Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “PD”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed2003

Nanosized Au2Pd41(CO)27(PEt3)15 containing two geometrically unprecedented 13-coordinated Au-centered (mu 13-Au)Pd13 polyhedra connected by triangular face-sharing and three interpenetrating 12-coordinated Pd-centered (mu 12-Pd)Au2Pd10 icosahedra: geometrical change in centered polyhedra induced by Au/Pd electronegativity-mismatch.

The synthesis, isolation, and stereochemical characterization of Au(2)Pd(41)(CO)(27)(PEt(3))(15)(1) are described. This nanosized Au(2)Pd(41) cluster (maximum metal-core diameter, 1.04 nm) was originally obtained with Au(2)Pd(21)(CO)(20)(PEt(3))(10) as low-yield by-products together with Pd(145)(CO)(x)(PEt(3))(30)(x approximately 60) from the reaction of Pd(PEt(3))(2)Cl(2) and Au(PPh(3))Cl in DMF with NaOH under CO atmosphere. The subsequent preparation of Au(2)Pd(21)(CO)(20)(PEt(3))(10) in greatly improved yields (preceding article) thereby provided the starting material that led to the isolation of 1 in reasonable yields (54%) from an overnight refluxing of the preformed Au(2)Pd(21) cluster in THF under N(2). Both the composition (subsequently ascertained from elemental analysis) and molecular geometry of 1 were unequivocally established from a low-temperature CCD X-ray diffraction study, which revealed a cubic unit cell of P2(1)3 symmetry with four molecules of 1 and four co-crystallized triphenylphosphine oxide molecules each lying on a crystallographic three-fold axis. The entire Au(2)Pd(41) core of pseudo-C(3h) symmetry may be viewed as a central Au(2)Pd(29) fragment of pseudo-D(3h) symmetry composed of two heretofore geometrically unknown 13-coordinated Au-centered (mu(13)-Au)Pd(13) polyhedra that share a common internal Pd(i)(3) triangular face perpendicular to the C(3) principal axis and of three three-fold-related interpenetrating 12-coordinated Pd-centered (mu(12)-Pd)Au(2)Pd(10) icosahedra. A comparative analysis of this central Au(2)Pd(29) fragment in with an internal Au(i)(2)Pd(i)(3) trigonal bipyramid vs. the corresponding central Pd(29) fragment in the known homopalladium Pd(35)(CO)(23)(PMe(3))(15) (2) with an internal Pd(i)(5) trigonal bipyramid resulting from five interpenetrating 12-coordinated Pd-centered [(mu(12)-Pd)Pd(12)] icosahedra is particularly illuminating; it provides a striking illustration of the remarkable observed difference between Pd- vs. Au-centered polyhedra which is attributed to a large electronegativity-mismatch in radial bonding interactions that occurs upon replacement of the Pd-centered atom with a highly electronegative Au-centered atom. The entire Au(2)Pd(41) core-geometry is obtained by additional face-condensations of 12 tetracapping Pd(cap) atoms. This cluster is stabilized by 15 PEt(3) ligands and 27 doubly- and triply-bridging CO ligands. A close geometrical resemblance between the three three-fold-related Au(2)Pd(14) moities within the Au(2)Pd(41) core in 1 and the entire Au(2)Pd(14) core in the known [Au(2)Pd(14)(CO)(9)(PMe(3))(11)](2+) dication (3) is observed; resulting stereochemical implications are given.

Crystallography, X-Ray↗
PubMed2001

PD-L2 is a second ligand for PD-1 and inhibits T cell activation.

Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.

Amino Acid Sequence↗
PubMed2002

PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2.

Programmed death-1 (PD-1) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor expressed upon T cell activation. PD-1(-/-) animals develop autoimmune diseases, suggesting an inhibitory role for PD-1 in immune responses. Members of the B7 family, PD-L1 and PD-L2, are ligands for PD-1. This study examines the functional consequences of PD-1:PD-L engagement on murine CD4 and CD8 T cells and shows that these interactions result in inhibition of proliferation and cytokine production. T cells stimulated with anti-CD3/PD-L1.Fc-coated beads display dramatically decreased proliferation and IL-2 production, while CSFE analysis shows fewer cells cycling and a slower division rate. Costimulation with soluble anti-CD28 mAb can overcome PD-1-mediated inhibition by augmenting IL-2 production. However, PD-1:PD-L interactions inhibit IL-2 production even in the presence of costimulation and, thus, after prolonged activation, the PD-1:PD-L inhibitory pathway dominates. Exogenous IL-2 is able to overcome PD-L1-mediated inhibition at all times, indicating that cells maintain IL-2 responsiveness. Experiments using TCR transgenic CD4(+) or CD8(+) T cells stimulated with antigen-presenting cells expressing PD-L1 show that both T cell subsets are susceptible to this inhibitory pathway. However, CD8(+) T cells may be more sensitive to modulation by the PD-1:PD-L pathway because of their intrinsic inability to produce significant levels of IL-2.

Amino Acid Sequence↗
PubMed2006

PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis.

To compare the roles of programmed death 1 ligand 1 (PD-L1) and PD-L2 in regulating immunity to infection, we investigated responses of mice lacking PD-L1 or PD-L2 to infection with Leishmania mexicana. PD-L1(-/-) and PD-L2(-/-) mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD-L1(-/-) mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD-L2(-/-) mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down-regulation of the Th2 response. Both PD-L1(-/-) and PD-L2(-/-) mice produced levels of IFN-gamma similar to WT mice. However, the development of IL-4-producing cells was reduced in PD-L1(-/-) mice, demonstrating a role for PD-L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD-L1(-/-) mice. Although no alterations in Th1/Th2 skewing were observed in PD-L2(-/-) mice, PD-L2(-/-) mice exhibited a marked increase in L. mexicana-specific antibody production. Increased Leishmania-specific IgG production may suppress the healing response through FcgammaR ligation on macrophages. Taken together, our results demonstrate that PD-L1 and PD-L2 have distinct roles in regulating the immune response to L. mexicana.

Animals↗
PubMed2003

Insertion reactions into Pd[bond]O and Pd[bond]N bonds: preparation of alkoxycarbonyl, carbonato, carbamato, thiocarbamate, and thioureide complexes of palladium(II).

Mononuclear palladium hydroxo complexes of the type [Pd(N[bond]N)(C(6)F(5))(OH)] [(N[bond]N = 2,2'-bipyridine (bipy), 4,4'-dimethyl-2,2'-bipyridine (Me(2)bipy), 1,10-phenanthroline (phen), or N,N,N',N'-tetramethylethylenediamine (tmeda)] have been prepared by reaction of [Pd(N[bond]N)(C(6)F(5))(acetone)]ClO(4) with KOH in methanol. These hydroxo complexes react, in methanol, with CO (1 atm, room temperature) to yield the corresponding methoxycarbonyl complexes [Pd(N[bond]N)(C(6)F(5))(CO(2)Me)]. Similar alkoxycarbonyl complexes [Pd(N[bond]N)(C(6)F(5))(CO(2)R)] (N[bond]N = bis(3,5-dimethylpyrazol-1-yl)methane); R = Me, Et, or (i)Pr) are obtained when [Pd(N[bond]N)(C(6)F(5))Cl] is treated with KOH in the corresponding alcohol ROH and CO is bubbled through the solution. The reactions of [Pd(N[bond]N)(C(6)F(5))(OH)] (N[bond]N = bipy or Me(2)bipy) with CO(2), in tetrahydrofuran, lead to the formation of the binuclear carbonate complexes [(N[bond]N)(C(6)F(5))Pd(mu-eta(2)-CO(3))Pd(C(6)F(5))(N[bond]N)]. Complexes [Pd(N[bond]N)(C(6)F(5))(OH)] react in alcohol with PhNCS to yield the corresponding N-phenyl-O-alkylthiocarbamate complexes [Pd(N[bond]N)(C(6)F(5))[SC(OR)NPh]]. Similarly, the reaction of [Pd(bipy)(C(6)F(5))(OH)] with PhNCO in methanol gives the N-phenyl-O-methylcarbamate complex [Pd(bipy)(C(6)F(5))[NPhC(O)OR]]. The reactions of [(N[bond]N)Pd(C(6)F(5))(OH)] with PhNCS in the presence of Et(2)NH yield the corresponding thioureidometal complexes [Pd(N[bond]N)(C(6)F(5))[NPhCSNR(2)]]. The crystal structures of [Pd(tmeda)(C(6)F(5))(CO(2)Me)], [Pd(2)(Me(2)bipy)(2)(C(6)F(5))(2)(mu-eta(2)-CO(3))].2CH(2)Cl(2), and [Pd(tmeda)(C(6)F(5))[SC(OMe)NPh]] have been determined.

Journal Article↗
PubMed2005

Infrared chemiluminescence study of CO2 formation in CO + NO reaction on Pd(110) and Pd(111) surfaces.

Infrared (IR) chemiluminescence studies of CO2 formed during steady-state CO + NO reaction over Pd(110) and Pd(111) surfaces were carried out. Kinetics of the CO + NO reaction were studied over Pd(110) using a molecular-beam reaction system in the pressure range of 10-2-10-1 Torr. The activity of the CO + NO reaction on Pd(110) was much higher than that of Pd(111), which was quite different from the result of other experiments under a higher pressure range. On the basis of the experimental data on the dependence of the reaction rate on CO and NO pressures and the reaction rate constants obtained by using a reaction model, the coverage of NO, CO, N, and O was calculated under various flux conditions. From the analysis of IR emission spectra in the CO + O2 reaction on Pd(110) and Pd(111), the antisymmetric vibrational temperature (TVAS) was seen to be higher than the bending vibrational temperature (TVB) on Pd(110). In contrast, TVB was higher than TVAS on Pd(111). These behaviors suggest that the activated complex for CO2 formation is more bent on Pd(111) than that on Pd(110), which is reflected by the surface structure. Both TVB and TVAS for the CO + O2 reaction on Pd(110) and Pd(111) increased gradually with increasing surface temperature (TS). On the other hand, in the case of the CO + NO reaction on Pd(110) and Pd(111), TVAS decreased and TVB increased significantly with increasing TS. TVB was lower than TVAS at lower TS, while TVB was higher than TVAS at higher TS. Comparison of the data obtained for the two reactions indicates that TVB in the CO + NO reaction on Pd(110) at TS = 800 and 850 K is much higher than that in the CO + O2 reaction on Pd(110).

Journal Article↗
PubMed2004

PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells.

Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(B7-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo, we generated PD-L1-deficient (PD-L1(-/-)) mice. CD4(+) and CD8(+) T cell responses were markedly enhanced in PD-L1(-/-) mice compared with wild-type mice in vitro and in vivo. PD-L1(-/-) dendritic cells stimulated greater wild-type CD4(+) T cell responses than wild-type dendritic cells, and PD-L1(-/-) CD4(+) T cells produced more cytokines than wild-type CD4(+) T cells in vitro, demonstrating an inhibitory role for PD-L1 on APCs and T cells. In vivo CD8(+) T cell responses also were significantly enhanced, indicating that PD-L1 has a role in limiting the expansion or survival of CD8(+) T cells. Studies using the myelin oligodendrocyte model of experimental autoimmune encephalomyelitis showed that PD-L1 on T cells and in host tissues limits responses of self-reactive CD4(+) T cells in vivo. PD-L1 deficiency converted the 129S4/SvJae strain from a resistant to experimental autoimmune encephalomyelitis-susceptible strain. Transfer of encephalitogenic T cells from wild-type mice into PD-L1(-/-) recipients led to exacerbated disease. Disease was even more severe in PD-L1(-/-) recipients of PD-L1(-/-) T cells. These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits naïve and effector T cell responses and plays a critical role in T cell tolerance.

Adoptive Transfer↗
PubMed2000

Electrochemical characteristics of high-Pd alloys in relation to Pd-allergy.

OBJECTIVE: The aim of this study was to determine whether the Pd-Cu-based dental ceramic alloys possess any electrochemical characteristics distinguishable from that of other Pd-containing alloys. Of all Pd-containing alloys, this particular alloy group has been linked to frequent incidence of allergy and hypersensitivity reactions. Electrochemical corrosion may instigate these reactions. METHODS: Four groups of alloys, Pd-Cu, Pd-Ga-(with and without Ag), Pd-Ag, and Au-Pd, were evaluated by traditional corrosion measurement techniques in a phosphated buffer saline solution at 20 degrees C. The electrochemical characteristics measured were: (1) 20 h open circuit potential (OCP); (2) 20 h corrosion rate (Icorr); and (3) anodic polarization (E-i) curves. RESULTS: The OCP values (232 +/- 25 mV) of the Ag-free Pd-Ga and Pd-Cu-based alloys were higher than and distinctly different from that (144 +/- 52 mV) of the Ag-containing alloys. The Icorr values of different alloys, despite varied compositions, were indistinguishable from one another. The E-i curves of all alloys were essentially similar, with the Ag-containing (> 5 wt%) alloys showing a subtle difference in their anodic slope within 100 mV above their corrosion potentials. SIGNIFICANCE: The OCP values of Pd-Cu alloys and the Ag-free Pd-Ga alloy are comparable to that reported for pure Pd (239 +/- 21 mV), which indicates that during corrosion these alloys undergo dealloying and consequent Pd-enrichment on their surface. Such a condition is conducive to the release of allergenic Pd++ ions and offers a plausible explanation for the frequent incidence of hypersensitivity reactions associated with the Pd-Cu alloys. The OCP values in other alloys are attributed to dealloying followed by surface enrichment with Ag and/or Au and the possible formation of an insoluble AgCl surface film on the respective alloy surfaces. These events have the potential to suppress or prevent Pd++ ion release. Alloys showing these characteristics have seldom been linked to allergic reactions.

Allergens↗
PubMed2006

Kinetics and mechanism of the reactions of Pd(II) complexes with azoles and diazines. Crystal structure of [Pd(bpma)(H2O)](ClO4)2.2H2O.

Substitution reactions of the complexes [Pd(bpma)(H2O)]2+, [Pd(bpma)Cl]+, [Pd(dien)(H2O)]2+ and [Pd(dien)Cl]+, where bpma = bis(2-pyridylmethyl)amine and dien = diethylentriamine or 1,5-diamino-3-azapentane, with some nitrogen-donor ligands such as triazole, pyrazole, pyrimidine, pyrazine and pyridazine, were studied in an aqueous 0.10 M NaClO4 at pH 2.8 using variable-temperature and -pressure stopped-flow spectrophotometry. The second-order rate constants indicate that the Pd(II) complexes of bpma, viz. [Pd(bpma)(H2O)]2+ and [Pd(bpma)Cl]+, are more reactive than the complexes of dien, viz. [Pd(dien)(H2O)]2+ and [Pd(dien)Cl]+. Also, the aqua complexes, [Pd(bpma)(H2O)]2+ and [Pd(dien)(H2O)]2+, are much more reactive than the corresponding chloro complexes. The most reactive nucleophile of the five-membered rings is triazole and for the six-membered rings the most reactive one is pyridazine. Activation parameters were determined for all reactions and the negative entropies and volumes of activation (Delta S++, Delta V++) support an associative ligand substitution mechanism. The crystal structure of [Pd(bpma)(H2O)](ClO4)2.2H2O was determined by X-ray diffraction. Crystals are monoclinic with the space group P2(1)/c. The coordination geometry of [Pd(bpma)(H2O)]2+ is distorted square-planar. The Pd-N (central) bond distance, 1.958(5) A, is shorter than the other two Pd-N distances, 2.007(5) and 2.009(5) A. The Pd-O distance is 2.043(5) A.

Journal Article↗
PubMed2003

PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.

PD-L1 and PD-L2 are ligands for PD-1, a costimulatory molecule that plays an inhibitory role in regulating T cell activation in the periphery. We find that PD-L1 is highly expressed on inflammatory macrophages as compared with resident peritoneal macrophages but can be induced on resident macrophages by classical activation stimuli such as lipopolysaccharide, IFN-gamma, and polyinosinic-polycytidylic acid. Further up-regulation of PD-L1 on inflammatory macrophages can also be induced by subsequent exposure to lipopolysaccharide and IFN-gamma. In contrast, PD-L2 is not expressed on inflammatory macrophages but can be induced by alternative activation via IL-4. Although PD-L1 is highly inducible on a variety of antigen-presenting cell lines as well as resident macrophages, PD-L2 is most significantly inducible only on inflammatory macrophages. PD-L1 up-regulation depends on TLR4 and STAT1, whereas PD-L2 expression depends on IL-4R alpha and STAT6. Consistent with these results, T helper 1T helper 2 (Th1/Th2) cells also differentially up-regulate PD-L1 and PD-L2 expression on inflammatory macrophages. Hence, Th1 cells as well as microbial products can enhance PD-L1 expression on many different macrophage populations, whereas Th2 cells instruct only inflammatory macrophages to up-regulate PD-L2. These results suggest that PD-L1 and PD-L2 might have different functions in regulating type 1 and type 2 responses.

Amino Acid Sequence↗
PubMed2005

Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes.

Positive selection during thymocyte development is driven by the affinity and avidity of the TCR for MHC-peptide complexes expressed in the thymus. In this study, we show that programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory receptors, inhibits TCR-mediated positive selection through PD-1 ligand 1 (PD-L1):PD-1 interactions. Transgenic mice that constitutively overexpress PD-1 on CD4+CD8+ thymocytes display defects in positive selection in vivo. Using an in vitro model system, we find that PD-1 is up-regulated following TCR engagement on CD4+CD8+ murine thymocytes. Coligation of TCR and PD-1 on CD4+CD8+ thymocytes with a novel PD-1 agonistic mAb inhibits the activation of ERK and up-regulation of bcl-2, both of which are downstream mediators essential for positive selection. Inhibitory signals through PD-1 can overcome the ability of positive costimulators, such as CD2 and CD28, to facilitate positive selection. Finally, defects in positive selection that result from PD-1 overexpression in thymocytes resolve upon elimination of PD-L1, but not PD-1 ligand 2, expression. PD-L1-deficient mice have increased numbers of CD4+CD8+ and CD4+ thymocytes, indicating that PD-L1 is involved in normal thymic selection. These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire.

Animals↗
PubMed1996

Iodination of alpha-Phosphino Enolate Complexes of Palladium(II) and Platinum(II). Synthesis and Crystal Structures of [(dmba)Pd{Ph(2)PC(I)C(O)Ph}] and of the Dipalladium(II) Complex [(dmba)Pd{Ph(2)PCC(O)Ph}Pd(I)(tmeda)] Obtained by Palladium(0) Insertion into the Carbon-Iodine Bond.

Electrophilic attack of 1 equiv of I(2) on a PC(sp)2 carbon of the Pt(II) complex (1) afforded (2) in 90% yield. Complex 2 was subsequently deprotonated by NaOEt in ethanol to give the bis(enolato) complex (3). This alpha-phosphino, alpha-iodo enolato complex was obtained directly and quantitatively by the reaction of 1 with 1 equiv of N-iodosuccinimide (NIS). When 2 equiv of NIS was used, the symmetrical complex (4) was formed selectively. In contrast to I(2), NIS was also able to functionalize the phosphino enolate ligand of complexes to give the corresponding iodo derivatives (C N = dmba (5) or 8-mq (6)). These represent the first examples in which a phosphino enolate C-H bond has been directly functionalized, i.e. replaced by a C-X bond. Attempts to use this procedure with or with were unsuccessful. Reaction of 5 with Pd(dba)(2) in the presence of tetramethylenediamine (tmeda) or 2,2'-bipyridine (bipy) afforded (7) and (8), respectively. The solid state structures of complexes 5 and 7.CH(2)Cl(2) have been determined by single-crystal X-ray diffraction: 5 crystallizes in the monoclinic space group P2(1)/n with Z = 4 in a unit cell of dimensions a = 12.867(3) Å, b = 10.625(3) Å, c = 19.509(6) Å, and beta = 102.23(2) degrees; 7.CH(2)Cl(2) crystallizes in the monoclinic space group C2/c with Z = 8 in a unit cell of dimensions a = 35.906(3) Å, b = 13.565(3) Å, c = 15.775(2) Å, and beta = 95.099(10) degrees. Complex 7 contains two palladium(II) centers, in a square-planar environment, connected by the P-C unit of a phosphino enolate ligand which adopts an unprecedented &mgr;-eta(2)(P,C):eta(2)(P,O) bonding mode. The two coordination planes are almost orthogonal and make a dihedral angle of 88.0(2) degrees, which minimizes the steric hindrance between the ligands.

Journal Article↗
PubMed2005

Effect of PD I administration on dopamine receptors mRNAs expression in the lesioned striatum of PD rat model.

To study the effect of PD I administration on dopamine receptors (DR1, DR2) mRNAs expression in the lesioned striatum of the PD rat model and confirm if PD I has the effect of dopamine receptor agonist. The PD rats with unilateral 6-hydroxydopamine lesioned were administrated with PD I, L-dopa methyl/benserazide, L-dopa methyl /benserazide/ PD I, normal saline respectively for 4 weeks and their behavioral changes were observed. Then the rats were sacrificed and RT-PCR technique was used to detect changes of dopamine receptors (DR1, DR2) mRNAs expression in the ipsilateral striatum 1 day after the last treatment. The results showed that treatment with PD I plus L-dopa resulted in a stable contralateral rotation behavior; treatment with L-dopa resulted in a progressively increased contralateral rotation behavior. Rotation behavior induced by anhydromorphine decreased with PD I or PD I plus L-dopa treatment. Treatment With L-dopa or PD I plus L-dopa, up-regulation of DR1 mRNA and down-regulation of DR2 mRNA were observed in the ipsilateral striatum which were more obvious than that treated with PD I or vehicle (P < 0.05). It was concluded that long-term treatment with PD I could alleviate the behavior of PD rats. PD I had no apparent effect on the dopamine receptors (DR1, DR2) mRNAs expression in the ipsilateral striatum and the PD I has no agonist effect on dopamine receptors.

Animals↗
PubMed2004

PK-PD integration and PK-PD modelling of nonsteroidal anti-inflammatory drugs: principles and applications in veterinary pharmacology.

Much useful information relevant to elucidation of mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) at the molecular level can be obtained from integrating pharmacokinetic (PK) and pharmacodynamic (PD) data, such data being obtained usually, although not necessarily, in separate studies. Integrating PK and PD data can also provide a basis for selecting clinically relevant dosing schedules for subsequent evaluation in disease models and clinical trials. The principles underlying and uses of PK-PD integration are illustrated in this review for phenylbutazone in the horse and cow, carprofen and meloxicam in the horse, carprofen and meloxicam in the cat and nimesulide in the dog. In the PK-PD modelling approach for NSAIDs, the PK and PD data are generated (usually though not necessarily) in vivo in the same investigation and then modelled in silico, usually using the integrated effect compartment or indirect response models. Drug effect is classically modelled with the sigmoidal E(max) (Hill) equation to derive PD parameters which define efficacy, potency and sensitivity. The PK-PD modelling approach for NSAIDs can be undertaken at the molecular level using surrogates of inhibition of cyclooxygenase (COX) isoforms (or indeed other enzymes e.g. 5-lipoxygenase). Examples are provided of the generation of PD parameters for several NSAIDs (carprofen, ketoprofen, vedaprofen, flunixin and tolfenamic acid) in species of veterinary interest (horse, calf, sheep and goat), which indicate that all drugs investigated except vedaprofen were non-selective for COX-1 and COX-2 in the four species investigated under the experimental conditions used, vedaprofen being a COX-1 selective NSAID. In these studies, plasma concentration was linked to COX inhibitory action in the biophase using an effect compartment model. Data for S-(+)-ketoprofen have been additionally subjected to inter-species modelling and allometric scaling of both PK and PD parameters. For several species values of four PK parameters were highly correlated with body weight, whilst values for PD parameters based on COX inhibition lacked allometric relationship with body weight. PK-PD modelling of NSAIDs has also been undertaken using clinical end-points and surrogates for clinical end-points in disease models. By measurement of clinically relevant indices in clinically relevant models, data generated for PD parameters have been used to set dosages and dose intervals for evaluation and confirmation in clinical trials. PK-PD modelling of NSAIDs is likely to prove superior to conventional dose titration studies for dosage schedule determination, as it sweeps the whole of the concentration-effect relationship for all animals and therefore permits determination of genuine PD parameters. It also introduces time as a second independent variable thus allowing prediction of dosage interval. Using indirect response models and clinically relevant indices, PD data have been determined for flunixin, phenylbutazone and meloxicam in the horse, nimesulide in the dog and meloxicam in the cat.

Animals↗
PubMed2002

Density functional study of the sigma and pi bond activation at the Pd=X (X = Sn, Si, C) bonds of the (H2PC2H4PH2)Pd=XH2 complexes. Is the bond cleavage homolytic or heterolytic?

The mechanism for the activation of the sigma bonds, the O-H of H2O, C-H of CH4, and the H-H of H2, and the pi bonds, the C[triple bond]C of C2H2, C=C of C2H4, and the C=O of HCHO, at the Pd=X (X = Sn, Si, C) bonds of the model complexes (H2PC2H4PH2)Pd=XH2 5 has been theoretically investigated using a density functional method (B3LYP). The reaction is significantly affected by the electronic nature of the Pd=X bond, and the mechanism is changed depending on the atom X. The activation of the O-H bond with the lone pair electron is heterolytic at the Pd=X (X = Sn, Si) bonds, while it is homolytic at the Pd=C bond. The C-H and H-H bonds without the lone pair electron are also heterolytically activated at the Pd=X bonds independent of the atom X, where the hydrogen is extracted as a proton by the Pd atom in the case of X = Sn, Si and by the C atom in the case of X=C because the nucleophile is switched between the Pd and X atoms depending on the atom X. In contrast, the pi bond activation of C[triple bond]C and C=C at the Pd=Sn bond proceeds homolytically, and is accompanied by the rotation of the (H2PC2H4PH2)Pd group around the Pd-Sn axis to successfully complete the reaction by both the electron donation from the pi orbital to Sn p orbital and the back-donation from the Pd dpi orbital to the pi orbital. On the other hand, the activation of the C=O pi bond with the lone pair electron at the Pd=Sn bond has two reaction pathways: one is homolytic with the rotation of the (H2PC2H4PH2)Pd group and the other is heterolytic without the rotation. The role of the ligands controlling the activation mechanism, which is heterolytic or homolytic, is discussed.

Journal Article↗
PubMed2006

PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis.

Interactions between PD-1 and its two differentially expressed ligands, PD-L1 and PD-L2, attenuate T cell activation and effector function. To determine the role of these molecules in autoimmune disease of the CNS, PD-1-/-, PD-L1-/- and PD-L2-/- mice were generated and immunized to induce experimental autoimmune encephalomyelitis (EAE). PD-1-/- and PD-L1-/- mice developed more severe EAE than wild type and PD-L2-/- mice. Consistent with this, PD-1-/- and PD-L1-/- cells produced elevated levels of the pro-inflammatory cytokines IFN-gamma, TNF, IL-6 and IL-17. These results demonstrate that interactions between PD-1/PD-L1, but not PD-1/PDL-2, are crucial in attenuating T cell responses in EAE.

Animals↗
PubMed2002

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

Animals↗
PubMed2004

Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy.

Programmed death receptor ligand 1 (PD-L1, also called B7-H1) is a recently described B7 family member. In contrast to B7-1 and B7-2, PD-L1 does not interact with either CD28 or CTLA-4. To date, one specific receptor has been identified that can be ligated by PD-L1. This receptor, programmed death receptor 1 (PD-1), has been shown to negatively regulate T-cell receptor (TCR) signaling. Upon ligating its receptor, PD-L1 has been reported to decrease TCR-mediated proliferation and cytokine production. PD-1 gene-deficient mice developed autoimmune diseases, which early led to the hypothesis of PD-L1 regulating peripheral tolerance. In contrast to normal tissues, which show minimal surface expression of PD-L1 protein, PD-L1 expression was found to be abundant on many murine and human cancers and could be further up-regulated upon IFN-gamma stimulation. Thus, PD-L1 might play an important role in tumor immune evasion. This review discusses the currently available data concerning negative T-cell regulation via PD-1, the blockade of PD-L1/PD-1 interactions, and the implications for adoptive T-cell therapies.

Animals↗