The Experts below are selected from a list of 1863 Experts worldwide ranked by ideXlab platform
Bart Jan Kullberg - One of the best experts on this subject based on the ideXlab platform.
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delayed clearance of intraabdominal abscesses caused by candida albicans in tumor necrosis factor Alpha and Lymphotoxin Alpha deficient mice
2002Co-Authors: Alieke G Vonk, Mihai G Netea, Johan H J M Van Krieken, Jos W M Van Der Meer, Bart Jan KullbergAbstract:The role of endogenous tumor necrosis factor-Alpha (TNF) and Lymphotoxin-Alpha (LT) in a model of intraabdominal Candida sepsis and abscess formation was investigated. Significantly more abscesses were observed in TNF/LT double knockout (TNF(-/-)LT(-/-)) mice, compared with that in wild-type (TNF(+/+)LT(+/+)) mice. Outgrowth of Candida in abscesses of TNF(-/-)LT(-/-) mice was 10-fold increased on day 14 and 60-fold increased on day 21 of infection. The interleukin-10rcolon;interferon-gamma ratio, measured in supernatants of stimulated splenocytes, shifted from 131 for TNF(-/-)LT(-/-) mice and 13.9 for TNF(+/+)LT(+/+) mice on day 8 to 0.11 for TNF(-/-)LT(-/-) mice and 11.66 for TNF(+/+)LT(+/+) mice on day 14 of infection. The diminished host resistance is explained by an impaired extracellular killing capacity of granulocytes and a delayed development of a T helper 1 response in TNF(-/-)LT(-/-) mice. In conclusion, TNF and LT are critical to the stimulation of effector cells that leads to elimination of Candida from abscesses.
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divergent effects of tumor necrosis factor Alpha and Lymphotoxin Alpha on lethal endotoxemia and infection with live salmonella typhimurium in mice
2002Co-Authors: Edi Dharmana, Mihai G Netea, Ineke Verschueren, Monique Keuter, Bart Jan KullbergAbstract:During septic shock with Gram-negative microorganisms, mortality is determined by two independent factors: high concentrations of circulating proinflammatory cytokines and multiplication of the microorganisms in the organs of the host. We studied the role of endogenous tumor necrosis factor-Alpha (TNF) and Lymphotoxin-Alpha (LT) in the pathogenesis of lethal endotoxemia and infection with viable Salmonella typhimurium. Compared to wild-type control mice, TNF-/-LT-/- knock-out mice were more resistant (100% versus 25% mortality) to a lethal challenge with LPS, due to a significantly decreased production of the proinflammatory cytokines TNF, IL-1Alpha and IL-1beta. In contrast, TNF-/-LT-/- mice were highly susceptible to infection with viable S. typhimurium as compared to wild-type mice (100% versus 0% mortality), and this was accompanied by a 100-fold greater bacterial load in their organs. The effect of endogenous TNF and LT during infection was mediated by a defective recruitment of neutrophils at the site of infection, as well as a reduced intracellular killing of S. typhimurium by these cells. These results show that TNF and LT have crucial, yet opposite effects on lethal endotoxemia induced by S. typhimurium LPS and on the infection of mice with live Salmonella microorganisms, and suggest caution when extrapolating results obtained in the lethal endotoxemia model to bacteremia in patients.
Jonathon D Sedgwick - One of the best experts on this subject based on the ideXlab platform.
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multiple deficiencies underlie nk cell inactivity in Lymphotoxin Alpha gene targeted mice
1999Co-Authors: Mark J Smyth, Jonathon D Sedgwick, Ricky W Johnstone, Erika Cretney, Nicole M Haynes, Heiner Korner, Lynn D Poulton, Alan G BaxterAbstract:We have evaluated the NK cell antitumor activity in Lymphotoxin (LT)-deficient mice. Both NK cell-mediated tumor rejection and protection from experimental metastases were significantly compromised in LT-α-deficient mice. Analysis of LT-α-deficient mice revealed that the absolute number of αβTCR− NK1.1+ NK cells was reduced in bone marrow and thymus, but with overall proportional decreases in other hemopoietic organs. In addition, the antitumor potential of αβTCR− NK1.1+ cells, as determined by their lytic capacity and perforin expression, was reduced 1.5- to 3-fold in LT-α-deficient mice, as compared with wild-type mice. Combined defects in NK cell development and effector function contribute to compromised NK cell antitumor function in LT-α-deficient mice.
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tnf Lymphotoxin Alpha double mutant mice resist septic arthritis but display increased mortality in response to staphylococcus aureus
1998Co-Authors: Olof H Hultgren, Heinrich Korner, Hanspietro Eugster, Jonathon D Sedgwick, Andrzej TarkowskiAbstract:To evaluate the importance of the proinflammatory cytokines TNF and Lymphotoxin-Alpha (LT Alpha) in an experimental model of Staphylococcus aureus sepsis and arthritis, we used TNF/LT Alpha-double-deficient mice raised on the C57BL/6 background. Mice were i.v. inoculated with a toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus strain, LS-1. Intravenous inoculation of a high dose of bacteria (1 x 10(7)/mouse) resulted in 67% mortality in TNF/LT Alpha-deficient mice, whereas none of the controls died (p = 0.009). Those results correlated to a significantly decreased phagocytosis in vitro and inefficient bacterial clearance in vivo in mice lacking capacity to produce TNF/LT Alpha. Thus, at day 6 after inoculation, S. aureus could not be found in the bloodstream of controls, but bacteremia developed in all TNF/LT Alpha-deficient mice examined (p = 0.02). Interestingly, upon infection with a lower dose of staphylococci (3 x 10(6)/mouse) the mortality was overall low, but the frequency of arthritis was clearly higher in the wild-type group as compared with the TNF/LT Alpha-deficient mice (40% vs 13%). Histopathologic examination revealed a lower frequency of synovitis (38% vs 90%, p < 0.05) and erosivity (25% vs 60%, NS) in TNF/LT Alpha-deficient mice as compared with wild-type counterparts. Our results show the importance of TNF/LT Alpha in defense against systemic S. aureus infections and point out the detrimental role of these cytokines as mediators of inflammatory response in S. aureus arthritis.
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distinct roles for Lymphotoxin Alpha and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue
1997Co-Authors: Heinrich Korner, Matthew C Cook, Sean D Riminton, Frances A Lemckert, Robert M Hoek, Birgit Ledermann, Frank Kontgen, Barbara Fazekas De St Groth, Jonathon D SedgwickAbstract:Specialized roles for the pro-inflammatory cytokines tumor necrosis factor (TNF) and Lymphotoxin (LT) were characterized in TNF/LTα−/− and TNF−/− mice established by direct gene targeting of C57BL/6 ES cells. The requirement for LT early in lymphoid tissue organogenesis is shown to be distinct from the more subtle and varied role of TNF in promoting correct microarchitectural organization of leukocytes in LN and spleen. Development of normal Peyer's patch (PP) structure, in contrast, is substantially dependent on TNF. Only mice lacking LT exhibit retarded B cell maturation in vivo and serum immunoglobulin deficiencies. A temporal hierarchy in lymphoid tissue development can now be defined, with LT being an essential participant in general lymphoid tissue organogenesis, developmentally preceeding TNF that has a more varied and subtle role in promotion of correct spatial organization of leukocytes in LN and spleen. PP development in TNF−/− mice is unusual, indicating that TNF is a more critical participant for this structure than it is for other lymphoid tissues.
K I Welsh - One of the best experts on this subject based on the ideXlab platform.
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association of tumour necrosis factor Alpha Lymphotoxin Alpha and hla drb1 gene polymorphisms with lofgren s syndrome in czech patients with sarcoidosis
2005Co-Authors: Frantisek Mrazek, Lydie Izakovicova Holla, Beata Hutyrova, Vitězslav Kolek, K I Welsh, R M Du Bois, Vladimir Znojil, Anna Vasku, Jiri Vacha, Martin PetrekAbstract:Sarcoidosis is a granulomatous disorder showing a clear association with MHC (HLA) class I and class II genes. In order to investigate whether polymorphisms of nearby pro-inflammatory genes located within the MHC class III region may also contribute to susceptibility to sarcoidosis or to its clinical manifestation, tumour necrosis factor Alpha (TNF-Alpha) and Lymphotoxin-Alpha (LT-Alpha) genes were chosen for analysis in a case-control study.
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association of tumour necrosis factor α Lymphotoxin α and hla drb1 gene polymorphisms with lofgren s syndrome in czech patients with sarcoidosis
2005Co-Authors: Frantisek Mrazek, Lydie Izakovicova Holla, Beata Hutyrova, Vitězslav Kolek, K I Welsh, R M Du Bois, Vladimir Znojil, Anna Vasku, Jiri Vacha, Martin PetrekAbstract:Sarcoidosis is a granulomatous disorder showing a clear association with MHC (HLA) class I and class II genes. In order to investigate whether polymorphisms of nearby pro-inflammatory genes located within the MHC class III region may also contribute to susceptibility to sarcoidosis or to its clinical manifestation, tumour necrosis factor Alpha (TNF-Alpha) and Lymphotoxin-Alpha (LT-Alpha) genes were chosen for analysis in a case-control study.
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tumour necrosis factor Alpha and Lymphotoxin Alpha genepolymorphisms in czech patients with sarcoidosis associationwith lofgren syndrome
2003Co-Authors: Frantisek Mrazek, Lydie Izakovicova Holla, Beata Hutyrova, Vitězslav Kolek, Jiři Vacha, K I Welsh, R M Du Bois, Martin PetřekAbstract:To reveal possible association of nearby pro-inflammatory genes located within the MHC class III region with susceptibility to sarcoidosis or clinical course of the disease, two common polymorphisms of tumour necrosis factor (TNF) Alpha and Lymphotoxin (LT) Alpha genes were investigated.
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tnf and Lymphotoxin Alpha polymorphisms associated with common variable immunodeficiency role in the pathogenesis of granulomatous disease
1997Co-Authors: Charles G Mullighan, G C Fanning, H M Chapel, K I WelshAbstract:A subgroup of common variable immunodeficiency (CVID) patients have distinct clinical features, particularly granulomata splenomegaly, characteristic blood lymphocyte phenotype, and elevated circulating TNF levels. To investigate the genetic basis for this phenotype, 150 CVID patients and 200 controls were genotyped for six biallelic TNF and Lymphotoxin-Alpha (LT Alpha) polymorphisms and eight class I and II HLA loci using PCR and sequence specific primers (PCR-SSP) sequence-specific primers. Clinical and immunophenotypic data were collected for 90 patients to examine associations with CVID patient subgroups. The presence of granulomata (22% of patients) was strongly associated with splenomegaly, T and B lymphopenia, reduced CD4+ CD45RA+ T cells, and CD8+ CD57+ lymphocytosis, confirming the concept of a subgroup of patients with distinct clinical and laboratory features. The uncommon TNF +488A allele was strongly associated with this subgroup (p = 0.0005). The association between "granulomatous" CVID and TNF +488A was independent of HLA class I and II associations. We postulate that the presence of the TNF +488A allele, or alleles in linkage disequilibrium with it, contributes to the high levels of TNF and granulomatous complications characteristic of this subgroup of patients.
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polymerase chain reaction haplotyping using 3 mismatches in the forward and reverse primers application to the biallelic polymorphisms of tumor necrosis factor and Lymphotoxin Alpha
1997Co-Authors: G C Fanning, Michael Bunce, C M Black, K I WelshAbstract:A polymerase chain reaction with sequence-specific primers (PCR-SSP) system that operates under identical conditions to HLA phototyping was devised for characterizing polymorphisms in tumor necrosis factor (TNF) and Lymphotoxin Alpha (LT-Alpha). Mismatches at the 3' end were incorporated into the forward and reverse primers of each PCR so as to unequivocally establish the cis/trans status between the biallelic sites. Three previously described biallelic polymorphisms in TNF and three in LT-Alpha were characterized in a 24-reaction PCR-SSP system. The method was used to genotype 20 cell lines and 201 HLA class I and II typed controls from the United Kingdom at the TNF and LT-Alpha loci. Population frequencies of TNF haplotypes were determined as was linkage disequilibrium with HLA-A, B, Cw, DRB1 and DQB1 loci. In each gene there were 8 theoretical polymorphic combinations; 4 were observed in TNF and 4 in LT-Alpha. A total of 11 TNF-LT-Alpha haplotypes were determined from apparent homozygous controls and statistical analysis.
Heinrich Korner - One of the best experts on this subject based on the ideXlab platform.
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Lymphotoxin Alpha beta 2 membrane Lymphotoxin is critically important for resistance to leishmania major infection in mice
2007Co-Authors: Dong Liu, Heinrich Korner, Yijun Fan, Xi Yang, Jude E UzonnaAbstract:Although the essential role of TNF-Alpha in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine Lymphotoxin Alphabeta2 (LTAlpha1beta2, membrane Lymphotoxin) plays any role in this process. In this study, we investigated the contribution of membrane Lymphotoxin in host response to L. major infection by using LTbeta-deficient (LTbeta(-/-)) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LTbeta(-/-) mice developed chronic nonhealing cutaneous lesions due to progressive and unresolving inflammation that is accompanied by uncontrolled parasite proliferation. This chronic disease was associated with striking reduction in IL-12 and Ag-specific IFN-gamma production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LTbeta(-/-) mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although administration of rIL-12 to L. major-infected LTbeta(-/-) mice caused complete resolution of chronic lesions, it only partially (but significantly) reduced parasite proliferation. In contrast, blockade of LIGHT signaling in infected LTbeta(-/-) mice resulted in acute and progressive lesion development, massive parasite proliferation, and dissemination to the visceral organs. Although infected LTbeta(-/-) WT bone marrow chimeric mice were more resistant than LTbeta(-/-) mice, they still had reduced ability to control parasites and showed defective IL-12 and IFN-gamma production compared with infected WT mice. These results suggest that membrane Lymphotoxin plays critical role in resistance to L. major by promoting effective T cell-mediated anti-Leishmania immunity.
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both Lymphotoxin Alpha and tnf are crucial for control of toxoplasma gondii in the central nervous system
2003Co-Authors: Dirk Schluter, Laiyu Kwok, Sonja Lutjen, Sabine Soltek, Sigrid Hoffmann, Heinrich Korner, Martina DeckertAbstract:Immunity to Toxoplasma gondii critically depends on TNFR type I-mediated immune reactions, but the precise role of the individual ligands of TNFR1, TNF and Lymphotoxin-Alpha (LTAlpha), is still unknown. Upon oral infection with T. gondii, TNF(-/-), LTAlpha(-/-), and TNF/LTAlpha(-/-) mice failed to control intracerebral T. gondii and succumbed to an acute necrotizing Toxoplasma encephalitis, whereas wild-type (WT) mice survived. Intracerebral inducible NO synthase expression and-early after infection-splenic NO levels were reduced. Additionally, peritoneal macrophages produced reduced levels of NO upon infection with T. gondii and had significantly reduced toxoplasmastatic activity in TNF(-/-), LTAlpha(-/-), and TNF/LTAlpha(-/-) mice as compared with WT animals. Frequencies of parasite-specific IFN-gamma-producing T cells, intracerebral and splenic IFN-gamma production, and T. gondii-specific IgM and IgG titers in LTAlpha(-/-) and TNF/LTAlpha(-/-) mice were reduced only early after infection. In contrast, intracerebral IL-10 and IL-12p40 mRNA expression and splenic IL-2, IL-4, and IL-12 production were identical in all genotypes. In addition, TNF(-/-), LTAlpha(-/-), and TNF/LTAlpha(-/-), but not WT, mice succumbed to infection with the highly attenuated ts-4 strain of T. gondii or to a subsequent challenge infection with virulent RH toxoplasms, although they had identical frequencies of IFN-gamma-producing T cells as compared with WT mice. Generation and infection of bone marrow reconstitution chimeras demonstrated an exclusive role of hematogeneously produced TNF and LTAlpha for survival of toxoplasmosis. These findings demonstrate the crucial role of both LTAlpha and TNF for control of intracerebral toxoplasms.
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tnf Lymphotoxin Alpha double mutant mice resist septic arthritis but display increased mortality in response to staphylococcus aureus
1998Co-Authors: Olof H Hultgren, Heinrich Korner, Hanspietro Eugster, Jonathon D Sedgwick, Andrzej TarkowskiAbstract:To evaluate the importance of the proinflammatory cytokines TNF and Lymphotoxin-Alpha (LT Alpha) in an experimental model of Staphylococcus aureus sepsis and arthritis, we used TNF/LT Alpha-double-deficient mice raised on the C57BL/6 background. Mice were i.v. inoculated with a toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus strain, LS-1. Intravenous inoculation of a high dose of bacteria (1 x 10(7)/mouse) resulted in 67% mortality in TNF/LT Alpha-deficient mice, whereas none of the controls died (p = 0.009). Those results correlated to a significantly decreased phagocytosis in vitro and inefficient bacterial clearance in vivo in mice lacking capacity to produce TNF/LT Alpha. Thus, at day 6 after inoculation, S. aureus could not be found in the bloodstream of controls, but bacteremia developed in all TNF/LT Alpha-deficient mice examined (p = 0.02). Interestingly, upon infection with a lower dose of staphylococci (3 x 10(6)/mouse) the mortality was overall low, but the frequency of arthritis was clearly higher in the wild-type group as compared with the TNF/LT Alpha-deficient mice (40% vs 13%). Histopathologic examination revealed a lower frequency of synovitis (38% vs 90%, p < 0.05) and erosivity (25% vs 60%, NS) in TNF/LT Alpha-deficient mice as compared with wild-type counterparts. Our results show the importance of TNF/LT Alpha in defense against systemic S. aureus infections and point out the detrimental role of these cytokines as mediators of inflammatory response in S. aureus arthritis.
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distinct roles for Lymphotoxin Alpha and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue
1997Co-Authors: Heinrich Korner, Matthew C Cook, Sean D Riminton, Frances A Lemckert, Robert M Hoek, Birgit Ledermann, Frank Kontgen, Barbara Fazekas De St Groth, Jonathon D SedgwickAbstract:Specialized roles for the pro-inflammatory cytokines tumor necrosis factor (TNF) and Lymphotoxin (LT) were characterized in TNF/LTα−/− and TNF−/− mice established by direct gene targeting of C57BL/6 ES cells. The requirement for LT early in lymphoid tissue organogenesis is shown to be distinct from the more subtle and varied role of TNF in promoting correct microarchitectural organization of leukocytes in LN and spleen. Development of normal Peyer's patch (PP) structure, in contrast, is substantially dependent on TNF. Only mice lacking LT exhibit retarded B cell maturation in vivo and serum immunoglobulin deficiencies. A temporal hierarchy in lymphoid tissue development can now be defined, with LT being an essential participant in general lymphoid tissue organogenesis, developmentally preceeding TNF that has a more varied and subtle role in promotion of correct spatial organization of leukocytes in LN and spleen. PP development in TNF−/− mice is unusual, indicating that TNF is a more critical participant for this structure than it is for other lymphoid tissues.
Tobias Junt - One of the best experts on this subject based on the ideXlab platform.
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restoration of lymphoid organ integrity through the interaction of lymphoid tissue inducer cells with stroma of the t cell zone
2008Co-Authors: Elke Scandella, Sanjiv A. Luther, Beatrice Bolinger, Evelyn Lattmann, Simone Miller, Stephanie Favre, Dan R Littman, Daniela Finke, Tobias JuntAbstract:The generation of lymphoid microenvironments in early life depends on the interaction of lymphoid tissue-inducer cells with stromal lymphoid tissue-organizer cells. Whether this cellular interface stays operational in adult secondary lymphoid organs has remained elusive. We show here that during acute infection with lymphocytic choriomeningitis virus, antiviral cytotoxic T cells destroyed infected T cell zone stromal cells, which led to profound disruption of secondary lymphoid organ integrity. Furthermore, the ability of the host to respond to secondary antigens was lost. Restoration of the lymphoid microanatomy was dependent on the proliferative accumulation of lymphoid tissue-inducer cells in secondary lymphoid organs during the acute phase of infection and Lymphotoxin Alpha(1)beta(2) signaling. Thus, crosstalk between lymphoid tissue-inducer cells and stromal cells is reactivated in adults to maintain secondary lymphoid organ integrity and thereby contributes to the preservation of immunocompetence.
