Search

The precise identification of the types and respective roles of the tumor-associated myeloid cells, which include tumor-associated Mϕs (TAMs), neutrophils, dendritic cells, and myeloid-derived suppressor cells, is under intensive investigation. Although tumor-associated myeloid cells may contribute to tumor cell eradication by virtue of their effector functions, they are retained to fulfill predominantly protumorigenic roles. It follows that depletion of tumor-associated myeloid cells represents one of the currently pursued therapeutic options in advanced malignancies. In that regard, RG7155/emactuzumab, a specific anti-CSF-1R humanized Ab, has been reported recently to deplete CSF-1R+ TAMs, in association with objective clinical responses in patients with advanced cancer. Because RG7155/emactuzumab has also been shown to deplete blood non-classic CD14dim/−CD16++ monocytes, which in large part include the CD16++slan+ monocytes, we asked whether RG7155/emactuzumab could target tumor-associated slan+ cells. In this study, we confirmed that slan+ cells localize only to metastatic tumor-draining lymph nodes, not to primary tumors or distant metastases in patients with different types of carcinoma. Notably, by cell scoring on serial sections, we found that slan+ cells represent a minor fraction of the total CSF-1R+ cell pool, suggesting that slan+ cells potentially represent minor targets of anti-CSF-1R therapy. Therefore, a protumorigenic role for slan+ cells, such as that of CSF-1R+TAMs, based on our current data, remains questionable.

We evaluated CA19-9 as a marker of various malignancies and compared the results of 2 commercial immunoassays. The Abbott ARCHITECT i2000 and Roche cobas 410 immunoassays were used on 500 consecutive samples to evaluate the frequency of positive results by cancer type and the correlation between assays. The patients were tested before or after surgery and/or during chemotherapy. The rate of results exceeding conventional thresholds was 92.3% in pancreatic cancer, 36.8% in gastric cancer, and ranged from 3.0% to 35.9% in other tumors. Agreement (90.6%) and correlation (R(2) = 0.865) between the 2 assays were good and the frequency of highly discordant results was low (6/500). In some cases, interference by heterophilic antibodies was demonstrated. The 2 methods were comparable in diagnostic accuracy and had good correlation but are not interchangeable. Patients should always be monitored for CA19-9 with the same method and it should be indicated in the report.

The X-ray variations of hard state black hole X-ray binaries above 2 keV show 'hard lags', in that the variations at harder energies follow variations at softer energies, with a time-lag \tau depending on frequency \nu approximately as \tau \propto \nu^{-0.7}. Several models have so far been proposed to explain this time delay, including fluctuations propagating through an accretion flow, spectral variations during coronal flares, Comptonisation in the extended hot corona or a jet, or time-delays due to large-scale reflection from the accretion disc. In principle these models can be used to predict the shape of the energy spectrum as well as the frequency-dependence of the time-lags, through the construction of energy-dependent response functions which map the emission as a function of time-delay in the system. Here we use this approach to test a simple reflection model for the frequency-dependent lags seen in the hard state of GX 339-4, by simultaneously fitting the model to the frequency-dependent lags and energy spectrum measured by XMM-Newton in 2004 and 2009. Our model cannot simultaneously fit both the lag and spectral data, since the relatively large lags require an extremely flared disc which subtends a large solid angle to the continuum at large radii, in disagreement with the observed Fe K\alpha emission. Therefore, we consider it more likely that the lags > 2 keV are caused by propagation effects in the accretion flow, possibly related to the accretion disc fluctuations which have been observed previously.

We use the XMM-Newton EPIC-pn instrument in timing mode to extend spectral time-lag studies of hard state black hole X-ray binaries into the soft X-ray band. We show that variations of the disc blackbody emission substantially lead variations in the power-law emission, by tenths of a second on variability time-scales of seconds or longer. The large lags cannot be explained by Compton scattering but are consistent with time-delays due to viscous propagation of mass accretion fluctuations in the disc. However, on time-scales less than a second the disc lags the power-law variations by a few ms, consistent with the disc variations being dominated by X-ray heating by the power-law, with the short lag corresponding to the light-travel time between the power-law emitting region and the disc. Our results indicate that instabilities in the accretion disc are responsible for continuum variability on time-scales of seconds or longer and probably also on shorter time-scales.

CD8+ T cells modulate neutrophil apoptosis and surface marker expression via TNF-α, IFN-γ and GM-CSF, while CD4+ T cells effects involve IFN-γ and GM-CSF. Neutrophils and T cells often co-infiltrate pathological tissues, which suggests that these 2 cell types may interact with each other. Over the years, in vitro studies have demonstrated that neutrophils and T cells are capable of modulating each otherˈs responses. However, few studies have examined the cross-talk between human neutrophils and CD8+ T cells, although murine models clearly show the critical role of their interaction in bacterial infections and cancer. Herein, we evaluated the interaction between human neutrophils and CD8+ T cells in a coculture system using highly purified cell preparations and compared the responses to ones from cocultures of neutrophils and CD4+ T cells. We report that anti-CD3-activated CD4+ and more potently, anti-CD3-activated CD8+ T cells modulate apoptosis and expression of activation markers by neutrophils, and neutrophils have no or little effect on T cell survival, expression of surface markers, and cytokine release. The observed effects of CD8+ T cells on neutrophils were mainly attributable to the release of TNF-α, IFN-γ, and GM-CSF, and the effects of CD4+ T cells involved IFN-γ and GM-CSF production. This study expands our knowledge of the molecular bases, whereby human CD4+ and CD8+ T cells modulate neutrophil survival and antigen expression.

The immune system is equipped with a plethora of mechanisms that protect the host from the harmful effects of environmental insults. However, the traditional “hierarchical” view of the immune response, in which innate, “nonspecific” cells are first recruited to the site of damage, before the highly “specific”, adaptive immune response develops, has been questioned recently. First, the innate response is much more specific than recognized previously: indeed, each cell of the innate system is not only endowed with an ever-expanding array of germ-line-encoded receptors, which differentiate between distinct insults, but also is modulated continuously by other leukocytes that concomitantly interact with and respond to that particular insult. The other reason is that the cells of the innate system are instrumental for the adaptive system to accomplish its function, as they can also modulate the activity of lymphocytes reciprocally during the entire course of the immune response. This complex pattern of interactions is illustrated by recent advances on the functions of PMNs, clearly showing that unexpectedly, these cells also contribute to the regulation of the host immune response by crosstalk with innate and adaptive leukocytes, including NK cells. Herein, given the peculiar role of neutrophils and NK cells in inflammation, clearance of pathogens/viral-infected cells, and cancer immunosurveillance, we summarize the current knowledge about the mechanisms whereby neutrophils and NK cells interact and regulate the activities of one another, as well as discuss their potential implications involved in the pathogenesis of chronic, inflammatory pathologies, infections, and tumors.

We have shown previously that the che- mokine receptors CXCR3 and CXCR6 are coex- pressed by Th1 cells infiltrating the lung and the granuloma of patients with sarcoidosis. In this study, we evaluated the role of CCL20/CCR6 in- teraction in the pathogenesis of acute and chronic pulmonary sarcoidosis. By flow cytometry and mo- lecular analyses, we have demonstrated that Th1 cells isolated from the bronchoalveolar lavage (BAL) of patients with sarcoidosis and T cell alve- olitis are equipped with CCR6. Furthermore, CCR6 T cells coexpressed the chemokine recep- tors CXCR3 and CXCR6. Immunohistochemical analysis of lung specimens has shown that CCR6 T cells infiltrate lung interstitium and surround the central core of the granuloma. It is interesting that CCR6 was never detected on the alveolar macro- phage (AM) surface, and it is observed in the cyto- plasm of AMs from patients with sarcoidosis and alveolitis. The CCR6 ligand CCL20 was expressed by macrophages, multinucleated giant cells, and epithelioid cells infiltrating the granuloma. Fur- thermore, detectable levels of CCL20 protein are seen in the BAL fluid components of patients with active sarcoidosis, and sarcoid AMs release the CCR6 ligand in vitro. From a functional point of view, sarcoid Th1 cells were able to respond to CXCL10, CXCL16, and CCL20 in migratory as- says. In vitro kinetic studies demonstrated that CCR6 is induced rapidly by IL-2, IL-18, and IFN-. In conclusion, T cells expressing CCR6, CXCR3, and CXCR6 act coordinately with respec- tive ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease. J. Leu- koc. Biol. 82: 946-955; 2007.

Contrary to their traditional characterization as terminally differentiated effectors of inflammation, neutrophils are remarkably versatile cells. Indeed, their capacity to change phenotype under specific circumstances, their active involvement in the regulation and resolution of inflammation, their response to a wide variety of cytokines and chemotactic molecules, and their regulatory role in angiogenesis and tumor fate have made it clear that they represent far more than “short-lived cells devoid of transcriptional activities, that only release preformed mediators and kill pathogens”. The multiple and amazing functional capacities of this cell type are also illustrated by the fact that the neutrophil may function as an important source of cytokines, at levels comparable with and in some cases, higher than those made by other leukocytes. To date, the families of cytokines, which in vitro or in vivo have been convincingly reported as being produced by neutrophils, include proinflammatory/anti-inflammatory cytokines, immunoregulatory cytokines, chemokines, angiogenic/fibrogenic factors, and tumor necrosis factor (TNF) superfamily members. The latter molecules are multifaceted cytokines whose integrated actions not only influence the development, homeostasis, and adaptive responses of many cells and tissue types but are also implicated in the antitumoral response. The recent findings that neutrophils produce in a finely regulated manner a TNF superfamily member involved in tumor cell killing and autoimmunity, namely TNF-related apoptosis-inducing ligand, open an additional perspective to exploit neutrophils for novel roles in anticancer responses and modulation of autoimmune diseases.

Neutrophils are versatile cells, which play a role, not only in inflammatory processes but also in immune and antitumoral responses. Recently, we have reported that interferon (IFN)-activated neutro- phils are able to release biologically active tumor necrosis factor (TNF)-related apoptosis-inducing li- gand (TRAIL/APO2 ligand), a molecule exerting se- lective, apoptotic activities toward tumor and virus- infected cells, as well as immunoregulatory functions on activated T lymphocytes. Herein, we show that only a minor fraction of the total TRAIL, newly syn- thesized by IFN-activated neutrophils within 24 h, is released outside, the rest being retained intracellu- larly, mainly in secretory vesicles and light mem- brane fractions. We demonstrate that the intracellu- lar pool of TRAIL present in IFN-pretreated neutro- phils is rapidly mobilizable to the cell surface and can be secreted following exposure to proinflammatory mediators such as TNF-, lipopolysaccharide, formyl- methionyl-leucyl-phenylalanine, CXC chemokine li- gand 8/interleukin-8, insoluble immunocomplexes, and heat shock protein Gp96. These various proin- flammatory agonists functioned as effective secreta- gogue molecules only, in that they failed to augment TRAIL mRNA expression or TRAIL de novo synthe- sis in freshly isolated neutrophils or cultured with or without IFN. In addition, supernatants from IFN- treated neutrophils stimulated with proinflammatory mediators induced the apoptosis of target cells more effectively than supernatants from neutrophils acti- vated with IFNs alone. Collectively, our results un- cover a novel mechanism, whereby the release of soluble TRAIL by neutrophils can be greatly ampli- fied and further reinforce the notion that neutrophils are important cells in tumor surveillance and immunomodulation. J. Leukoc. Biol. 79: 123-132; 2006.

This study examined the establishment of neutrophilic inflammation in humans. We tested the hypotheses that neutrophil recruitment was associated with local CXCL8 production and that neutrophils themselves might contribute to the regulation of the size of the inflammatory response. Humans were challenged i.d. with endotoxin. Biopsies of these sites were examined for cytokine production and leukocyte recruitment by qPCR and IHC. Additional in vitro models of inflammation examined the ability of neutrophils to produce and sequester cytokines relevant to neutrophilic inflammation. i.d. challenge with 15 ng of a TLR4-selective endotoxin caused a local inflammatory response, in which 1% of the total biopsy area stained positive for neutrophils at 6 h, correlating with 100-fold up-regulation in local CXCL8 mRNA generation. Neutrophils themselves were the major source of the early cytokine IL-1β. In vitro, neutrophils mediated CXCL8 but not IL-1β clearance (90% clearance of ≤2 nM CXCL8 over 24 h). CXCL8 clearance was at least partially receptor-dependent and modified by inflammatory context, preserved in models of viral infection but reduced in models of bacterial infection. In conclusion, in a human inflammatory model, neutrophils are rapidly recruited and may regulate the size and outcome of the inflammatory response through the uptake and release of cytokines and chemokines in patterns dependent on the underlying inflammatory stimulus.

Spectre a haute resolution de Mira Ceti obtenu par l'IUE le 7 juillet 1983. Les resultats confirment la presence de raies d'emission larges, et on ne detecte aucune raie d'emission etroite