complete TB treatment, may account for the high mortality observed in this population. J. Med. Virol. 75:202,208, 2005. © 2004 Wiley-Liss, Inc. 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