Biomedical subjects

Christopher J Howard

Publications and source records attributed to Christopher J Howard.

16 recordsLinked to original sources

PubMed2006

Workshop cluster 1+ gammadelta T-cell receptor T cells from calves express high levels of interferon-gamma in response to stimulation with interleukin-12 and -18.

Gammadelta T-cell receptor(+) T lymphocytes are an important element of the innate immune system. Early production of interferon (IFN)-gamma by gammadelta T cells may have a role in linking innate and adaptive immune responses and contribute to T helper-1 bias. We investigated the role of cytokines in the activation and induction of IFN-gamma secretion by bovine workshop cluster 1(+) (WC1(+)) gammadelta T cells. The effects of culture with interleukin (IL)-12, IL-18, IL-15 and IL-2 were investigated; these cytokines are known to influence murine and human gammadelta T cells. We report that bovine WC1(+)gammadelta T cells are synergistically stimulated by IL-12 and IL-18 to secrete large quantities of IFN-gamma. Neonatal calves were shown to have significantly higher numbers of circulating WC1(+)gammadelta T cells than adult animals. In addition, the response of peripheral blood WC1(+)gammadelta T cells was significantly higher in neonatal calves compared with adult animals. However, in adult animals the response of lymph node WC1(+)gammadelta T cells to IL-12/IL-18 was more pronounced than that of peripheral blood WC1(+)gammadelta T cells. We hypothesize that the induction of IFN-gamma secretion from WC1(+)gammadelta T cells by IL-12 and IL-18 is likely to be an important element of the innate response to pathogens such as Mycobacterium bovis. The high numbers of WC1(+)gammadelta T cells in neonatal calves, and their inherent ability to respond to inflammatory cytokines, could be a key factor in the enhanced responses seen in calves to BCG vaccination.

Aging↗

PubMed2006

Structures and phase transitions in the ordered double perovskites Ba2BiIIIBiVO6 and Ba2BiIIISbVO6.

High-resolution neutron powder diffraction has been used to investigate the structures and phase transitions in the double perovskites Ba(2)Bi(3+)Bi(5+)O(6) (dibarium dibismuth hexaoxide) and Ba(2)BiSbO(6) (dibarium bismuth antimony hexaoxide) in the temperature ranges 4.2-973 and 4.2-625 K, respectively. The charge-ordered bismuthate adopts four structures in the temperature range - monoclinic in P2(1)/n, monoclinic in I2/m, rhombohedral in R3, and finally cubic in Fm3m. The low-temperature monoclinic structure has been determined for the first time. The transitions from P2(1)/n to I2/m, at 132 K, and R3 to Fm3m, at 820 K, are tricritical in nature; the transition from I2/m to R3 at ca 430 K is discontinuous. The behaviour of Ba(2)BiSbO(6) is very similar, except that the transition temperatures are lower - 250 K for I2/m to R3 and 515 K for R3 to Fm3m - and the low-temperature structure is not formed at all. The R3 to Fm3m transition in this compound is closer to second order in nature, although there is evidence for some contribution from higher-order terms.

Journal Article↗

PubMed2006

Structures of the cation-deficient perovskite Nd(0.7)Ti(0.9)Al(0.1)O3 from high-resolution neutron powder diffraction in combination with group-theoretical analysis.

The crystal structures of Nd(0.7)Ti(0.9)Al(0.1)O3, taken to represent the ideal Nd(2/3)TiO3, have been elucidated from 4 to 1273 K using high-resolution neutron powder diffraction in combination with group-theoretical analysis. The room-temperature structure is monoclinic in C2/m, on a cell with a = 7.6764 (1), b = 7.6430 (1), c = 7.7114 (1) A, beta = 90.042 (2) degrees . Pertinent features are the layered ordering of the A-site Nd cations/vacancies along the z axis and out-of-phase tilting of the (Ti/Al)O6 octahedra around both the x and z axes. From about 750 to 1273 K, the octahedra are tilted around just one axis (x axis) perpendicular to the direction of the cation ordering, giving rise to an orthorhombic structure with space-group symmetry Cmmm.

Journal Article↗

PubMed2005

Structures of the ordered double perovskites Sr2YTaO6 and Sr2YNbO6.

The ordered perovskite Sr(2)YTaO(6), distrontium yttrium tantalum hexaoxide, has been reported as showing an unusual triclinic structure, at odds with the results from a recent group-theoretical analysis. A new investigation establishes that Sr(2)YTaO(6) and the isostructural Sr(2)YNbO(6), distrontium yttrium niobium hexaoxide, in fact both adopt the commonly occurring monoclinic structure, with the space-group symmetry P2(1)/n.

Calcium Compounds↗

PubMed2004

Structures and phase transitions in perovskites--a group-theoretical approach.

Applications of computer-based group-theoretical methods to perovskite crystallography are reviewed. Such methods furnish a systematic account of the effects on the high-symmetry parent structure of diverse distortions. New results are presented for elpasolites (ordered double perovskites) when both ferroelectric cation displacement and simple octahedral tilting are allowed. Group-theoretical results prove invaluable in assisting experimental studies of perovskites since, if the nature of the distortion is known, they limit the possible structures or, in relation to more extensive studies, constrain the sequences of structures that may occur. Spontaneous strains and the estimation of order parameters are briefly discussed. Group-theoretical methods are undoubtedly a powerful aid to the study of perovskite crystallography, and their computer implementation makes them more accessible than hitherto.

Journal Article↗

PubMed2004

Octahedral tilting in cation-ordered perovskites--a group-theoretical analysis.

Group-theoretical methods are used to enumerate the structures of ordered perovskites, in which 1:2 and 1:3 ordering of B and B' cations is considered in combination with the ubiquitous BX6 (or B'X6) octahedral tilting. The cation ordering on the B-cation site is described by irreducible representations of the Pm3 m space group of the cubic aristotype: Lambda1 (k = 1/3,1/3,1/3) for the cation ordering pattern in the 1:2 compound A3BB2'X9 and M1+ (k = 1/2,1/2,0) for the cation ordering in the 1:3 compound A4BB3'X12. The octahedral tilting is mediated by the irreducible representations M3+ and R4+. Ten distinct structures have been identified in the 1:2 case and 11 structures for 1:3.

Journal Article↗

PubMed2004

Structure for perovskites with layered ordering of A-site cations.

The structure of La(1/3)NbO3 is that of a perovskite with La3+ cations ordered into alternate layers of perovskite A-sites. This is the description of a tetragonal structure and yet the room-temperature structure shows an orthorhombic distortion. The structure of La(2/3)TiO3 shows similar features. It has been recognized only very recently that the orthorhombic distortion in both these compounds is due to octahedral tilting. It seems clear from the literature that Ce(2/3)TiO3, Pr(2/3)TiO3, Nd(2/3)TiO3 and Ce(1/3)NbO3 adopt the same structure. Structures of other perovskites, such as Ln(2/3)TiO3, Ln(1/3)NbO3 and Ln(1/3)TaO3 (Ln = lanthanoid), when orthorhombically distorted, may be similar.

Journal Article↗

PubMed2004

Live Salmonella enterica serovar Typhimurium (S. Typhimurium) elicit dendritic cell responses that differ from those induced by killed S. Typhimurium.

The immune response of bovine monocytes-derived dendritic cells (DC) exposed to either live or killed Salmonella enterica serovar Typhimurium was compared. Both live and killed bacteria induced changes in morphology with distinctive formation of processes and up-regulation of the ability of DC to stimulate allogeneic T-cell proliferation. Also, both live and killed bacteria up-regulated the expression of MHC-I, MHC-II and CD80. However, live bacteria induced greater up-regulation of the expression of CD40 and CD86 than killed bacteria. Live bacteria also induced greater up-regulation of transcription for IL-6, IL-12 and GM-CSF than killed bacteria as measured by quantitative RT-PCR. These data suggest that blood-monocyte-derived DC may follow distinct maturation pathways following exposure to live or killed bacteria. These differences are likely to have consequences for the priming of the adaptive immune responses.

Animals↗

PubMed2004

DEC-205 expression on migrating dendritic cells in afferent lymph.

Previous studies have identified a 210 000-molecular weight molecule expressed at a high level on the surface of dendritic cells (DCs) in afferent lymph of cattle and evident on cells with the morphology of DCs in lymphoid tissues. Expression is either absent from other immune cells or is present at a lower level. The molecular weight and cellular distribution suggested that the molecule, called bovine WC6 antigen (workshop cluster), might be an orthologue of human DEC-205 (CD205). To establish whether this was the case, the open reading frame of bovine DEC-205 was amplified, by polymerase chain reaction, from thymic cDNA (accession no. AY264845). The cDNA sequence of bovine DEC-205 had 86% and 78% nucleic acid identity with human and mouse molecules, respectively. COS-7 cells transfected with a plasmid containing the cattle DEC-205 coding region expressed a molecule that stained with WC6-specific monoclonal antibody, showing that ruminant WC6 is an orthologue of DEC-205. Two-colour flow cytometry of mononuclear cells from afferent lymph draining cattle skin, and from blood, confirmed the high level of expression on large cells in lymph that were uniformly DC-LAMP positive and major histocompatibility complex class II positive. Within this DEC-205+ DC-LAMP+ population were subpopulations of cells that expressed the mannose receptor or SIRPalpha. The observations imply that DCs in afferent lymph are all DEC-205high, but not a uniform population of homogeneous mature DCs.

Amino Acid Sequence↗

PubMed2003

Ordered double perovskites -- a group-theoretical analysis.

Group-theoretical methods are used to enumerate the structures of ordered double perovskites, A(2)BB'X(6), in which the ordering of cations B and B' into alternate octahedra is considered in combination with the ubiquitous BX(6) (or B'X(6)) octahedral tilting. The cation ordering on the B-cation site is described by the irreducible representation R(1)(+) of the Pm3;m space group of the cubic aristotype, while the octahedral tilting is mediated by irreducible representations M(3)(+) and R(4)(+). There are 12 different structures identified, and the corresponding group-subgroup relationships are displayed. Known structures are briefly reviewed.

Journal Article↗

PubMed2003

A novel MyD-1 (SIRP-1alpha) signaling pathway that inhibits LPS-induced TNFalpha production by monocytes.

MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNFalpha) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNFalpha secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNFalpha secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNFalpha production and consequent inflammatory disease.

Antibodies, Monoclonal↗

PubMed2003

Differential response of bovine monocyte-derived macrophages and dendritic cells to infection with Salmonella typhimurium in a low-dose model in vitro.

Exposing bovine dendritic cells (DC) and macrophages (MPhi) to Salmonella typhimurium at a ratio of 1 cell to 10 bacteria had a cytotoxic effect that was not evident with a ratio of 1000 cells to 1 bacterium. This lower dose was considered to mimic more closely the in vivo situation and a comparison was made with this model of the consequences of infection for MPhi and DC. DC infected with S. typhimurium up-regulated cell surface expression of major histocompatibility class I (MHC-I), MHC-II, CD40, CD80 and CD86. In contrast, infected MPhi did not exhibit detectable changes in expression of cell surface molecules, except for a marginal increase in CD40. mRNA transcription for tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase was up-regulated in both infected DC and infected MPhi, although mRNA transcription for granulocyte-macrophage colony-stimulating factor and IL-12p40 was up-regulated only in infected DC and for IL-10 was only in infected MPhi. Infected DC had an increased ability to stimulate both allogeneic and antigen-specific T-cell responses compared to non-infected controls. In contrast, infected MPhi showed an increased ability to induce allogeneic responses but this was less than seen for DC and no enhancement of ability to induce antigen-specific T cell responses was seen. Thus, in a low-dose infection model that does not result in the cytotoxicity of a substantial percentage of antigen presenting cells, bovine MPhi and DC respond differently to infection with S. typhimurium and this could have important implications for the development of the immune response.

Animals↗

PubMed2003

A tumour necrosis factor alpha autocrine loop contributes to proliferation and nuclear factor-kappaB activation of Theileria parva-transformed B cells.

Theileria infection of bovine leucocytes induces uncontrolled proliferation and a transformed phenotype comparable to tumour cells. Infected cells have many characteristics of activated leucocytes and use autocrine loops to augment proliferation. We have shown previously that, in infected B cells, PI3-K controls a granulocyte-macrophage colony-stimulating factor (GM-CSF) autocrine loop to increase both proliferation and activation of the activator protein 1 (AP-1) transcription factor. We show here that the same infected B cells also use a tumour necrosis factor (TNF) alpha autocrine loop that again contributes to proliferation and augments nuclear factor (NF)-kappaB activation. Interestingly, both pharmacological inhibition of TNF synthesis and neutralizing anti-TNF antibodies lead to a reduction in proliferation and a 50% drop in NF-kappaB activation, without inducing apoptosis.

Animals↗

PubMed2002

Group-theoretical analysis of octahedral tilting in ferroelectric perovskites.

Group-theoretical methods are used to analyze perovskite structures where both ferroelectric cation displacements and simple tilting of octahedral units are present. This results in a list of 40 different structures, each with a unique space-group symmetry. The list is compared with that of Aleksandrov & Bartolomé [Phase Transit. (2001), 74, 255-335] and a number of differences are found. The group-subgroup relationships between the structures are also determined, along with an indication of those phase transitions that must be first order by Landau theory.

Journal Article↗

PubMed2002

MyD-1 (SIRPalpha) regulates T cell function in the absence of exogenous danger signals, via a TNFalpha-dependent pathway.

Signal inhibitory regulatory proteins are a family of transmembrane glycoproteins involved in the negative regulation of receptor tyrosine kinase signaling pathways. MyD-1 is a recently described member of this family. In this report we have assessed the function of MyD-1 in regulating T cell function utilizing an anti-MyD-1-specific monoclonal antibody (mAb). We show that ligating MyD-1 on antigen-presenting cells (APC) inhibits subsequent T cell activation induced by either anti-CD3 mAb or by allogeneic APC but has no effect on responses to either tuberculin purified protein derivative or tetanus toxoid antigens. Moreover, we show that the inhibition of T cell responses is not due to any change of costimulatory molecule expression on APC. We observed that the production of TNFalpha, a cytokine that we have earlier identified as important in the mechanism of MyD-1 immune regulation, is inhibited by cross-linking of MyD-1. We further show that TNFalpha is critically important in the regulation of T cell responses in the absence of danger signals, and indeed addition of TNFalpha can overcome the inhibitory effects of anti-MyD-1 antibody. This information may lead to a better understanding of the regulation of T cell responses in the absence of danger and therefore offer a possible therapeutic target to modulate aberrant immune responses.

Animals↗

PubMed2002

Modulation of immune responses to Mycobacterium bovis in cattle depleted of WC1(+) gamma delta T cells.

It is accepted that cell-mediated immune responses predominate in mycobacterial infections. Many studies have shown that CD4(+) T cells produce Th1 cytokines, such as gamma interferon (IFN-gamma), in response to mycobacterial antigens and that the cytolytic activity of CD8(+) cells toward infected macrophages is important. However, the extent and manner in which gamma delta T cells participate in this response remain unclear. In ruminants, gamma delta T cells comprise a major proportion of the peripheral blood mononuclear cell population. We have previously shown that WC1(+) gamma delta T cells are involved early in Mycobacterium bovis infection of cattle, but their specific functions are not well understood. Here we describe an in vivo model of bovine tuberculosis in which the WC1(+) gamma delta T cells were depleted from the peripheral circulation and respiratory tract, by infusion of WC1(+)-specific monoclonal antibody, prior to infection. While no effects on disease pathology were observed in this experiment, results indicate that WC1(+) gamma delta T cells, which become significantly activated (CD25(+)) in the circulation of control calves from 21 days postinfection, may play a role in modulating the developing immune response to M. bovis. WC1(+)-depleted animals exhibited decreased antigen-specific lymphocyte proliferative response, an increased antigen-specific production of interleukin-4, and a lack of specific immunoglobulin G2 antibody. This suggests that WC1(+) gamma delta TCR(+) cells contribute, either directly or indirectly, toward the Th1 bias of the immune response in bovine tuberculosis--a hypothesis supported by the decreased innate production of IFN-gamma, which was observed in WC1(+)-depleted calves.

Animals↗