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1.
Phys Rev E ; 102(2-1): 023310, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32942385

ABSTRACT

Plasma flows encountered in high-energy-density experiments display features that differ from those of equilibrium systems. Nonequilibrium approaches such as kinetic theory (KT) capture many, if not all, of these phenomena. However, KT requires closure information, which can be computed from microscale simulations and communicated to KT. We present a concurrent heterogeneous multiscale approach that couples molecular dynamics (MD) with KT in the limit of near-equilibrium flows. To reduce the cost of gathering information from MD, we use active learning to train neural networks on MD data obtained by randomly sampling a small subset of the parameter space. We apply this method to a plasma interfacial mixing problem relevant to warm dense matter, showing considerable computational gains when compared with the full kinetic-MD approach. We find that our approach enables the probing of Coulomb coupling physics across a broad range of temperatures and densities that are inaccessible with current theoretical models.

3.
Sci Rep ; 7(1): 9577, 2017 08 29.
Article in English | MEDLINE | ID: mdl-28851941

ABSTRACT

The classification of miscible and immiscible systems of binary alloys plays a critical role in the design of multicomponent alloys. By mining data from hundreds of experimental phase diagrams, and thousands of thermodynamic data sets from experiments and high-throughput first-principles (HTFP) calculations, we have obtained a comprehensive classification of alloying behavior for 813 binary alloy systems consisting of transition and lanthanide metals. Among several physics-based descriptors, the slightly modified Pettifor chemical scale provides a unique two-dimensional map that divides the miscible and immiscible systems into distinctly clustered regions. Based on an artificial neural network algorithm and elemental similarity, the miscibility of the unknown systems is further predicted and a complete miscibility map is thus obtained. Impressively, the classification by the miscibility map yields a robust validation on the capability of the well-known Miedema's theory (95% agreement) and shows good agreement with the HTFP method (90% agreement). Our results demonstrate that a state-of-the-art physics-guided data mining can provide an efficient pathway for knowledge discovery in the next generation of materials design.

4.
J Chem Theory Comput ; 11(10): 4644-54, 2015 Oct 13.
Article in English | MEDLINE | ID: mdl-26574255

ABSTRACT

We present an algorithm for the calculation of the density matrix that for insulators scales linearly with system size and parallelizes efficiently on multicore, shared memory platforms with small and controllable numerical errors. The algorithm is based on an implementation of the second-order spectral projection (SP2) algorithm [ Niklasson, A. M. N. Phys. Rev. B 2002 , 66 , 155115 ] in sparse matrix algebra with the ELLPACK-R data format. We illustrate the performance of the algorithm within self-consistent tight binding theory by total energy calculations of gas phase poly(ethylene) molecules and periodic liquid water systems containing up to 15,000 atoms on up to 16 CPU cores. We consider algorithm-specific performance aspects, such as local vs nonlocal memory access and the degree of matrix sparsity. Comparisons to sparse matrix algebra implementations using off-the-shelf libraries on multicore CPUs, graphics processing units (GPUs), and the Intel many integrated core (MIC) architecture are also presented. The accuracy and stability of the algorithm are illustrated with long duration Born-Oppenheimer molecular dynamics simulations of 1000 water molecules and a 303 atom Trp cage protein solvated by 2682 water molecules.

5.
Article in English | MEDLINE | ID: mdl-26172802

ABSTRACT

Quantum molecular dynamics (QMD) simulations are used to calculate the equation of state, structure, and transport properties of liquid gallium along the principal shock Hugoniot. The calculated Hugoniot is in very good agreement with experimental data up to a pressure of 150 GPa as well as with our earlier classical molecular dynamics calculations using a modified embedded atom method (MEAM) potential. The self-diffusion and viscosity calculated using QMD agree with experimental measurements better than the MEAM results, which we attribute to capturing the complexity of the electronic structure at elevated temperatures. Calculations of the DC conductivity were performed around the Hugoniot. Above a density of 7.5 g/cm(3), the temperature increases rapidly along the Hugoniot, and the optical conductivity decreases, indicating simple liquid metal behavior.

6.
Phys Rev Lett ; 107(26): 264502, 2011 Dec 23.
Article in English | MEDLINE | ID: mdl-22243159

ABSTRACT

We use the Richtmyer-Meshkov instability (RMI) at a metal-gas interface to infer the metal's yield stress (Y) under shock loading and release. We first model how Y stabilizes the RMI using hydrodynamics simulations with a perfectly plastic constitutive relation for copper (Cu). The model is then tested with molecular dynamics (MD) of crystalline Cu by comparing the inferred Y from RMI simulations with direct stress-strain calculations, both with MD at the same conditions. Finally, new RMI experiments with solid Cu validate our simulation-based model and infer Y~0.47 GPa for a 36 GPa shock.

7.
Phys Rev Lett ; 95(7): 075502, 2005 Aug 12.
Article in English | MEDLINE | ID: mdl-16196791

ABSTRACT

In situ x-ray diffraction studies of iron under shock conditions confirm unambiguously a phase change from the bcc (alpha) to hcp (epsilon) structure. Previous identification of this transition in shock-loaded iron has been inferred from the correlation between shock-wave-profile analyses and static high-pressure x-ray measurements. This correlation is intrinsically limited because dynamic loading can markedly affect the structural modifications of solids. The in situ measurements are consistent with a uniaxial collapse along the [001] direction and shuffling of alternate (110) planes of atoms, and are in good agreement with large-scale nonequilibrium molecular dynamics simulations.

8.
Br J Pharmacol ; 141(4): 737-45, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14757700

ABSTRACT

1. TRPM8 (CMR1) is a Ca(2+)-permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands. 2. The effects of 70 odorants and menthol-related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examined using a FLIPR assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS-3, WS-23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists. 3. The EC(50) values of the agonists defined their relative potencies: icilin (0.2+/-0.1 microM)>FrescolatML (3.3+/-1.5 microM) > WS-3 (3.7+/-1.7 microM) >(-)menthol (4.1+/-1.3 microM) >frescolatMAG (4.8+/-1.1 microM) > cooling agent 10 (6+/-2.2 microM) >(+)menthol (14.4+/-1.3 microM) > PMD38 (31+/-1.1 microM) > WS-23 (44+/-7.3 microM) > Coolact P (66+/-20 microM) > geraniol (5.9+/-1.6 mM) > linalool (6.7+/-2.0 mM) > eucalyptol (7.7+/-2.0 mM) > hydroxycitronellal (19.6+/-2.2 mM). 4. Known VR1 antagonists (BCTC, thio-BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC(50): 0.8+/-1.0, 3.5+/-1.1 and 18+/-1.1 microM, respectively). 5. The Ca(2+) response of hVR1-transfected HEK293 cells to the endogenous VR1 agonist N-arachidonoyl-dopamine was potentiated by low pH. In contrast, menthol- and icilin-activated TRPM8 currents were suppressed by low pH. 6. In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.


Subject(s)
Ion Channels/metabolism , Neoplasm Proteins/metabolism , Receptors, Drug/metabolism , Animals , Calcium Signaling/drug effects , Cell Line , Cloning, Molecular , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Diagnostic Imaging , Dose-Response Relationship, Drug , Fluorometry , Hydrogen-Ion Concentration , Ion Channels/antagonists & inhibitors , Ion Channels/genetics , Ligands , Mice , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Odorants , Receptors, Drug/antagonists & inhibitors , Receptors, Drug/genetics , TRPM Cation Channels , Transfection
9.
Br J Pharmacol ; 133(8): 1414-23, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11498529

ABSTRACT

1. Immune response-modulating drugs such as thalidomide may be of therapeutic value in the treatment of chronic inflammatory bowel diseases including Crohn's disease (CD). In the present study, we have investigated whether thalidomide exerts this effect by impairing endothelial cell-leukocyte interaction through down-regulation of the expression of pro-inflammatory gene products in these cells. 2. Transient CD-like colitis was induced in male Wistar rats by single enema with trinitrobenzene sulphonic acid (TNBS) in ethanol followed by macroscopic scoring, histology, intravital microscopy, RT - PCR and immunohistochemistry (IHC) analyses. Thalidomide or its analogue supidimide were administered in olive oil by intragastric instillation 6 h prior to the induction of colitis and then daily for one week. 3. Both thalidomide and supidimide (200 mg kg(-1) d(-1)) significantly attenuated TNBS-induced colitis as compared to vehicle-treated control animals (44 and 37% inhibition, respectively), and this effect persisted for 7 days post cessation of thalidomide treatment (46% inhibition). 4. Moreover, thalidomide significantly reduced leukocyte sticking to postcapillary venular endothelial cells in the submucosa (by 45%), improved functional capillary density and perfusion, and attenuated endothelial interleukin-8 expression, as judged by IHC analysis. According to RT - PCR analysis, both thalidomide and supidimide also significantly reduced vascular cell adhesion molecule-1 mRNA expression in the affected part of the descending colon. 5. These findings suggest that thalidomide and one of its derivatives impairs CD-like TNBS-induced colitis in the rat by down-regulating endothelial adhesion molecule and chemokine expression and, as a consequence, the interaction of these cells with circulating leukocytes.


Subject(s)
Colitis/chemically induced , Colitis/drug therapy , Endothelium/cytology , Leukocytes/cytology , Thalidomide/pharmacology , Trinitrobenzenesulfonic Acid/pharmacology , Animals , CD40 Ligand/genetics , Cell Adhesion/drug effects , Colon/cytology , Colon/drug effects , Endothelium/drug effects , Gene Expression Regulation/drug effects , Humans , Interleukin-8/metabolism , Leukocytes/drug effects , Male , Mice , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Rats , Rats, Wistar , Vascular Cell Adhesion Molecule-1/genetics
10.
Phys Rev E Stat Nonlin Soft Matter Phys ; 63(1 Pt 2): 016121, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11304328

ABSTRACT

An new equilibrium molecular-dynamics method (the uniaxial Hugoniostat) is proposed to study the energetics and deformation structures in shocked crystals. This method agrees well with nonequilibrium molecular-dynamics simulations used to study shock-wave propagation in solids and liquids.

11.
Eur J Immunol ; 30(10): 2864-70, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11069068

ABSTRACT

The interaction of proinflammatory type 1 T helper (Th1) cells expressing the CD40 ligand (CD154) with endothelial cells expressing the corresponding receptor (CD40) may play an important role in chronic inflammation including arteriosclerosis. Here we demonstrate that activation of CD40 in human cultured endothelial cells (e.g. by interaction with freshly isolated human T cells) not only up-regulates expression of various adhesion molecules, chemokines and cytokines, but within 12-24 h also causes the release of bioactive interleukin-12 (IL-12 p70) through induction of IL-12 p40 synthesis. IL-12 p35, on the other hand, appears to be constitutively expressed in these cells. Despite enhancing expression of the other gene products, cytokines such as interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha, alone or in combination, failed to induce IL-12 p40 expression, whereas IFN-gamma markedly augmented CD154-induced IL-12 p40 and p70 release. Of note was that the magnitude of CD154-induced IL-12 synthesis in the cultured endothelial cells was comparable to that evoked in freshly isolated human monocytes. This CD40-mediated induction of endothelial IL-12 synthesis may thus lead to an enhanced activation of the adherent CD154-expressing Th1 cells, thereby fuelling the proinflammatory response.


Subject(s)
CD40 Ligand/immunology , Endothelium, Vascular/metabolism , Gene Expression Regulation , Interleukin-12/biosynthesis , Cells, Cultured , Endothelium, Vascular/cytology , Gene Expression Regulation/drug effects , Humans , Interferon-gamma/pharmacology , Interleukin-12/genetics , Interleukin-6/biosynthesis , Interleukin-6/genetics , Interleukin-8/biosynthesis , Interleukin-8/genetics , Reverse Transcriptase Polymerase Chain Reaction , Th1 Cells/immunology , Tumor Necrosis Factor-alpha/pharmacology , Umbilical Veins
12.
Gastroenterology ; 116(6): 1428-40, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10348827

ABSTRACT

BACKGROUND & AIMS: Murine liver sinusoidal endothelial cells (LSECs) constitutively express accessory molecules and can present antigen to memory Th1 CD4(+) T cells. Using a T-cell receptor transgenic mouse line, we addressed the question whether LSECs can prime naive CD4(+) T cells. METHODS: Purified LSECs were investigated for their ability to induce activation and differentiation of naive CD4(+) T cells in comparison with bone marrow-derived antigen-presenting cells and macrovascular endothelial cells. Activation of T cells was determined by cytokine production. LSECs were further studied for expression of interleukin (IL)-12 by reverse-transcription polymerase chain reaction, and the unique phenotype of LSECs was determined by flow cytometry. RESULTS: We provide evidence that antigen-presenting LSECs can activate naive CD62Lhigh CD4(+) T cells. Activation of naive CD4(+) T cells by LSECs occurred in the absence of IL-12. In contrast, macrovascular endothelial cells from aorta could not activate naive CD4(+) T cells. The unique functional characteristics of microvascular LSECs together with a unique phenotype (CD4(+), CD11b+, CD11c+, CD80(+), CD86(+)) make these cells different from macrovascular endothelial cells. Furthermore, LSECs did not require in vitro maturation to activate naive CD4(+) T cells. Most importantly, LSECs failed to induce differentiation toward Th1 cells, whereas conventional antigen-presenting cell populations induced a Th1 phenotype in activated CD4(+) T cells. Upon restimulation, CD4(+) T cells, which were primed by antigen-presenting LSECs, expressed interferon gamma, IL-4, and IL-10, which is consistent with a Th0 phenotype. Exogenous cytokines (IL-1beta, IL-12, or IL-18) present during T-cell priming by antigen-presenting LSECs could not induce a Th1 phenotype, but neutralization of endogenously produced IL-4 during T-cell priming led to a reduced expression of IL-4 and IL-10 by CD4(+) T cells upon restimulation. The addition of spleen cells to cocultures of LSECs and naive CD4(+) T cells during T-cell priming led to differentiation of T cells toward a Th1 phenotype. CONCLUSIONS: The ability of antigen-presenting LSECs to induce cytokine expression in naive CD4(+) T cells and their failure to induce differentiation toward a Th1 phenotype may contribute to the unique hepatic microenvironment that is known to promote tolerance.


Subject(s)
Antigen-Presenting Cells/physiology , CD4-Positive T-Lymphocytes/metabolism , Cytokines/biosynthesis , Liver/cytology , Th1 Cells/physiology , Animals , Biomarkers , CD4-Positive T-Lymphocytes/physiology , Cell Differentiation/physiology , Cell Line , Cells, Cultured , Endothelium/cytology , Female , Gene Expression/physiology , Interferon-gamma/biosynthesis , Interleukin-12/genetics , Interleukin-12/pharmacology , Mice , Mice, Inbred BALB C , Monocytes/cytology , Phenotype
13.
Clin Exp Immunol ; 115(1): 42-55, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9933419

ABSTRACT

Immunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-gamma) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-gamma production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-alpha gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-alpha production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA.


Subject(s)
Arthritis, Experimental/metabolism , Collagen , Cytokines/biosynthesis , Immunosuppressive Agents/pharmacology , Macrophages/metabolism , Methotrexate/pharmacology , T-Lymphocytes/metabolism , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/prevention & control , CD4-Positive T-Lymphocytes/metabolism , Interferon-gamma/biosynthesis , Interleukin-15/pharmacology , Interleukin-4/biosynthesis , Interleukin-6/biosynthesis , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Mice, Knockout , Mice, Transgenic , Spleen/cytology , Spleen/metabolism , Tumor Necrosis Factor-alpha/biosynthesis
14.
J Immunol ; 162(3): 1401-7, 1999 Feb 01.
Article in English | MEDLINE | ID: mdl-9973395

ABSTRACT

Endotoxin is physiologically present in portal venous blood at concentrations of 100 pg/ml to 1 ng/ml. Clearance of endotoxin from portal blood occurs through sinusoidal lining cells, i.e., Kupffer cells, and liver sinusoidal endothelial cells (LSEC). We have recently shown that LSEC are fully efficient APCs. Here, we studied the influence of endotoxin on the accessory function of LSEC. Incubation of Ag-presenting LSEC with physiological concentrations of endotoxin lead to >/=80% reduction of the accessory function, measured by release of IFN-gamma from CD4+ T cells. In contrast, conventional APC populations rather showed an increase of the accessory function after endotoxin treatment. Inhibition of the accessory function in LSEC by endotoxin was not due to lack of soluble costimulatory signals, because neither supplemental IL-1beta, IL-2, IFN-gamma, or IL-12 could rescue the accessory function. Ag uptake was not influenced by endotoxin in LSEC. However, we found that endotoxin led to alkalinization of the endosomal/lysomal compartment specifically in LSEC but not in bone marrow macrophages, which indicated that Ag processing, i.e., proteolytic cleavage of protein Ags into peptide fragments, was affected by endotoxin. Furthermore, endotoxin treatment down-regulated surface expression of constitutively expressed MHC class II, CD80, and CD86. In conclusion, it is conceivable that endotoxin does not alter the clearance function of LSEC to remove gut-derived Ags from portal blood but specifically affects Ag processing and expression of the accessory molecules in these cells. Consequently, Ag-specific immune responses by CD4+ T cells are efficiently down-regulated in the hepatic microenvironment.


Subject(s)
Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Endothelium, Vascular/drug effects , Endothelium, Vascular/immunology , Endotoxins/toxicity , Liver/blood supply , Liver/cytology , Lymphocyte Activation/drug effects , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Animals , Antigen Presentation/drug effects , Antigens, CD/metabolism , B7-1 Antigen/metabolism , B7-2 Antigen , Cytokines/pharmacology , Endosomes/drug effects , Endosomes/immunology , Endosomes/metabolism , Endothelium, Vascular/cytology , Female , Histocompatibility Antigens Class II/metabolism , Hydrogen-Ion Concentration , Lysosomes/drug effects , Lysosomes/immunology , Lysosomes/metabolism , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred BALB C , Mice, Transgenic , Receptors, Antigen, T-Cell, alpha-beta/genetics
15.
Graefes Arch Clin Exp Ophthalmol ; 237(12): 952-61, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10654163

ABSTRACT

Neovascular diseases are the leading causes of blindness in humans. Although several promising compounds have been isolated, pharmacological treatment remains difficult. Thalidomide has inhibitory effects on angiogenesis in the corneal micropocket assay. However, the results vary considerably depending on the administration route and animal model. The aim of this study, therefore, was to investigate thalidomide and two of its derivatives, supidimide and EM12, in the rabbit corneal micropocket assay. Using both basic fibroblast growth factor and vascular endothelial growth factor for initiation of the neovascular response, we were able to show a significant inhibition of neovascularisation with all three substances. EM12, the most teratogenic derivative analysed, was demonstrated to be the most potent inhibitor of angiogenesis in this model. Thalidomide and supidimide did not show systemic side effects in the applied dosage. An equal dosage of EM12, however, resulted in significant weight loss of the animals, but did not increase angiogenic activity compared with lower doses. Together with earlier findings, these data support a strong correlation between the antiangiogenic potential and the teratogenic activity of thalidomide and structurally related compounds.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Cornea/drug effects , Corneal Neovascularization/drug therapy , Thalidomide/therapeutic use , Administration, Oral , Angiogenesis Inhibitors/administration & dosage , Animals , Capillaries/drug effects , Capillaries/growth & development , Cornea/pathology , Corneal Neovascularization/chemically induced , Corneal Neovascularization/pathology , Disease Models, Animal , Endothelial Growth Factors/toxicity , Female , Fibroblast Growth Factor 2/toxicity , Lymphokines/toxicity , Protein Isoforms/toxicity , Rabbits , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
18.
Microbiol Immunol ; 41(11): 847-53, 1997.
Article in English | MEDLINE | ID: mdl-9444325

ABSTRACT

Several genes involved in the determination of Listeria monocytogenes pathogenesis have been identified. Among them, plcA gene encodes phosphatidylinositol-specific phospholipase C (PI-PLC), plcB gene encodes a broad-range phospholipase C (PC-PLC), and actA encodes a protein contributing to actin assembly in infected cells. The interaction of L. monocytogenes wild type (LO 28) strain and two derivative mutants, plcA- (BUG 206) and actA-/plcB- (LUT 12), with macrophages and T lymphocytes was investigated in a mouse model of listeriosis. Both mutants showed evidence of attenuation. The plcA- mutant, but not the plcB- mutant, expressed an increase in susceptibility to the anti-listerial activity of macrophages. Both mutants showed a decreased ability to induce IL-12 production by bone marrow macrophages when co-stimulated with E. coli LPS or IFN-gamma. In vivo, L. monocytogenes plcA- mutant was found to be a more effective stimulator of T cells than the wild LO 28 strain.


Subject(s)
Actins/genetics , Listeria monocytogenes/immunology , Listeriosis/immunology , Type C Phospholipases/genetics , Actins/biosynthesis , Animals , Cells, Cultured , Dose-Response Relationship, Immunologic , Escherichia coli , Female , Genes, Bacterial , Interleukin-12/biosynthesis , Lipopolysaccharides/pharmacology , Listeria monocytogenes/genetics , Listeria monocytogenes/pathogenicity , Listeriosis/microbiology , Lymphocyte Activation , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/microbiology , Macrophages, Peritoneal/physiology , Mice , Mice, Inbred BALB C , Mutation , Phagocytosis , Phosphatidylinositols , Spleen/microbiology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/microbiology , Type C Phospholipases/biosynthesis
19.
Ann N Y Acad Sci ; 795: 227-40, 1996 Oct 31.
Article in English | MEDLINE | ID: mdl-8958934

ABSTRACT

A destructive joint disease can be induced in susceptible DBA/1 mice by immunization with type II collagen emulsified with oil and either killed Mycobacterium tuberculosis or IL-12 as adjuvant. Cellular and humoral anti-collagen immune mechanisms appear to be involved in the pathogenesis of arthritis. We have characterized the adjuvant effect or IL-12 in more detail and addressed the question whether mycobacteria might act via the induction of endogenous IL-12. Injections of IL-12 into collagen-immunized DBA/1 mice promoted the development of IFN-gamma-producing CD4+ T cells and strongly upregulated the production of complement-fixing IgG2a and IgG2b antibodies resulting in severe arthritis. Neutralization of IFN-gamma in vivo largely inhibited the increase in antibody synthesis and prevented joint disease in IL-12-treated mice. However, collagen-specific IFN-gamma synthesis by T cells was further enhanced in these animals. Furthermore, IL-12 treatment promoted the development of IFN-gamma-producing T cells but failed to enhance antibody synthesis and to induce arthritis in C57BL/6 or BALB/c mice immunized with collagen in oil. These results indicate that the induction (by IL-12) of a strong collagen-specific T-cell response alone is not sufficient to trigger arthritis. Attempts to show a role for endogenous IL-12 in DBA/1 mice immunized with collagen with mycobacteria as adjuvant gave no reliable results. Whereas anti-IL-12 treatment delayed the onset and ameliorated the disease in some experiments, it failed to do so in other experiments, or, control reagents also had some effect. A slight inhibition of collagen-specific IgG2a synthesis was observed in most experiments in the sera of anti-IL-12-treated mice. Taken together, the results show that exogenous IL-12 can promote arthritis via its direct effect on T cells and its effect on antibody production, which is at least in part IFN-gamma-dependent. On the other hand, whether or not endogenous IL-12 is involved in the adjuvant effect of mycobacteria needs further clarification.


Subject(s)
Arthritis/immunology , Autoimmune Diseases/immunology , Collagen/immunology , Interleukin-12/antagonists & inhibitors , Interleukin-12/immunology , Adjuvants, Immunologic , Animals , Antibody Formation , Immunity, Cellular , Interferon-gamma/physiology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Spleen/metabolism
20.
Int Immunol ; 8(8): 1221-7, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8918691

ABSTRACT

DBA/1 (H-2q) and C57BL/6 (H-2b) mice develop an intermediate immune responses when immunized with chicken type II collagen (CII) emulsified with incomplete Freund's adjuvant (IFA). Only a few animals develop a mild form of arthritis. As reported before and confirmed herein, administration of IL-12 to DBA/1 mice immunized with CII in IFA strongly enhances the cellular and humoral (auto)immune response to CII and induces severe destructive joint disease with an incidence of 80-100%. In contrast, the same treatment did not promote joint disease in C57BL/6 mice. Characterization of the IL-12 effect on the CII-specific immune response of C57BL/6 mice revealed that IL-12 promoted the development of CII-specific T cells producing IFN-gamma in DBA/1 and C57BL/6 mice equally well. However, whereas treatment with IL-12 in DBA/1 mice strongly up-regulated the synthesis of CII-specific antibodies, especially of the IgG2a and IgG2b subclasses, it rather slightly down-regulated the CII-specific IgG2a and IgG2b synthesis in C57BL/6 mice. This may indicate that the effect of IL-12 on the CII-specific antibody synthesis is of crucial importance in the pathogenesis of type II collagen-induced arthritis (CIA). The failure of IL-12 to up-regulate IgG2a and IgG2b synthesis in C57BL/6 mice is specific for CII as antigen and not a general property of this strain because the keyhole limpet hemacyanin-specific antibody response is up-regulated by IL-12 in C57BL/6 mice. Furthermore, it is not the H-2b haplotype of C57BL/6 mice but rather the genetic background (DBA/1 versus BL/6 or BL/10) that limits the effect of IL-12 on the CII-specific antibody response because IL-12 treatment of CII-immunized B10.Q (H-2q) mice also failed to induce arthritis and to enhance CII-specific IgG2a and IgG2b synthesis. However, as in the two other strains, injection of IL-12 promoted the development of splenic T cells producing IFN-gamma upon activation with CII. These results indicate that an enhancement of the cellular and humoral anti-CII response by IL-12 is required for inducing arthritis.


Subject(s)
Arthritis/etiology , Collagen/immunology , Immunity, Cellular , Interleukin-12/pharmacology , Th1 Cells/immunology , Animals , Antibody Formation , Antigens/administration & dosage , Arthritis/immunology , Chickens , Collagen/administration & dosage , Female , Freund's Adjuvant/administration & dosage , Hemocyanins/administration & dosage , Hemocyanins/immunology , Immunization , Immunoglobulin G/biosynthesis , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA
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