78 research outputs found
Dominant-Negative Tumor Necrosis Factor Protects from Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and Endotoxin-Induced Liver Injury without Compromising Host Immunity to BCG and Mycobacterium tuberculosis
BackgroundTumor necrosis factor (TNF) is associated with the development of inflammatory pathologies. Antibodies and soluble TNF (solTNF) receptors that neutralize excessive TNF are effective therapies for inflammatory and autoimmune diseases. However, clinical use of TNF inhibitors is associated with an increased risk of infections MethodsA novel dominant-negative (DN) strategy of selective TNF neutralization, consisting of blocking solTNF while sparing transmembrane TNF (tmTNF), was tested in mouse models of mycobacterial infection and acute liver inflammation. XENP1595, a DN-TNF biologic, was compared with etanercept, a TNF receptor 2 (TNFR2)-IgG1 Fc fusion protein that inhibits murine solTNF and tmTNF ResultsXENP1595 protected mice from acute liver inflammation induced by endotoxin challenge in Mycobacterium bovis bacillus Calmette-Guérin (BCG)-infected mice, but, in contrast to etanercept, it did not compromise host immunity to acute M. bovis BCG and Mycobacterium tuberculosis infections in terms of bacterial burden, granuloma formation, and innate immune responses ConclusionsA selective inhibitor of solTNF efficiently protected mice from acute liver inflammation yet maintained immunity to mycobacterial infections. In contrast, nonselective inhibition of solTNF and tmTNF suppressed immunity to M. bovis BCG and M. tuberculosis. Therefore, selective inhibition of solTNF by DN-TNF biologics may represent a new therapeutic strategy for the treatment of inflammatory diseases without compromising host immunit
Topical Administration of a Soluble TNF Inhibitor Reduces Infarct Volume After Focal Cerebral Ischemia in Mice
Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice
BACKGROUND: Glial cell activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in acute traumatic injuries to the CNS, including spinal cord injury (SCI). Elevated levels of the proinflammatory cytokine tumor necrosis factor (TNF), which exists in both a soluble (sol) and a transmembrane (tm) form, have been found in the lesioned cord early after injury. The contribution of solTNF versus tmTNF to the development of the lesion is, however, still unclear. METHODS: We tested the effect of systemically or centrally blocking solTNF alone, using XPro1595, versus using the drug etanercept to block both solTNF and tmTNF compared to a placebo vehicle following moderate SCI in mice. Functional outcomes were evaluated using the Basso Mouse Scale, rung walk test, and thermal hyperalgesia analysis. The inflammatory response in the lesioned cord was investigated using immunohistochemistry and western blotting analyses. RESULTS: We found that peripheral administration of anti-TNF therapies had no discernable effect on locomotor performances after SCI. In contrast, central administration of XPro1595 resulted in improved locomotor function, decreased anxiety-related behavior, and reduced damage to the lesioned spinal cord, whereas central administration of etanercept had no therapeutic effects. Improvements in XPro1595-treated mice were accompanied by increases in Toll-like receptor 4 and TNF receptor 2 (TNFR2) protein levels and changes in Iba1 protein expression in microglia/macrophages 7 and 28Â days after SCI. CONCLUSIONS: These studies suggest that, by selectively blocking solTNF, XPro1595 is neuroprotective when applied directly to the lesioned cord. This protection may be mediated via alteration of the inflammatory environment without suppression of the neuroprotective effects of tmTNF signaling through TNFR2
Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcgammaRIIb and CD19.
The Fc receptor (FcgammaRIIb) inhibits B cell responses when coengaged with B cell receptor (BCR), and has become a target for new autoimmune disease therapeutics. For example, BCR and FcgammaRIIb coengagement via the Fc-engineered anti-CD19 XmAb5871 suppresses humoral immune responses. We now assess effects of XmAb5871 on other activation pathways, including the pathogen-associated molecular pattern receptor, TLR9. Since TLR9 signaling is implicated in autoimmune diseases, we asked if XmAb5871 could inhibit TLR9 costimulation. We show that XmAb5871 decreases ERK and AKT activation, cell proliferation, cytokine, and IgG production induced by BCR and/or TLR9 signals. XmAb5871 also inhibited differentiation of citrullinated peptide-specific plasma cells from rheumatoid arthritis patients. XmAb5871 may therefore have potential to suppress pathogenic B cells in autoimmune diseases
Soluble TNF Mediates the Transition from Pulmonary Inflammation to Fibrosis
BACKGROUND: Fibrosis, the replacement of functional tissue with excessive fibrous tissue, can occur in all the main tissues and organ systems, resulting in various pathological disorders. Idiopathic Pulmonary Fibrosis is a prototype fibrotic disease involving abnormal wound healing in response to multiple sites of ongoing alveolar epithelial injury. METHODOLOGY/PRINCIPAL FINDINGS: To decipher the role of TNF and TNF-mediated inflammation in the development of fibrosis, we have utilized the bleomycin-induced animal model of Pulmonary Fibrosis and a series of genetically modified mice lacking components of TNF signaling. Transmembrane TNF expression is shown to be sufficient to elicit an inflammatory response, but inadequate for the transition to the fibrotic phase of the disease. Soluble TNF expression is shown to be crucial for lymphocyte recruitment, a prerequisite for TGF-b1 expression and the development of fibrotic lesions. Moreover, through a series of bone marrow transfers, the necessary TNF expression is shown to originate from the non-hematopoietic compartment further localized in apoptosing epithelial cells. CONCLUSIONS: These results suggest a primary detrimental role of soluble TNF in the pathologic cascade, separating it from the beneficial role of transmembrane TNF, and indicate the importance of assessing the efficacy of soluble TNF antagonists in the treatment of Idiopathic Pulmonary Fibrosis
Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice
Inhibition of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations and Ca2+ Dysregulation in Aged Rats
The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4â6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca2+ channel (VSCC) activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling
Accessing the strong interaction between Î baryons and charged kaons with the femtoscopy technique at the LHC
The interaction between Î baryons and kaons/antikaons is a crucial ingredient for the strangeness S=0 and S=-2 sector of the mesonâbaryon interaction at low energies. In particular, the Lambda-Kbar might help in understanding the origin of states such as the Csi(1620), whose nature and properties are still under debate. Experimental data on Lambda-K and Lambda-Kbar systems are scarce, leading to large uncertainties and tension between the available theoretical predictions constrained by such data. In this Letter we present the measurements of ÎâKKâ and ÎâKK+ correlations obtained in the high-multiplicity triggered data sample in pp collisions at sqrt(s) = 13 TeV recorded by ALICE at the LHC. The correlation function for both pairs is modeled using the LednickĂœâLyuboshits analytical formula and the corresponding scattering parameters are extracted. The ÎâKK+ correlations show the presence of several structures at relative momenta k* above 200 MeV/c, compatible with the Ω baryon, the , and resonances decaying into ÎâKâ pairs. The low k* region in the ÎâKK+ also exhibits the presence of the state, expected to strongly couple to the measured pair. The presented data allow to access the ÎK+ and ÎKâ strong interaction with an unprecedented precision and deliver the first experimental observation of the decaying into ÎKâ
First measurement of prompt and non-prompt Dâ+ vector meson spin alignment in pp collisions at s=13 TeV
This letter reports the first measurement of spin alignment, with respect to the helicity axis, for D*+ vector mesons and their charge conjugates from charm-quark hadronisation (prompt) and from beauty-meson decays (non-prompt) in hadron collisions. The measurements were performed at midrapidity (|y| D0 (-> K- pi+) pi+ decay products, in the D*+ rest frame, with respect to the D*+ momentum direction in the pp centre of mass frame. The rho_00 value for prompt D*+ mesons is consistent with 1/3, which implies no spin alignment. However, for non-prompt D*+ mesons an evidence of rho_00 larger than 1/3 is found. The measured value of the spin density element is in the interval, which is consistent with a Pythia 8 Monte Carlo simulation coupled with the EvtGen package, which implements the helicity conservation in the decay of D*+ meson from beauty mesons. In non-central heavy-ion collisions, the spin of the D*+ mesons may be globally aligned with the direction of the initial angular momentum and magnetic field. Based on the results for pp collisions reported in this letter it is shown that alignment of non-prompt D*+ mesons due to the helicity conservation coupled to the collective anisotropic expansion may mimic the signal of global spin alignment in heavy-ion collisions
Measurement of the non-prompt D-meson fraction as a function of multiplicity in proton-proton collisions at = 13 TeV
The fractions of non-prompt (i.e. originating from beauty-hadron decays) D0
and D+ mesons with respect to the inclusive yield are measured as a function of the
charged-particle multiplicity in proton-proton collisions at a centre-of-mass energy of âs =
13 TeV with the ALICE detector at the LHC. The results are reported in intervals of
transverse momentum (pT) and integrated in the range 1 < pT < 24 GeV/c. The fraction
of non-prompt D0 and D+ mesons is found to increase slightly as a function of pT in
all the measured multiplicity intervals, while no significant dependence on the charged-
particle multiplicity is observed. In order to investigate the production and hadronisation
mechanisms of charm and beauty quarks, the results are compared to PYTHIA 8 as well
as EPOS 3 and EPOS 4 Monte Carlo simulations, and to calculations based on the colour
glass condensate including three-pomeron fusion
- âŠ