Home About us Contact
|
Home About us Contact | ||
|
|
||
Immune Modulation (immune + modulation)
Selected AbstractsImmune modulation of HLA-G dimer in maternal-fetal interfaceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Kimiko Kuroki Abstract HLA-G is a non-classical human MHC class I molecule, which has several characteristics distinct from classical MHC, such as low polymorphism and restricted tissue distribution. HLA-G is expressed on placenta, thymus and some tumors. At the maternal-fetal interface, trophoblasts do not express major classical MHC class I molecules (MHCI), HLA-A and -B, to prevent normal T cell responses. Instead, HLA-G is expressed and can suppress a wide range of immune responses by binding to inhibitory immune cell surface receptors, such as leukocyte Ig-like receptor (LILR) B1 and LILRB2. HLA-G exists in various forms, including ,2m-associated or -free disulfide-linked dimers that can be expressed either at the cell surface or in soluble form. However, until recently the physiological role of these different molecular forms has been unclear. In this issue of the European Journal of Immunology, one article demonstrates that the disulfide-linked homodimer of ,2m-associated HLA-G is the major fraction expressed by trophoblast cells. The HLA-G dimer modulates the function of LILRB1-expressing antigen-presenting cells by principally binding to LILRB1. On the other hand, another recent report showed that ,2m-free disulfide-linked HLA-G dimers are produced by villous cytotrophoblast cells. Taken together, these results provide strong evidence in support of the hypothesis that HLA-G dimers play a role in immune suppression at the maternal-fetal interface. Further in-depth investigation will help to clarify the precise mechanism of HLA-G receptor recognition and signaling in vivo and the role of these interactions in successful reproduction. See accompanying article: http://dx.doi.org/10.1002/eji.200737089 [source] Immune modulation by helminthic infections: worms and viral infectionsPARASITE IMMUNOLOGY, Issue 10 2006S. M. KAMAL SUMMARY Helminthic infections occur worldwide, especially in developing countries. About one-quarter of the world's population, 1·5 billion, are infected with one or more of the major soil-transmitted helminths, including hookworms, ascarids, and whipworms. Schistosomes infect more than 200 million people worldwide with 600 million at risk in 74 countries. The interaction between helminths and the host's immune system provokes particular immunomodulatory and immunoregulatory mechanisms that ensure their survival in the host for years. However, these changes might impair the immunological response to bystander bacterial, viral, and protozoal pathogens and to vaccination. Modulation of the immune system by infection with helminthic parasites is proposed to reduce the levels of allergic responses and to protect against inflammatory bowel disease. In this review, we summarize the immunological milieu associated with helminthic infections and its impact on viral infections, mainly hepatitis B virus, hepatitis C virus, and human immunodeficiency virus in humans and experimental animals. [source] Novel treatments for autistic spectrum disordersDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2005Susan E. Levy Abstract In no area of developmental pediatric practice is there more controversy regarding the choice of treatment than related to children with autistic spectrum disorders (ASD). Complementary and alternative medical therapies (CAM) are often elected because they are perceived as treating the cause of symptoms rather than the symptoms themselves. CAM used for autism can be divided by proposed mechanism: immune modulation, gastrointestinal, supplements that affect neurotransmitter function, and nonbiologic intervention. Secretin as a therapy for autism is discussed as an example of how a clinical observation rapidly grew to a widespread treatment before well-designed studies demonstrated absence of effect. The plausibility for behavioral effect was not substantiated by clinical studies. CAM used for treatment of autism is examined in terms of rationale, evidence of efficacy, side effects, and additional commentary. Families and clinicians need access to well-designed clinical evidence to assist them in choice of therapies. © 2005 Wiley-Liss, Inc. MRDD Research Reviews 2005;11:131,142. [source] Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparumEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010Linda J. Wammes Abstract Chronic helminth infections induce T-cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on proliferation and cytokine responses to BCG and Plasmodium falciparum -parasitized RBC in Indonesian schoolchildren. Geohelminth-infected children's in vitro T-cell proliferation to either BCG or pRBC was reduced compared to that of uninfected children. Although the frequency of CD4+CD25hiFOXP3+ T cells was similar regardless of infection status, the suppressive activity differed between geohelminth-infected and geohelminth-uninfected groups: Ag-specific proliferative responses increased upon CD4+CD25hi T-cell depletion in geohelminth-infected subjects only. In addition, IFN-, production in response to both BCG and parasitized RBC was increased after removal of CD4+CD25hi T cells. These data demonstrate that geohelminth-associated Treg influence immune responses to bystander Ag of mycobacteria and plasmodia. Geohelminth-induced immune modulation may have important consequences for co-endemic infections and vaccine trials. [source] Probiotics: do they have a role in oral medicine and dentistry?EUROPEAN JOURNAL OF ORAL SCIENCES, Issue 3 2005Jukka H. Meurman This review describes current knowledge on probiotic bacteriotherapy from the oral health perspective. Recent experimental studies and results from randomized controlled trials have shown that certain gut bacteria, in particular species of Lactobacillus and Bifidobacterium, may exert beneficial effects in the oral cavity by inhibiting cariogenic streptococci and Candida sp. Probiotics have been successfully used to control gastro-intestinal diseases. They also appear to alleviate symptoms of allergy and diseases with immunological pathology. The mechanisms of probiotic action appear to link with colonization resistance and immune modulation. Lactic acid bacteria can produce different antimicrobial components such as organic acids, hydrogen peroxide, carbon peroxide, diacetyl, low molecular weight antimicrobial substances, bacteriocins, and adhesion inhibitors, which also affect oral microflora. However, data is still sparse on the probiotic action in the oral cavity. More information is needed on the colonization of probiotics in the mouth and their possible effect on and within oral biofilms. There is every reason to believe that the putative probiotic mechanisms of action are the same in the mouth as they are in other parts of the gastrointestinal tract. Because of the increasing global problem with antimicrobial drug resistance, the concept of probiotic therapy is interesting and pertinent, and merits further research in the fields of oral medicine and dentistry. [source] Host immune responses in ex vivo approaches to cutaneous gene therapy targeted to keratinocytesEXPERIMENTAL DERMATOLOGY, Issue 10 2005Z. Lu Abstract:, Epidermal gene therapy may benefit a variety of inherited skin disorders and certain systemic diseases. Both in vivo and ex vivo approaches of gene transfer have been used to target human epidermal stem cells and achieve long-term transgene expression in immunodeficient mouse/human chimera models. Immunological responses however, especially in situations where a neoantigen is expressed, are likely to curtail expression and thereby limit the therapy. In vivo gene transfer to skin has been shown to induce transgene-specific immune responses. Ex vivo gene transfer approaches, where keratinocytes are transduced in culture and transplanted back to patient, however, may avoid signals provided to the immune system by in vivo administration of vectors. In the current study, we have developed a stable epidermal graft platform in immunocompetent mice to analyze host responses in ex vivo epidermal gene therapy. Using green fluorescent protein (GFP) as a neoantigen and an ex vivo retrovirus-mediated gene transfer to mouse primary epidermal cultures depleted of antigen-presenting cells (APCs), we show induction of GFP-specific immune responses leading to the clearance of transduced cells. Similar approach in immunocompetent mice tolerant to GFP resulted in permanent engraftment of transduced cells and continued GFP expression. Activation of transgene-specific immune responses in ex vivo gene transfer targeted to keratinocytes require cross-presentation of transgene product to APCs, a process that is most amenable to immune modulation. This model may be used to explore strategies to divert transgene-specific immune responses to less destructive or tolerogenic ones. [source] Potency and selectivity of inhibition of cathepsin K, L and S by their respective propeptidesFEBS JOURNAL, Issue 20 2000Jocelyne Guay The prodomains of several cysteine proteases of the papain family have been shown to be potent inhibitors of their parent enzymes. An increased interest in cysteine proteases inhibitors has been generated with potential therapeutic targets such as cathepsin K for osteoporosis and cathepsin S for immune modulation. The propeptides of cathepsin S, L and K were expressed as glutathione S -transferase-fusion proteins in Escherichia coli. The proteins were purified on glutathione affinity columns and the glutathione S -transferase was removed by thrombin cleavage. All three propeptides were tested for inhibitor potency and found to be selective within the cathepsin L subfamily (cathepsins K, L and S) compared with cathepsin B or papain. Inhibition of cathepsin K by either procathepsin K, L or S was time-dependent and occurred by an apparent one-step mechanism. The cathepsin K propeptide had a Ki of 3.6,6.3 nm for each of the three cathepsins K, L and S. The cathepsin L propeptide was at least a 240-fold selective inhibitor of cathepsin K (Ki = 0.27 nm) and cathepsin L (Ki = 0.12 nm) compared with cathepsin S (Ki = 65 nm). Interestingly, the cathepsin S propeptide was more selective for inhibition of cathepsin L (Ki = 0.46 nm) than cathepsin S (Ki = 7.6 nm) itself or cathepsin K (Ki = 7.0 nm). This is in sharp contrast to previously published data demonstrating that the cathepsin S propeptide is equipotent for inhibition of human cathepsin S and rat and paramecium cathepsin L [Maubach, G., Schilling, K., Rommerskirch, W., Wenz, I., Schultz, J.E., Weber, E. & Wiederanders, B. (1997), Eur J. Biochem. 250, 745,750]. These results demonstrate that limited selectivity of inhibition can be measured for the procathepsins K, L and S vs. the parent enzymes, but selective inhibition vs. cathepsin B and papain was obtained. [source] Microbes versus microbes: immune signals generated by probiotic lactobacilli and their role in protection against microbial pathogensFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 4 2002Martin L Cross Abstract Probiotic lactic acid bacteria can signal the immune system through innate cell surface pattern recognition receptors or via direct lymphoid cell activation. In some cases, this action has been shown to be sufficient to modulate local- and systemic-level in vivo immune responses. Practical applications of probiotics include their use in anti-tumour and anti-allergy immunotherapy, but there is also increasing evidence that some probiotics can stimulate a protective immune response sufficiently to enhance resistance to microbial pathogens. This review outlines the experimental and clinical evidence for enhanced anti-microbial immune protection by probiotic lactic acid bacteria, focussing on those studies where a correlative or suggestive link has been shown between immune modulation and enhanced protection. [source] Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotypeINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Andreas Weigert Abstract A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor-associated macrophages (TAMs), which are polarized towards an anti-inflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti-cancer strategies along this line. One potential immune modulating compound, sphingosine-1-phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P-producing enzymes for tumor progression. The growth of SphK2-deficient MCF-7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors was comparable. However, TAMs from SphK2-deficient tumors displayed a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-,, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization. © 2009 UICC [source] Cutaneous gene transfer for skin and systemic diseasesJOURNAL OF INTERNAL MEDICINE, Issue 1 2002P. A. KHAVARI This article is partially based on the findings presented at a symposium on Cutaneous Gene Therapy, held in Uppsala, September 2001, and abstracted in Acta Derm Venereol 81: 227,239. Abstract.,Khavari PA, Rollman O, Vahlquist A (Stanford University School of Medicine, Stanford, CA, USA; and Department of Medical Sciences, Dermatology, Uppsala University, Uppsala, Sweden). Cutaneous gene transfer for skin and systemic diseases (Review). J Intern Med 2002; 252: 1,10. Recent progress in molecular genetics has illuminated the basis for a wide variety of inherited and acquired diseases. Gene therapy offers an attractive therapeutic approach capitalizing upon these new mechanistic insights. The skin is a uniquely attractive tissue site for development of new genetic therapeutic approaches both for its accessibility as well as for the large number of diseases that are amenable in principle to cutaneous gene transfer. Amongst these opportunities are primary monogenic skin diseases, chronic wounds and systemic disorders characterized by low or absent levels of circulating polypeptides. For cutaneous gene therapy to be effective, however, significant progress is required in a number of domains. Recent advances in vector design, administration, immune modulation, and regulation of gene expression have brought the field much nearer to clinical utility. [source] Alcohol, Signaling, and ECM TurnoverALCOHOLISM, Issue 1 2010Devanshi Seth Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse. [source] Endocannabinoids and liver disease , reviewLIVER INTERNATIONAL, Issue 5 2005Ezra Gabbay Abstract: Aims: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. Methods: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. Results: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. Conclusions: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities. [source] The changing faces of Streptococcus antigen I/II polypeptide family adhesinsMOLECULAR MICROBIOLOGY, Issue 2 2010L. Jeannine Brady Summary Streptococcus mutans antigen I/II (AgI/II) protein was one of the first cell wall-anchored adhesins identified in Gram-positive bacteria. It mediates attachment of S. mutans to tooth surfaces and has been a focus for immunization studies against dental caries. The AgI/II family polypeptides recognize salivary glycoproteins, and are also involved in biofilm formation, platelet aggregation, tissue invasion and immune modulation. The genes encoding AgI/II family polypeptides are found among Streptococcus species indigenous to the human mouth, as well as in Streptococcus pyogenes, S. agalactiae and S. suis. Evidence of functionalities for different regions of the AgI/II proteins has emerged. A sequence motif within the C-terminal portion of Streptococcus gordonii SspB (AgI/II) is bound by Porphyromonas gingivalis, thus promoting oral colonization by this anaerobic pathogen. The significance of other epitopes is now clearer following resolution of regional crystal structures. A new picture emerges of the central V (variable) region, predicted to contain a carbohydrate-binding trench, being projected from the cell surface by a stalk formed by an unusual association between an N-terminal ,-helix and a C-terminal polyproline helix. This presentation mode might be important in determining functional conformations of other Gram-positive surface proteins that have adhesin domains flanked by ,-helical and proline-rich regions. [source] ORIGINAL ARTICLE: Endogenous Adenosine Down-Modulates Mid-Trimester IntraAmniotic Tumor Necrosis Factor-, ProductionAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 4 2009Uma Perni Problem, To determine whether adenosine in amniotic fluid down-regulates pro-inflammatory cytokine production. Method of study, Mid-trimester amniotic fluid from 21 women was incubated ex vivo in the presence or absence of human adenosine deaminase, the enzyme that irreversibly degrades adenosine. After 24 hr, supernatants were assayed by ELISA for tumor necrosis factor-, (TNF-,), interleukin (IL)-6, and IL-10. Clinical parameters were obtained after completion of laboratory testing. Results, Inclusion of adenosine deaminase resulted in a median increase in TNF-, production from 0.9 to 7.3 pg/mL (P = 0.0014). IL-6 production exhibited a non-significant median increase from <2.0 to 53.0 pg/mL (P = 0.0780). Median IL-10 production increased slightly from a median of <0.2 to 1.3 pg/mL. Adenosine deaminase-stimulated TNF-, production was proportional to parity and unrelated to gestational age, time of delivery, maternal age or indication for amniocentesis. Conclusion, Adenosine deaminase treatment increases TNF-, production by ex vivo -cultured amniotic fluid. Adenosine contributes to immune modulation in the amniotic cavity. [source] B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity,ANNALS OF NEUROLOGY, Issue 3 2010Martin S. Weber MD Objective Clinical studies indicate that anti-CD20 B-cell depletion may be an effective multiple sclerosis (MS) therapy. We investigated mechanisms of anti-CD20-mediated immune modulation using 2 paradigms of experimental autoimmune encephalomyelitis (EAE). Methods Murine EAE was induced by recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35-55, which does not require B cells. Results In EAE induced by rMOG, B cells became activated and, when serving as antigen-presenting cells (APCs), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B-cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less central nervous system (CNS) inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in MOG p35-55-induced EAE, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naive B cells. In this setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B-cell depletion reduced the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg), and increased the proinflammatory polarizing capacity of remaining myeloid APCs. Interpretation Our study highlights distinct roles for B cells in CNS autoimmunity. Clinical benefit from anti-CD20 treatment may relate to inhibition of proinflammatory B cell APC function. In certain clinical settings, however, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable. Differences in immune responses to MOG protein and peptide may be important considerations when choosing an EAE model for testing novel B cell-targeting agents for MS. ANN NEUROL 2010 [source] Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis CAPMIS, Issue 4 2010JIU-PING WANG Wang J-P, Zhang Y, Wei X, Li J, Nan X-P, Yu H-T, Li Y, Wang P-Z, Bai X-F. Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C. APMIS 2010; 118: 261,70. The mechanism of hepatitis C virus (HCV) involvement in innate immune responses and immune modulation has not been well characterized. In the present work, we studied Toll-like receptor (TLR) 2 and TLR4, which were recently recognized as the important components of innate immunity, as well as CD4+ CD25+ CD127low/, regulatory T cells (Tregs), which actively suppress pathological and physiological immune response during HCV infection. The study involved 31 chronic hepatitis C patients and 20 healthy controls. TLR2 and TLR4 expression in peripheral blood monocytes and the number of Tregs were examined by flow cytometric analysis. Overexpression of TLR2 and TLR4 was found in chronic hepatitis C patients as compared with controls. Furthermore, increased cytokine production, including that of ,-interferon, tumor necrosis factor-,, interleukin (IL)-6, and IL-8, was observed in peripheral blood mononuclear cells from chronic hepatitis C patients after challenge with TLR2 and TLR4 agonists. The number of Tregs was significantly higher in chronic hepatitis C patients and the increased Tregs were associated with HCV genotype 1b. In vitro studies demonstrated that circulating Tregs suppress T-cell responses in chronic hepatitis C patients. Significant correlations were found between the viral load and Treg number and between TLR2 and TLR4 level in chronic hepatitis C patients. Taken together with other published data, these results suggest that TLR2, TLR4, and Tregs correlate closely with chronic HCV infection. [source] Nutrition and immunity: an updateAQUACULTURE RESEARCH, Issue 3 2010Viviane Verlhac Trichet Abstract Immunity encompasses all mechanisms and responses used by the organism to defend itself against bacteria, viruses or parasites. Adequate supply and balance of nutrients are required for proper efficiency of the host defences. Research has identified dietary factors that affect human and animal immune responses like amino acids, fatty acids, minerals and vitamins. Some of these nutrients have been proven to have specific actions on immunity when provided at pharmacological doses. This paper will review these nutrients and their current use in aquaculture. The immune system is an efficient but complex system. Its complexity has made the assessment of the effects of diets difficult. Nevertheless, the standardization of methodology as well as the use of new techniques at the cell or the gene level should help to better understand the mechanisms of immune modulation. This paper will review the major functions of fish and shrimp immune system and the methodologies used. Cellular and humoral functions including cytokines will be discussed in relation to potential means to modulate them and the underlying mechanism. A better understanding of the mechanisms of modulation of the immune functions should help in the discovery of new dietary factors to improve the immune status of the animal, leading to better disease resistance. [source] Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque modelARTHRITIS & RHEUMATISM, Issue 2 2010Philana Ling Lin Objective An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor , (TNF,),neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non-human primate model. Methods Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6,8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF-neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55-TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison. Results Administration of TNF-neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin-12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria-induced interferon-, production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes. Conclusion These findings have important clinical implications for determining the mechanism of TNF neutralization,related tuberculosis. [source] | |||||||||||||