bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms of interleukin‐1α constitute independent risk factors for chronic graft‐versus‐host disease after allogeneic bone marrow transplantation
Authors: Cullup Hannah , Dickinson Anne M. , Cavet James , Jackson Graham H. , Middleton Peter G.
Published: August 2003

Summary. The interleukin‐1 (IL‐1) family of cytokines is widely involved in inflammatory processes and diseases with an inflammatory component. Polymorphisms of the IL‐1α, IL‐1β and IL‐1Ra genes have been implicated in a number of autoimmune or inflammatory conditions, with polymorphism of the IL‐1Ra gene showing association with severity of graft‐versus‐host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We compared the clinical outcomes (GVHD and survival) of 115 patients after human leucocyte antigen (HLA)‐identical sibling allogeneic BMT with their genotype for two polymorphisms present in the IL‐1α gene, which have been implicated in immune‐related pathology. Possession of allele 2 of the IL‐1α−889 polymorphism and allele 2 of the IL‐1α variable number tandem repeat (VNTR) polymorphism in the donor genotype was associated with the occurrence of chronic, but not acute GVHD. A local normal population was also genotyped for these polymorphisms, and subsequent analysis identified conserved haplotypes in this gene region. Haplotypes containing allele 2 at both IL‐1α−889 and IL‐1α VNTR loci were extremely uncommon, suggesting that both risk alleles would be inherited independently. Both loci could therefore function as independent disease association markers. The polymorphisms of the IL‐1α gene could be used to predict chronic GVHD in HLA‐matched sibling transplants alongside clinical risk factors.
Molecular characterization of six unrelated Italian patients affected by pyrimidine 5′‐nucleotidase deficiency
Authors: Bianchi Paola , Fermo Elisa , Alfinito Fiorella , Vercellati Cristina , Baserga Mariangiola , Ferraro Filomena , Guzzo Immacolata , Rotoli Bruno , Zanella Alberto
Published: August 2003

Summary. Pyrimidine 5′‐nucleotidase deficiency is a rare autosomal recessive disorder characterized by haemolytic anaemia, marked basophilic stippling and accumulation of pyrimidine nucleotides within the erythrocytes. The gene encoding for this enzyme (P5′N‐1) has been cloned recently, and seven mutations have so far been identified in 11 unrelated families. We describe the haematological and molecular characteristics of six unrelated Italian patients affected by pyrimidine 5′‐nucleotidase deficiency (one from northern and five from southern Italy). The sequence of the complete P5′N‐1 gene showed the presence of four different new mutations: a missense mutation AAT–AGT at codon 190 (Asn–Ser), one splicing mutation (IVS9‐1 g‐c) and two frameshift mutations, DelG576 and InsGG743. Although the molecular defect was homozygous in all patients but one, parents' consanguinity could be confirmed in only one case. InsGG743 was detected in two cases, and DelG576 was found in three patients originating from southern Italy, suggesting a possible geographical distribution of the genetic defect. Haematological data showed the presence of peripheral spherocytosis in all cases, although only one had a concomitant membrane defect. An increase in serum ferritin levels was observed in the splenectomized patients, suggesting that the iron status of these subjects should be monitored and that they should be investigated for potential additional risk factors for iron accumulation.
Use of VFSA for resolution, sensitivity and uncertainty analysis in 1D DC resistivity and IP inversion
Authors: Bhattacharya Bimalendu B. , Shalivahan  , Sen Mrinal K.
Published: August 2003

We present results from the resolution and sensitivity analysis of 1D DC resistivity and IP sounding data using a non‐linear inversion. The inversion scheme uses a theoretically correct Metropolis–Gibbs' sampling technique and an approximate method using numerous models sampled by a global optimization algorithm called very fast simulated annealing (VFSA). VFSA has recently been found to be computationally efficient in several geophysical parameter estimation problems. Unlike conventional simulated annealing (SA), in VFSA the perturbations are generated from the model parameters according to a Cauchy‐like distribution whose shape changes with each iteration. This results in an algorithm that converges much faster than a standard SA. In the course of finding the optimal solution, VFSA samples several models from the search space. All these models can be used to obtain estimates of uncertainty in the derived solution. This method makes no assumptions about the shape of an a posteriori probability density function in the model space. Here, we carry out a VFSA‐based sensitivity analysis with several synthetic and field sounding data sets for resistivity and IP. The resolution capability of the VFSA algorithm as seen from the sensitivity analysis is satisfactory. The interpretation of VES and IP sounding data by VFSA, incorporating resolution, sensitivity and uncertainty of layer parameters, would generally be more useful than the conventional best‐fit techniques.
3D wavepath migration
Authors: Sun Hongchuan , Schuster Gerard T.
Published: August 2003

3D Kirchhoff migration (KM) smears a trace's time sample along a quasi‐ellipsoid in the model space. This is a costly and sometimes noisy process as reflection energy is smeared far away from the actual reflector position, introducing far‐field migration artefacts. As a reduced form of 3D KM, 3D wavepath migration (WM) smears a picked reflection arrival to a small Fresnel zone portion centred about the specular reflection point, leading to fewer migration artefacts and reduced computation time. Both the traveltime and the angle of incidence are required by WM for locating the specular reflection point. Our results with 3D prestack synthetic data show that WM generates fewer migration artefacts and can sometimes define complex structure better than KM. Our results with 3D prestack field data show that WM can mostly suppress migration artefacts and can sometimes resolve reflection interfaces better than KM. The CPU comparison shows that, for both the synthetic and field data examples, WM can be more than an order of magnitude faster than KM. The limitation with 3D WM is that the angle of incidence calculation is sensitive to the recording geometry and the signal‐to‐noise (S/N) ratio, which can lead to blurred images.
Reflection and transmission responses of layered transversely isotropic viscoelastic media
Authors: Stovas Alexey , Ursin Bjorn
Published: August 2003

We consider a layered heterogeneous viscoelastic transversely isotropic medium with a vertical symmetry axis (a viscoelastic TIV medium) and parameters that depend on depth only. This takes into account intrinsic attenuation, anisotropy and thin layering. The seismic wavefield is decomposed into up‐ and downgoing waves scaled by the vertical energy flux. This scaling gives important symmetry relationships for both reflection and transmission (R/T) responses. For a stack of homogeneous layers, the exact reflection response can be computed in a numerically stable way by a simple layer‐recursive algorithm. We derive exact plane‐wave R/T coefficients and several linear and quadratic approximations between two viscoelastic TIV media, as functions of the real‐valued horizontal slowness. The approximations are valid for pre‐ and post‐critical values of horizontal slowness provided that the proper complex square roots are used when computing the vertical slowness. Numerical examples demonstrate that the quadratic approximations can be used for large differences in medium parameters, while the linear approximations can be used for small differences. For weak anisotropy it is sufficient to use an isotropic background medium, while for strong anisotropy it is necessary to use a weak TIV or TIV background medium. We also extend the O'Doherty–Anstey formula to the P‐ and SV‐wave transmission responses of a stack of viscoelastic TIV layers, taking into account intrinsic attenuation, anisotropy and thin layering.
The Wilson–Burg method of spectral factorization with application to helical filtering
Authors: Fomel Sergey , Sava Paul , Rickett James , Claerbout Jon F.
Published: August 2003

Spectral factorization is a computational procedure for constructing minimum‐phase (stable inverse) filters required for recursive inverse filtering. We present a novel method of spectral factorization. The method iteratively constructs an approximation of the minimum‐phase filter with the given autocorrelation by repeated forward and inverse filtering and rearranging of the terms. This procedure is especially efficient in the multidimensional case, where the inverse recursive filtering is enabled by the helix transform.

To exemplify a practical application of the proposed method, we consider the problem of smooth two‐dimensional data regularization. Splines in tension are smooth interpolation surfaces whose behaviour in unconstrained regions is controlled by the tension parameter. We show that such surfaces can be efficiently constructed with recursive filter preconditioning and we introduce a family of corresponding two‐dimensional minimum‐phase filters. The filters are created by spectral factorization on a helix.
Using a non‐integer moment of the impulse response to estimate the half‐space conductivity
Authors: Lee Terry J. , Smith Richard S. , Hyde Christophe S.B.
Published: August 2003

The nth‐order moments of the electromagnetic impulse response are useful for interpreting electromagnetic data. We have derived an analytic expression for the half‐order moment of a conductive half‐space. By inverting this expression, the measured half‐order moment can be used to estimate an apparent conductivity of the ground. The first‐order moment can also be used to estimate the half‐space conductivity. A sensitivity analysis indicates that for an airborne EM configuration, the half‐order moment will be most sensitive to material in the top 26–48 m, while the first‐order moment will be sensitive to deeper material (down to depths between 66 and 127 m).
Frequency‐dependent anisotropy due to meso‐scale fractures in the presence of equant porosity
Authors: Chapman Mark
Published: August 2003

Fractured rock is often modelled under the assumption of perfect fluid pressure equalization between the fractures and equant porosity. This is consistent with laboratory estimates of the characteristic squirt‐flow frequency. However, these laboratory measurements are carried out on rock samples which do not contain large fractures. We consider coupled fluid motion on two scales: the grain scale which controls behaviour in laboratory experiments and the fracture scale. Our approach reproduces generally accepted results in the low‐ and high‐frequency limits. Even under the assumption of a high squirt‐flow frequency, we find that frequency‐dependent anisotropy can occur in the seismic frequency band when larger fractures are present. Shear‐wave splitting becomes dependent on frequency, with the size of the fractures playing a controlling role in the relationship. Strong anisotropic attenuation can occur in the seismic frequency band. The magnitude of the frequency dependence is influenced strongly by the extent of equant porosity. With these results, it becomes possible in principle to distinguish between fracture‐ and microcrack‐induced anisotropy, or more ambitiously to measure a characteristic fracture length from seismic data.
Traveltime computation for 3D anisotropic media by a finite‐difference perturbation method
Authors: Soukina S.M. , Gajewski D. , Kashtan B.M.
Published: August 2003

The first‐order perturbation theory is used for fast 3D computation of quasi‐compressional (qP)‐wave traveltimes in arbitrarily anisotropic media. For efficiency we implement the perturbation approach using a finite‐difference (FD) eikonal solver. Traveltimes in the unperturbed reference medium are computed with an FD eikonal solver, while perturbed traveltimes are obtained by adding a traveltime correction to the traveltimes of the reference medium. The traveltime correction must be computed along the raypath in the reference medium. Since the raypath is not determined in FD eikonal solvers, we approximate rays by linear segments corresponding to the direction of the phase normal of plane wavefronts in each cell. An isotropic medium as a reference medium works well for weak anisotropy. Using a medium with ellipsoidal anisotropy as a background medium in the perturbation approach allows us to consider stronger anisotropy without losing computational speed. The traveltime computation in media with ellipsoidal anisotropy using an FD eikonal solver is fast and accurate. The relative error is below 0.5% for the models investigated in this study. Numerical examples show that the reference model with ellipsoidal anisotropy allows us to compute the traveltime for models with strong anisotropy with an improved accuracy compared with the isotropic reference medium.
Modelling frequency‐dependent seismic anisotropy in fluid‐saturated rock with aligned fractures: implication of fracture size estimation from anisotropic measurements
Authors: Maultzsch Sonja , Chapman Mark , Liu Enru , Li Xiang Yang
Published: August 2003

Measurements of seismic anisotropy in fractured rock are used at present to deduce information about the fracture orientation and the spatial distribution of fracture intensity. Analysis of the data is based upon equivalent‐medium theories that describe the elastic response of a rock containing cracks or fractures in the long‐wavelength limit. Conventional models assume frequency independence and cannot distinguish between microcracks and macrofractures. The latter, however, control the fluid flow in many subsurface reservoirs. Therefore, the fracture size is essential information for reservoir engineers. In this study we apply a new equivalent‐medium theory that models frequency‐dependent anisotropy and is sensitive to the length scale of fractures. The model considers velocity dispersion and attenuation due to a squirt‐flow mechanism at two different scales: the grain scale (microcracks and equant matrix porosity) and formation‐scale fractures. The theory is first tested and calibrated against published laboratory data. Then we present the analysis and modelling of frequency‐dependent shear‐wave splitting in multicomponent VSP data from a tight gas reservoir. We invert for fracture density and fracture size from the frequency dependence of the time delay between split shear waves. The derived fracture length matches independent observations from borehole data.
CD25+, interleukin‐10‐producing CD4+ T cells are required for suppressor cell production and immune privilege in the anterior chamber of the eye
Authors: Skelsey Molly E. , Mayhew Elizabeth , Niederkorn Jerry Y.
Published: August 2003

An important factor in the establishment of ocular immune privilege is the dynamic down regulation of T helper 1 (Th1) immune responses that occurs in response to antigens delivered intraocularly; a phenomenon that has been termed anterior chamber‐associated immune deviation (ACAID). ACAID is characterized by the generation of splenic regulatory cells that inhibit the expression of delayed‐type hypersensitivity. Previous studies have shown that antigens introduced into the anterior chamber of the eye induce the generation of a CD4+ T‐cell population that suppress the induction of Th1 immune responses and the appearance of a second population of CD8+ T regulatory cells that suppresses the expression of Th1 inflammatory responses (= efferent suppressor cells). Experiments described here characterized the function of the CD4+ ACAID suppressor cell population and its effect on the generation of CD8+ efferent suppressor cells that inhibit the expression of DTH in situ. Both in vivo and in vitro experiments demonstrated that CD4+ T cells are required for the generation of CD8+ efferent suppressor cells. CD4+ T cells do not require cell contact with CD8+ T cells; instead they produce soluble IL‐10 that is sufficient for the generation of ACAID suppressor cells. Finally, the CD4+ afferent T suppressor cells are not natural killer T cells, but do express the CD25 cell surface marker.
Interleukin‐12 and interleukin‐2‐induced invariant natural killer T‐cell cytokine secretion and perforin expression independent of T‐cell receptor activation
Authors: Hou Runhua , Goloubeva Olga , Neuberg Donna S. , Strominger Jack L. , Wilson S. Brian
Published: August 2003

Human invariant natural killer (iNK) T cells expressing an invariant Vα24‐Jα15 T‐cell receptor (TCR) are thought to be important regulators of autoimmunity and tumour surveillance. Two major subsets of iNK T cells, CD4+ or CD4− CD8− are known to exist, but the in vivo importance of CD4 expression is unclear. Since interleukin‐12 (IL‐12) is a key iNK T‐cell‐activating cytokine, the effect of IL‐12 plus or minus the T‐cell growth factor IL‐2 on a large panel of CD4+ versus CD4− CD8− iNK T‐cell clones was examined. Strikingly, IL‐12 and IL‐2 significantly activated iNK T cells to secrete IL‐4, interferon‐γ and granulocyte–macrophage colony‐stimulating factor, and up‐regulated perforin expression in the absence of TCR stimulation. Furthermore, IL‐2 and IL‐12 treatment resulted in a preferential increase in apoptosis of CD4− CD8− clones. Thus, independent of TCR activation, IL‐2 and IL‐12 can directly activate iNK T cells and provide a selective advantage to the CD4+ iNK T‐cell population.
Interferon‐α disables dendritic cell precursors: dendritic cells derived from interferon‐α‐treated monocytes are defective in maturation and T‐cell stimulation
Authors: Dauer Marc , Pohl Katrin , Obermaier Bianca , Meskendahl Tobias , Röbe Julian , Schnurr Max , Endres Stefan , Eigler Andreas
Published: August 2003

Dendritic cells (DC) can be derived from monocytes in vitro by culture with granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and interleukin‐4 (IL‐4). It is unknown whether this regimen reflects DC differentiation from blood precursors under physiological conditions. Induction of DC development from monocytes by interferon‐α (IFN‐α) may occur in vivo during infection or inflammation and thus may represent a more physiological approach to DC differentiation in vitro. Here, we show that incubation of GM‐CSF‐cultured monocytes with IFN‐α does not induce DC differentiation: cells maintain their original phenotype and cytokine secretion pattern. Even after stimulation with pro‐inflammatory or T‐cell‐derived activation signals, IFN‐α‐treated monocytes do not develop DC characteristics. Addition of IL‐4 during stimulation of IFN‐α‐treated monocytes results in the rapid development of DC‐like cells expressing co‐stimulatory molecules, CD83 and chemokine receptor CCR7, indicating that some degree of developmental plasticity is preserved. However, DC pre‐activated with IFN‐α are less effective in inducing allogeneic or antigen‐specific autologous T‐cell proliferation, produce less IL‐12 and express lower levels of CCR7 compared to DC generated by culture with GM‐CSF and IL‐4. Incubating GM‐CSF‐cultured monocytes simultaneously with IFN‐α and IL‐4 does not affect phenotypic maturation of DC, but reduces IL‐12 production upon pro‐inflammatory activation. We conclude that: (1) IFN‐α fails to induce DC differentiation and thus cannot replace IL‐4 in generating DC from monocytes in vitro; and (2) the presence of IFN‐α prior to or during differentiation of DC from monocyte precursors alters their response to maturation stimuli and may affect their capacity to stimulate T helper type 1 immune responses in vivo.
Influence of oestrogen receptor α and β on the immune system in aged female mice
Authors: Islander U. , Erlandsson M. C. , Hasséus B. , Jonsson C. A. , Ohlsson C. , Gustafsson J‐Å. , Dahlgren U. , Carlsten H.
Published: August 2003

Oestrogen has a dichotomous effect on the immune system. T and B lymphopoiesis in thymus and bone marrow is suppressed, whereas antibody production is stimulated by oestrogen. In this study the importance of the oestrogen receptors (ER) ER‐α and ER‐β in the aged immune system was investigated in 18 months old‐wild type (WT), ER‐α (ERKO), ER‐β (BERKO) and double ER‐α and ER‐β (DERKO) knock‐out mice, and compared with 4 months old WT mice. Cell phenotypes in bone marrow, spleen and thymus, and the frequency of immunoglobulin (Ig) spot forming cells (SFC) were determined. We show here that the 17‐β‐oestradiol (E2)‐induced downregulation of B lymphopoietic cells in bone marrow of young ovariectomized mice can be mediated through both ER‐α and ER‐β. However, only ER‐α is required for the age‐related increased frequency of immunoglobulin M (IgM) SFC in the bone marrow, as well as for the increased production of interleukin‐10 (IL‐10) from cultured splenocytes in aged mice. Furthermore, increased age in WT mice resulted in lower levels of both pro‐ and pre‐B cells but increased frequency of IgM SFC in the bone marrow, as well as increased frequency of both IgM and IgA SFC in the spleen. Results from this study provide valuable information regarding the specific functions of ER‐α and ER‐β in the aged immune system.
The role of antigen‐presenting cells and interleukin‐12 in the priming of antigen‐specific CD4+ T cells by immune stimulating complexes
Authors: Robson Neil C. , Beacock‐Sharp Helen , Donachie Anne M. , Mowat Allan McI.
Published: August 2003

Immune stimulating complexes (ISCOMs) containing the saponin adjuvant Quil A are vaccine adjuvants that promote a wide range of immune responses in vivo, including delayed‐type hypersensitivity (DTH) and the secretion of both T helper 1 (Th1) and Th2 cytokines. However, the antigen‐presenting cell (APC) responsible for the induction of these responses has not been characterized. Here we have investigated the role of dendritic cells (DC), macrophages (Mφ) and B cells in the priming of antigen‐specific CD4+ T cells in vitro by ISCOMs containing ovalbumin (OVA). OVA ISCOMs pulsed bone marrow (BM)‐derived DC but not BM Mφ, nor naïve B cells prime resting antigen‐specific CD4+ T cells, and this response is greatly enhanced if DC are activated with lipopolysaccharide (LPS). Of the APC found in the spleen, only DC had the capacity to prime resting antigen specific CD4+ T cells following exposure to OVA ISCOMs in vitro, while Mφ and B cells were ineffective. DC, but not B cells purified from the draining lymph nodes of mice immunized with OVA ISCOMs also primed resting antigen‐specific CD4+ T cells in vitro, suggesting that DC are also critical in vivo. Using DC and T cells from interleukin (IL)‐12 p40−/− mice, we also identified a crucial role for IL‐12 in the priming of optimal CD4+ T cell responses by OVA ISCOMs. We suggest that DC are the principal APC responsible for the priming of CD4+ T cells by ISCOMs in vivo and that directed targeting of these vectors to DC may enhance their efficancy as vaccine adjuvants.
Inhibition of complement activation by recombinant Sh‐CRIT‐ed1 analogues
Authors: Oh Kwang‐Seok , Kweon Mee‐Hyang , Rhee Ki‐Hyeong , Ho Lee Keyong , Sung Ha‐Chin
Published: August 2003

Sh‐CRIT‐ed1 is a potent anti‐complement peptide that inhibits the classical complement‐activation pathway by interfering with the formation of the C3‐convertase complex, C4b2a. C2 is an essential serum glycoprotein that provides the catalytic subunit of the C3 and C5 convertases of the classical pathways of complement activation. Because only in its C4‐bound state is C2a capable of cleaving its physiological protein substrates C3 and C5, the interaction of Sh‐CRIT‐ed1 with C2 plays a decisive role of inhibition in the classical complement‐activation process. However, the role of individual Sh‐CRIT‐ed1 amino acid residues in C2 binding is not fully understood. We constructed nine recombinant Sh‐CRIT‐ed1 (rSh1) analogues, substituted at conserved residues, and evaluated their anti‐complement and C2‐binding activities. Results from glutathione S‐transferase (GST) pull‐down and haemolytic assays suggested that residues 10K, 17E, 19K and 26Y are critical for the interaction of rSh1 with C2. We then constructed an improved anti‐complement peptide by duplicating Sh‐CRIT‐ed1 C‐terminal motifs (17H–26Y). This linear homodimer (rH17d) was more potent than rSh1 with respect to binding to C2 and anti‐complement activity (the 50% inhibitory concentration value was ≈1·2 µm versus ≈6·02 µm for rSh1). Furthermore, rH17d showed higher anti‐complement activity in vivo, providing additional evidence that this duplication is a more effective inhibitor of complement activation than rSh1. Taken together, these results identify four key residues in rSh1 and strongly suggest that rH17d is a potent inhibitor of complement activation that may have therapeutic applications.
Inhibition of DC‐SIGN‐mediated trans infection of T cells by mannose‐binding lectin
Authors: Spear Gregory T. , Zariffard M. Reza , Xin Ji , Saifuddin Mohammed
Published: August 2003

Some dendritic cells (DC) express a cell‐surface lectin called ‘dendritic cell‐specific intracellular adhesion molecule 3 (ICAM‐3)‐grabbing non‐integrin’ (DC‐SIGN). DC‐SIGN has been shown to mediate a type of infection called ‘trans’ infection, where DC bind human immunodeficiency virus (HIV) and efficiently transfer the virus to T cells. We investigated the possibility that mannose‐binding lectin (MBL), a soluble lectin that functions as a recognition molecule in innate immunity and that binds to HIV, could block trans infection mediated by DC‐SIGN. Binding studies with glycoprotein (gp)120/gp41‐positive and ‐negative virus preparations suggested that DC‐SIGN and MBL bind primarily to glycans on gp120/gp41, as opposed to glycans on host‐cell‐derived proteins, indicating a close overlap in the binding site of the two lectins and supporting the notion that MBL could prevent binding of HIV to DC‐SIGN. Preincubation of X4, R5 or dual‐tropic HIV strains with MBL prevented DC‐SIGN‐mediated trans infection of T cells. The mechanism of MBL blocking trans infection of T cells was at least partly caused by blocking of virus binding to DC‐SIGN positive cells. This study shows that MBL prevents DC‐SIGN‐mediated trans infection of T cells in vitro and suggests that in infected persons, MBL may inhibit DC‐SIGN‐mediated uptake and spread of HIV.
Unimpaired dendritic cell functions in MVP/LRP knockout mice
Authors: Mossink Marieke H. , De Groot Jan , Van Zon Arend , Fränzel‐Luiten Erna , Schoester Martijn , Scheffer George L. , Sonneveld Pieter , Scheper Rik J. , Wiemer Erik A. C.
Published: August 2003

Dendritic cells (DCs) act as mobile sentinels of the immune system. By stimulating T lymphocytes, DCs are pivotal for the initiation of both T‐ and B‐cell‐mediated immune responses. Recently, ribonucleoprotein particles (vaults) were found to be involved in the development and/or function of human DCs. To further investigate the role of vaults in DCs, we examined the effects of disruption of the major vault protein (MVP/LRP) on the development and antigen‐presenting capacity of DCs, using our MVP/LRP knockout mouse model. Mononuclear bone marrow cells were isolated from wild‐type and knockout mice and stimulated to differentiate to DCs. Like human DCs, the wild‐type murine DC cultures strongly expressed MVP/LRP. Nevertheless, the MVP/LRP‐deficient DCs developed normally and showed similar expression levels of several DC surface markers. No differences were observed in in vitro studies on the antigen uptake and presenting capacities of the wild‐type and MVP/LRP knockout DCs. Moreover, immunization of the MVP/LRP‐deficient mice with several T‐cell antigens led to responses similar to those observed in the wild‐type mice, indicating that the in vivo DC migration and antigen‐presentation capacities are intact. Moreover, no differences were observed in the induction of the T cell‐dependent humoral responses and orally induced peripheral T‐cell tolerance. In conclusion, vaults are not required for primary DC functions. Their abundance in DCs may, however, still reflect basic roles in myeloid cell proliferation and DC development.
Cell activation by monosaccharide lipid A analogues utilizing Toll‐like receptor 4
Authors: Tamai Riyoko , Asai Yasuyuki , Hashimoto Masahito , Fukase Koichi , Kusumoto Shoichi , Ishida Hideharu , Kiso Makoto , Ogawa Tomohiko
Published: August 2003

Lipid A is the bioactive centre of lipopolysaccharide (LPS), and its properties exhibit various endotoxic and biological effects toward host cells. We examined whether Toll‐like receptors (TLRs) are mediated by the signals from various synthetic acylated derivatives of d‐glucosamine monophosphate. All test synthetic monosaccharide lipid A analogues similar to acylated β‐(1‐6)‐d‐glucosamine disaccharide bisphosphates, such as Escherichia coli‐type lipid A (compound 506) and its precursor (compound 406), clearly induced nuclear factor (NF)‐κB activation in Ba/F3 cells expressing murine TLR4 and its accessory protein MD‐2 (Ba/mTLR4/mMD‐2), but no induction was found in those expressing murine TLR2 (Ba/mTLR2). Compound 411, the non‐reducing sugar moiety of compound 506, exhibited interleukin‐8 (IL‐8) and tumour necrosis factor‐α (TNF‐α)‐producing activities in human peripheral blood mononuclear cells (PBMC), whereas compound 401, the reducing moiety of compounds 506 and 406, and Gifu lipid A‐46 (GLA‐46), the non‐reducing moiety of compound 406, induced no production of IL‐8 and TNF‐α, which was similar to the findings for compound 406. Among the synthetic triacylated monosaccharide lipid A analogues, some compounds with three tetradecanoyl (C14) groups or that included a dodecanoyl (C12) group were more active toward murine and human cells than were other analogues with a decanoyl (C10) or hexadecanoyl (C16) group. Furthermore, IL‐8 production in PBMC stimulated with the active monosaccharide lipid A analogues as well as compound 506 was clearly inhibited by the monoclonal antibody to human TLR4. These findings suggest that monosaccharide lipid A analogues similar to disaccharide lipid As are capable of activating both murine and human cells through TLR4.
The Bcl‐2 family pro‐apoptotic molecule, BNIP3 regulates activation‐induced cell death of effector cytotoxic T lymphocytes
Authors: Wan J. , Martinvalet D. , Ji X. , Lois C. , Kaech S. M. , Von Andrian U. H. , Lieberman J. , Ahmed R. , Manjunath N.
Published: August 2003

BNIP3 is a recently described pro‐apoptotic member of the Bcl‐2 family and in BNIP3 cDNA‐transfected cell lines, cell death occurs via a caspase‐independent pathway with opening of the mitochondrial permeability transition (PT) pore and rapid loss of mitochondrial transmembrane potential (Δψm). However, its expression or function in physiologic cell types is not known. Our results using the T‐cell receptor transgenic mice P14, specific for lymphocyte choreomeningitis virus (LCMV) glycoprotein, show that in contrast to the other Bcl‐2 family pro‐apoptotic molecules, BNIP3 is transcriptionally highly up‐regulated in effector cytotoxic T lymphocytes (CTL). Because CTL have a propensity to undergo activation‐induced cell death (AICD) upon restimulation, we tested for other features associated with BNIP3‐induced cell death. AICD of CTL was caspase‐independent as determined by measuring caspase activation during target cell killing as well as by lack of inhibition with caspase inhibitors. Moreover, similar to BNIP3‐induced cell death, CTL apoptosis was associated with increased production of reactive oxygen species and decreased Δψm. Finally, retroviral transduction of BNIP3 antisense RNA diminished AICD in effector CTL. These results suggest that BNIP3 may play an important role in T‐cell homeostasis by regulating effector CTL numbers.
Enhanced mucosal and systemic immune responses to Helicobacter pylori antigens through mucosal priming followed by systemic boosting immunizations
Authors: Vajdy Michael , Singh Manmohan , Ugozzoli Mildred , Briones Maylene , Soenawan Elawati , Cuadra Lina , Kazzaz Jina , Ruggiero Paolo , Peppoloni Samuele , Norelli Francesco , Del Giudice Giuseppe , O'Hagan Derek
Published: August 2003

It is estimated that Helicobacter pylori infects the stomachs of over 50% of the world's population and if not treated may cause chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and gastric B‐cell lymphoma. The aim of this study was to enhance the mucosal and systemic immune responses against the H. pylori antigens cytotoxin‐associated gene A (CagA) and neutrophil‐activating protein (NAP), through combinations of mucosal and systemic immunizations in female BALB/c mice. We found that oral or intranasal (i.n.) followed by i.m. immunizations induced significantly higher serum titres against NAP and CagA compared to i.n. alone, oral alone, i.m. alone, i.m. followed by i.n. or i.m. followed by oral immunizations. However, only oral followed by i.m. immunizations induced anti‐NAP antibody‐secreting cells in the stomach. Moreover, mucosal immunizations alone or in combination with i.m., but not i.m. immunizations alone, induced mucosal immunoglobulin A (IgA) responses in faeces. Any single route or combination of immunization routes with NAP and CagA preferentially induced antigen‐specific splenic interleukin‐4‐secreting cells and far fewer interferon‐γ‐secreting cells in the spleen. Moreover, i.n. immunizations alone or in combination with i.m. immunizations induced predominantly serum IgG1 and far less serum IgG2a. Importantly, we found that while both i.n. and i.m. recall immunizations induced similar levels of serum antibody responses, mucosal IgA responses in faeces were only achieved through i.n. recall immunization. Collectively, our data show that mucosal followed by systemic immunization significantly enhanced local and systemic immune responses and that i.n. recall immunization is required to induce both mucosal and systemic memory type responses.
Differences in cytokine synthesis by the sub‐populations of dendritic cells from afferent lymph
Authors: Stephens Sue A. , Brownlie Joe , Charleston Bryan , Howard Chris J.
Published: August 2003

Two phenotypically distinct subpopulations of dendritic cells (SIRPα+ CC81Ag− DC and SIRPα− CC81Ag+ DC) have previously been identified in bovine afferent lymph which show functional differences when assayed in vitro. The purpose of this study was to investigate whether differences in cytokine production between the two subpopulations might occur which could influence the bias of the immune response they stimulate. Qualitative and quantitative polymerase chain reactions were used to detect specific mRNA transcripts and flow cytometry and enzyme‐linked immunosorbent assays were used to detect protein production. The SIRPα− CC81Ag+ DC produced considerably more interleukin‐12 (IL‐12) mRNA transcripts and protein than the SIRPα+ CC81Ag− DC. Conversely, SIRPα+ CC81Ag− DC contained more of both transcripts and protein for IL‐1 and of transcripts for IL‐6. A small percentage of both subpopulations produced interferon‐γ (IFN‐γ) as evidenced by cytoplasmic staining. Stimulation of DC by culture with CD40L+ cells increased the production of IL‐1, IL‐6 and IL‐12 but quantitative differences between the subpopulations remained. Production of IL‐10 was also evident following culture with CD40L+ cells or lipopolysaccharide primarily by the SIRPα+ CC81Ag− DC. No evidence was found for type 1 IFN production, and hence plasmacytoid DC, by DC in afferent lymph; both subpopulations appear to be myeloid in origin. These different cytokine repertoires of the two subpopulations of ex vivo DC isolated from afferent lymph imply functional differences that could influence the presentation of antigen to T cells and bias of the immune response following vaccination or infection.
Arginase and autoimmune inflammation in the central nervous system
Authors: Xu Lingyun , Hilliard Brendan , Carmody Ruaidhrí J. , Tsabary Galit , Shin Hyunshun , Christianson David W. , Chen Youhai H.
Published: August 2003

Using a high throughput gene microarray technology that detects ∼22 000 genes, we found that arginase I was the most significantly up‐regulated gene in the murine spinal cord during experimental autoimmune encephalomyelitis (EAE). By Northern blot and arginase enzyme assay, we detected high levels of arginase I mRNA and protein, respectively, in the spinal cord of EAE mice, but not in the spinal cord of normal mice or mice that had recovered from EAE. In vitro, both microglia and astrocytes produced arginase and nitric oxide synthase, two enzymes that are involved in arginine metabolism. To explore the roles of arginase in EAE, we injected the arginase inhibitor amino‐6‐boronohexanoic acid (ABH) into mice during the inductive and effector phases of the disease. Compared with mice that received vehicle control, mice treated with ABH developed milder EAE with delayed onset, reduced disease score and expedited recovery. Spleen mononuclear cells from ABH‐treated mice produced more nitric oxide and secreted less interferon‐γ and tumour necrosis factor‐α as compared to control mice. These results indicate that arginase plays important roles in autoimmune inflammation in the central nervous system.
Allograft inflammatory factor‐1 regulates trinitrobenzene sulphonic acid‐induced colitis
Authors: Morohashi Taiki , Iwabuchi Kazuya , Watano Keiko , Dashtsoodol Nyambayar , Mishima Tetsuya , Nakai Yukihito , Shimada Shigeki , Nishida Ryutaro , Fujii Satoshi , Onoé Kazunori
Published: August 2003

The expression of allograft inflammatory factor‐1 (AIF‐1) in 2,4,6‐trinitrobenzene sulphonic acid (TNBS)‐induced colitis, a model for T helper 1 (Th1) type disease, was investigated in BALB/c mice. The AIF‐1 expression was significantly increased in the colitis lesion compared to that in the normal colon. We then prepared AIF‐1 transgenic mice (Tgm) with the BALB/c background that express high levels of AIF‐1 in lymphoid tissues and the colon. When AIF‐1 Tgm were administrated TNBS, the TNBS‐induced colitis was ameliorated compared with that in non‐transgenic littermates. The amelioration of colitis was associated with the low expression of interleukin‐1β in the colon. The present findings suggest that AIF‐1 regulates Th1‐type inflammatory responses.
RETRACTED: 5‐lipoxygenase knockout mice exhibit a resistance to acute pancreatitis induced by cerulein
Authors: Cuzzocrea Salvatore , Rossi Antonietta , Serraino Ivana , Di Paola Rosanna , Dugo Laura , Genovese Tiziana , Britti Domenico , Sciarra Giuseppe , De Sarro Angelina , Caputi Achille P. , Sautebin Lidia
Published: August 2003

Here we compare the degree of pancreatitis caused by cerulein in mice lacking 5‐lipoxygenase (5‐LO) and in the corresponding wild‐type mice. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for intracellular adhesion molecule‐1 (ICAM‐1), P‐selectin and E‐selectin in the pancreas and lung of cerulein‐treated mice. In contrast, the degree of (1) pancreatic inflammation and tissue injury (histological score), (2) up‐regulation/expression of P‐selectin, E‐selectin and ICAM‐1, and (3) neutrophil infiltration was markedly reduced in pancreatic and lung tissue obtained from cerulein‐treated 5‐LO‐deficient mice. These findings support the view that 5‐LO plays an important, pro‐inflammatory role in the acute pancreatitis caused by cerulein in mice.
Potential role of soluble CD40 in the humoral immune response impairment of uraemic patients
Authors: Contin Cécile , Pitard Vincent , Delmas Yahsou , Pelletier Nadège , Defrance Thierry , Moreau Jean‐François , Merville Pierre , Déchanet‐Merville Julie
Published: August 2003

CD40/CD154 interaction is essential for both humoral and cellular immune response. We investigated whether this interaction could be altered in patients with kidney failure who are known to present an impaired immune response. To that aim, we measured the levels of the soluble form of CD40 (sCD40), which is known to interfere with CD40/CD154 interaction, in 43 chronic renal failure patients, 162 hemodialysed patients, and 83 healthy donors. Uraemic and haemodialysed patients presented a three‐ and fivefold increase, respectively, of the antagonist soluble form of CD40 in their serum, when compared to healthy subjects. Serum sCD40 levels correlated with those of creatinine in uraemic non‐haemodialysed patients. While sCD40 is widely excreted in urine of healthy individuals, it is not eliminated by dialysis sessions on classic membranes. The return to a normal kidney function in nine haemodialysed patients who received renal transplantation, leads to a rapid decrease of serum sCD40 levels. This natural sCD40 exhibited multimeric forms and was able to inhibit immunoglobulin production by CD154‐activated B lymphocytes in vitro. Furthermore, the positive correlation we observed between the serum levels of sCD40 and the deficient response to hepatitis B vaccination in uraemic patients suggests that sCD40 also compromises the humoral response in vivo.
Facets of heat shock protein 70 show immunotherapeutic potential
Authors: Todryk Stephen M. , Gough Michael J. , Pockley A. Graham
Published: August 2003

Amongst the families of intracellular molecules that chaperone and assist with the trafficking of other proteins, notably during conditions of cellular stress, heat shock protein (hsp) 70 is one of the most studied. Although its name suggests that expression is exclusively induced during cellular hyperthermia, members of the hsp70 family of proteins can be constitutively expressed and/or induced by a range of other cellular insults. The ubiquitous presence of hsp70 in eukaryotic and prokaryotic cells, combined with its high degree of sequence homology and intrinsic immunogenicity, have prompted the suggestion that inappropriate immune reactivity to hsp70 might lead to pro‐inflammatory responses and the development of autoimmune disease. Indeed, hsp70 has been shown to be a potent activator of innate immunity and aberrant expression of hsp70 in certain organs promotes immunopathology. However, studies also suggest that hsp70 might have immunotherapeutic potential, as hsp70 purified from malignant and virally infected cells can transfer and deliver antigenic peptides to antigen‐presenting cells to elicit peptide‐specific immunity and, in contrast to its reported pro‐inflammatory effects, the administration of recombinant hsp70 can attenuate experimental autoimmune disease. This review focuses on the immunoregulatory capacity of hsp70 and its potential therapeutic value.
Heat shock protein derived from a non‐autologous tumour can be used as an anti‐tumour vaccine
Authors: Casey David G. , Lysaght Joanne , James Tharappel , Bateman Andrew , Melcher Alan A. , Todryk Stephen M.
Published: August 2003

Antigenic cross‐reactivity between certain tumours has allowed the development of more widely applicable, major histocompatibility complex‐disparate (allogeneic) whole‐cell vaccines. This principle should also allow heat shock proteins (hsp) derived from certain tumours (and carrying cross‐reactive antigens) to be used as vaccines to generate anti‐tumour immunity in a range of cancer patients. Here, hsp70 derived from gp70‐antigen+ B16 melanoma generated cytotoxic‐T‐lymphocyte‐mediated immune protection in BALB/c mice against challenge with gp70‐antigen+ CT26 colorectal tumour cells. Using ovalbumin as a model tumour antigen, it is shown that hsp70 enhances peptide re‐presentation by dendritic cells via class I over equimolar whole ovalbumin antigen. However, while transfection of tumour cells with inducible hsp70 increases hsp yield from tumours, it does not enhance antigen recognition via purified hsp70 nor via whole cells or their lysate.
Effects of fire and spruce beetle outbreak legacies on the disturbance regime of a subalpine forest in Colorado
Authors: Kulakowski Dominik , Veblen Thomas T. , Bebi Peter
Published: August 2003

Aim There is increasing research attention being given to the role of interactions among natural disturbances in ecosystem processes. We studied the interactions between fire and spruce beetle (Dendroctonus rufipennis Kirkby) disturbances in a Colorado subalpine forest. The central questions of this research were: (1) How does fire history influence stand susceptibility to beetle outbreak? And conversely, (2) How does prior occurrence of a beetle outbreak influence stand susceptibility to subsequent fire?

Methods We reconstructed the spatial disturbance history in a c. 4600 ha area by first identifying distinct patches in the landscape on aerial photographs. Then, in the field we determined the disturbance history of each patch by dating stand origin, fire scars, dates of mortality of dead trees, and releases on remnant trees. A geographical information system (GIS) was used to overlay disturbance by fire and spruce beetle.

Results and main conclusions  The majority of stands in the study area arose following large, infrequent, severe fires occurring in c. 1700, 1796 and 1880. The study area was also affected by a severe spruce beetle outbreak in the 1940s and a subsequent low‐severity fire. Stands that originated following stand‐replacing fire in the late nineteenth century were less affected by the beetle outbreak than older stands. Following the beetle outbreak, stands less affected by the outbreak were more affected by low‐severity fire than stands more severely affected by the outbreak. The reduced susceptibility to low‐severity fire possibly resulted from increased moisture on the forest floor following beetle outbreak. The landscape mosaic of this subalpine forest was strongly influenced by the interactions between fire and insect disturbances.