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OBJECTIVE - Leptin and tumor necrosis factor (TNF)-α are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis. RESEARCH DESIGN AND METHODS - In this study, fasting plasma leptin, soluble TNF-α receptor 2 (TNF-α-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 ± 12 years, BMI 30.1 ± 6.6 kg/m2), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality. RESULTS - At baseline, leptin and TNF-α-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P < 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P < 0.02). CONCLUSIONS - In middle-aged women, MCP-1/CCL2, leptin, and TNF-α-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-α-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect

The aim of this study was to assess the potential of gastrointestinal peptide plasma levels as biomarkers of radiation-induced digestive tract damage. To this end, plasma levels of substance P, GRP, motilin, PYY, somatostatin-28, gastrin, and neurotensin were followed for up to 5 days in pigs after a 16-Gy whole-body X-irradiation, completed by a histopathological study performed at 5 days. Each peptide gave a specific response to irradiation. The plasma levels of GRP and substance P were not modified by irradiation exposure; neither were those of motilin and PYY. Concerning gastrin, a 2–3-fold increase of plasma concentration was observed in pig, which presented the most important histological alterations of the stomach. The plasma levels of somatostatin, unchanged from 1 to 4 days after irradiation, was also increased by 130% at 5 days. In contrast, a diminution of neurotensin plasma levels was noted, firstly at 1 day (–88%), and from 3 days after exposure (–50%). The present study suggested that changes in gastrin and neuro tensin plasma levels were associated with structural alterations of the stomach and ileum, respectively, indicating that they may be relevant biological indicators of radiation-induced digestive damage to these segments.Key words: gastrin, neurotensin, somatostatin, PYY, substance P, irradiation.

To determine the effect of mixed neutron and gamma-irradiation on the bile acid pool, which may be a key factor in radiation-induced diarrhoea.The bile duct of pigs was catheterized to derive bile over several experimental weeks, both before and after a 5.9 Gy neutron and gamma-irradiation. After measurement of the volume and sampling, bile was returned to the pig via a duodenal catheter. Samples of bile were analysed by HPLC for their individual and total bile acid content. Blood samples were also collected for total bile acid determination.Bile flow was significantly decreased during the first 24h and after the fifth day post-irradiation. Whereas total bile acid concentration in bile was not altered, profiles of individual bile acids were significantly altered as early as the first post-irradiation day. Such modifications in these profiles resulted in a change of the properties of the bile acid pool. An increased proportion of dihydroxylated bile acids known to be more deleterious for the intestine was observed.Neutron and gamma-irradiation leads to modifications of bile acid profiles, which may partly explain radiation-induced diarrhoea by a coherent physiopathological mechanism.

This study investigates the timing of p53 mutations detected in the malignant cells of a Burkitt's lymphoma cell line (BRG-P) with respect to other maturation or transforming events. The BRG-P cell line, derived from an AIDS patient, was of special value since it displayed subclones that had undergone an isotype switch from IgM to IgA1 (BRG-M and BRG-A cells). BRG-M and BRG-A cells were characterized by the same monoclonal c-myc and VDJ rearrangements and by the expression of Ig receptors with specificity for a 45 kDa protein of human breast cells. Analysis of p53 mutations in the different BRG subclones showed that 1) BRG-M cells displayed 2 different p53 mutations in trans; since the original BL cells also showed the same mutations, this finding indicated that both occurred in vivo; 2) one of the p53 alleles of BRG-A cells was lost, while the other showed a mutation different from those seen in BRG-M cells; and 3) all 3 mutations observed in BRG-M or BRG-A cells resulted in the functional inactivation of the transcriptional activation function of p53. Together, our data demonstrate that p53 mutations were relatively late events during lymphomagenesis. Moreover, in view of the role of p53 in cell apoptosis, it is conceivable that BRG cells were subjected to a strong selective pressure that favored p53 inactivation. Such inactivation was possibly required to counterbalance other potentially apoptotic events, including the presence of a deregulated c-myc oncogene and signals delivered by the host environment in situ.

Because dendritic cells (DC) play a major role in the initiation of T cell-mediated immunity, we studied the effects of glucocorticoids, well-known inhibitors of the immune and inflammatory response, on the differentiation and maturation of human DC. DC were differentiated from human monocytes by culture with GM-CSF and IL-4 for 7 days with and without dexamethasone (Dex). Cells treated with Dex (10−8 M) (Dex-DC) developed a characteristic dendritic morphology; however, membrane phenotype analysis demonstrated that they were not fully differentiated. Dex-DC expressed low levels of CD1a and, unlike untreated cells, high levels of CD14 and CD16. Molecules involved in Ag presentation (CD40, CD86, CD54) were also impaired. In contrast, molecules involved in Ag uptake (mannose receptor, CD32) and cell adhesion (CD11/CD18, CD54) were up-regulated. After exposure to TNF-α or CD40 ligand, Dex-DC expressed lower levels of CD83 and CD86 than untreated cells. Dex-DC showed a higher endocytic activity, a lower APC function, and a lower capacity to secrete cytokines than untreated cells. Overall, these results indicate that DC differentiated in the presence of Dex are at a more immature stage. Moreover, Dex also partially blocked terminal maturation of already differentiated DC. In conclusion, our data suggest that glucocorticoids may act at the very first step of the immune response by modulating DC differentiation, maturation, and function.

The aim of this study was to discover whether MCP-1/CCL2, a CC chemokine able to attract macrophages, is expressed in human pancreatic cancer and how it modulates cancer progression. All primary tumors were tested, and 6 of 14 pancreatic cancer cell lines were constitutively secreted CCL2. Analysis of the regulation demonstrated that the expression of CCL2 was significantly elevated and in a synergistic manner by IFN-gamma, tumor necrosis factor alpha, and interleukin 1beta. By immunohistochemistry and in situ hybridization, CCL2 production was confirmed in neoplastic ducts from surgical specimens. Serum levels of CCL2 in pancreatic cancer patients were significantly higher than in normal healthy subjects (P0.0001). Patients with high circulating levels of CCL2 had significantly higher survival rate than low CCL2 producers. Serum CCL2 levels positively correlated with tumor macrophage infiltration and inversely correlated with tumor proliferative activity (Ki67 expression). A direct effect of CCL2 on tumor cells is to be excluded, either because primary tumors as well as cell lines have no detectable CCL2 receptor (CCR2) and because addition of CCL2 on tumor cells in vitro did not modify cell cycle progression or apoptosis. In vitro, a model of tumor microenvironment showed a direct antiproliferative and proapoptotic activity of monocytes toward pancreatic cancer cell, which is mediated at least in part by interleukin 1beta. Moreover, other proinflammatory cytokines such as tumor necrosis factor alpha and IFN-gamma appeared able to induce apoptosis and to reduce the proliferative rate of pancreatic cancer. On the whole, the results presented in our investigation suggest that CCL2 could be a relevant negative regulator of pancreatic cancer progression.

This paper demonstrates a multi-domain SDN orchestrator using delay information to provision network services using BGP-LS and a novel monitoring system enabled by Segment Routing. Moreover, it is the first implementation and interoperability of the BGP-LS extensions for TE metrics.

In Centralized Radio Access Networks (C-RANs) Baseband Units (BBUs) are decoupled from Remote Radio Units (RRUs) and placed in BBU Hotels. In this way baseband processing resources can be shared among RRUs, providing opportunities for radio coordination and cost/energy savings. However, the failure of a BBU Hotel can affect a large number of RRUs creating severe outages in the radio network. For this reason, the design of a resilient C-RAN is extremely important. This paper focuses on the survivable BBU Hotel placement problem in C-RANs with an optical wavelength division multiplexing (WDM) transport. We first propose an algorithm that jointly decides (i) the placement of a minimum number of BBU Hotels and (ii) solves the Routing and Wavelength Assignment (RWA) problem for the fronthaul connections, ensuring that each RRU is connected to two different BBU Hotels (i.e., one primary and one backup). Then, we present a strategy for maximizing the sharing of backup BBU ports among RRUs, with the aim of reducing the total cost of the C-RAN while guaranteeing uninterrupted service provisioning in case of single BBU Hotel failure. Simulation results show that the proposed strategy helps reducing the overall C-RAN cost. On the other hand, it becomes also evident that the sharing benefits can be maximized only in the presence of a transport network with enough wavelength resources to handle potential bottlenecks that may occur when BBU Hotels are placed quite far from RRUs.

We assess the benefits of centralizing service processing in a few high-scale data center locations within an operator infrastructure. Results show up to 74% less cost while provisioning latency and availability constrained services.

Tumor grading is a method to quantify the putative clinical aggressiveness of a neoplasm based on specific histological features. A good grading system should be simple, easy to use, reproducible, and accurately segregate tumors into those with low versus high risk. The aim of this review is to summarize the histological and, when available, cytological grading systems applied in veterinary pathology, providing information regarding their prognostic impact, reproducibility, usefulness, and shortcomings. Most of the grading schemes used in veterinary medicine are developed for common tumor entities. Grading systems exist for soft tissue sarcoma, osteosarcoma, multilobular tumor of bone, mast cell tumor, lymphoma, mammary carcinoma, pulmonary carcinoma, urothelial carcinoma, renal cell carcinoma, prostatic carcinoma, and central nervous system tumors. The prognostic relevance of many grading schemes has been demonstrated, but for some tumor types the usefulness of grading remains controversial. Furthermore, validation studies are available only for a minority of the grading systems. Contrasting data on the prognostic power of some grading systems, lack of detailed instructions in the materials and methods in some studies, and lack of data on reproducibility and validation studies are discussed for the relevant grading systems. Awareness of the limitations of grading is necessary for pathologists and oncologists to use these systems appropriately and to drive initiatives for their improvement.

The mannose receptor (MR) is an endocytic and phagocytic receptor belonging to the C-type lectin superfamily. A number of functions have been ascribed to this receptor, which is involved in innate and adaptive immune responses. The MR binds carbohydrate moieties on several pathogens, such as bacteria, fungi, parasites, and viruses, and, therefore, is considered a pattern recognition receptor (PRR). In addition, MR binds endogenous molecules and was originally described as a membrane-associated component binding lysosomal glycosidases in alveolar macrophages. Since its identification more than 25 years ago, many other endogenous ligands were described, including hormones, enzymes, cell membranes, extracellular matrix components, and normal as well as tumoral mucins. The MR is preferentially expressed on immune cells of myeloid lineage, especially subsets of dendritic cells (DC) and tissue macrophages. In addition to immune cells, specialized endothelial cells are also MR-positive. Increasing evidence shows that the MR is involved in the silent clearance of inflammatory molecules. In this review, we discuss current knowledge about the receptor and show that endogenous ligands activate an anti-inflammatory and tolerogenic program in DC and macrophages, thus reinforcing the hypothesis that the MR has an important role in the maintenance of homeostasis.

Network slicing is a technique widely used in 5G networks where multiple logical networks (i.e., slices) run over a single shared physical infrastructure. Each slice may realize one or multiple services, whose specific requirements are negotiated beforehand and regulated through Service Level Agreements (SLAs). In Beyond 5G (B5G) networks it is envisioned that slices should be created, deployed, and managed in an automated fashion (i.e., without human intervention) irrespective of the technological and administrative domains over which a slice may span. Achieving this vision requires a combination of novel physical layer technologies, artificial intelligence tools, standard interfaces, network function virtualization, and software-defined networking principles. This paper provides an overview of the challenges facing network slicing automation with a focus on transport networks. Results from a selected group of use cases show the benefits of applying conventional optimization tools and machine-learning-based techniques while addressing some slicing design and provisioning problems.

La prospettiva postsecolare di Habermas ha avuto un impatto significativo nel dare forma al dibattito circa il ruolo della religione nelle società plurali del nostro tempo. Tuttavia, mentre le democrazie sono attraversate da una nuova ondata di sfide interreligiose, sembra che la sua visione di cittadini religiosi e secolari che interagiscono discorsivamente in un processo di apprendimento e riconciliazione per via di traduzione e deliberazione debba essere rivisto e aggiornato. I limiti della visione habermasiana possono essere in parte spiegati con la sua prevalente concentrazione sulla tradizione giudaico-cristiana. Occorre chiedersi in che misura la pluralità di contesti teologico-politici - Induismo, Buddismo, Islam e altre tradizioni religiose - sia rilevante per la teoria democratica, allo scopo di allargare e ridefinire i termini degli approcci basati sulla ragione pubblica. Fino a che punto la visione habermasiana può, e dovrebbe, confrontarsi con le questioni della fede, della santità, del messianismo che ha finora escluso dal dominio della riflessione filosofica? Inoltre, nei suoi scritti più tardi, Habermas non sembra prendere a sufficienza in considerazione il rapporto fra religione, violenza e dominazione socio-economica. Ci si interroga dunque su come il suo modello deliberativo possa essere esteso per misurarsi con tali problemi e in quale misura postsecolarismo e capitalismo siano legati. Anche se la preoccupazione primaria di Habermas è stata il progetto politico europeo, la connessione fra i suoi interventi sull'Europa e la sua "svolta" religiosa rimangono insufficientemente esplorati. Qual è il significato e quali le conseguenze pratiche della ridefinizione da parte di Habermas del ruolo della religione in un'epoca di accelerazione del pluralismo, sia in Europa sia fuori dell'Europa? Lo scopo di questa Special Issue di Europea Legacy è quello di prendere in considerazione le diverse implicazioni, volontarie o meno, della visione habermasiana della religione. Più specificamente, si esaminano prospettive sul ruolo, l'ampiezza, e l'efficacia della ragione pubblica habermasiana quando messa a confronto con le nuove sfide del dialogo interreligioso e dell'integrazione nelle società democratiche. Habermas’ post-secular perspective of socio-political integration has had a major formative effect on the debate surrounding the place of religion in present-day pluralist societies. And yet as democracies are currently beset by a new wave of interfaith challenges it would seem that his vision of religious and non-religious citizens publicly engaging in a process of learning and reconciliation through cooperative translation and deliberation would need to be reconsidered and adjusted. This apparent shortcoming may partly be explained by the prevalent Judeo-Christian focus of Habermas’ deliberative model. To what extent, then, is the plurality of political theological contexts—Hinduism, Buddhism, Islam, and other religious traditions—significant for democratic theory today, for broadening and refining the public reason approach? Should and can the Habermasian vision address more directly the issues of faith, holiness, and Messianism that he has excluded from the philosophical domain? Moreover, in his later writings, Habermas does not seem to take sufficiently into account the relation between religion, violence, and socio-economic domination. The question is how his deliberative model could be extended to address such problems and to what extent post-secularism and capitalism are interconnected. Although Habermas’ primary concern has been the European political project, the connection between his European interventions and his religious “turn” remain insufficiently explored. What is the significance and what are the practical consequences of Habermas’ re-definition of the role of religion in an age of accelerated pluralisation both in Europe and beyond it? The aim of this Special Issue of the European Legacy is to take stock of the diverse intended and perhaps unintended implications of the Habermasian view of religion. More specifically, we are consider perspectives on the role, scope, and ability of Habermasian public reason to meet the new challenges of interreligious dialogue and integration in democratic societies.

Centralized radio access network (C-RAN) has been considered as an architectural solution able to reduce capital and operational expenditure in dense 5G cellular networks while allowing better network performance. The C-RAN approach decouples baseband units from antenna sites and places them in selected locations, connected by the so-called fronthaul links. These links require expensive high-capacity connections, thus calling for cost-efficient deployment. This paper presents a hybrid fronthaul solution for C-RAN based on both optical fibers and free-space optics (FSO) to enhance fronthaul flexibility and minimize deployment costs. Two design strategies based on integer linear programming are proposed for both greenfield and brownfield deployments. The first strategy is referred to as joint planning (JP) and is based on the joint minimization of the number of deployed remote radio heads (RRHs) and the cost of the hybrid fiber/FSO fronthaul. The second strategy is based on two-step disjoint planning (DP) that first identifies a cost-optimal RRH placement and then finds the corresponding minimum cost deployment for the fronthaul links. Results obtained with JP and DP are compared in dense urban area scenarios (i.e., with characteristics similar to festivals or concerts), highlighting the advantage of the JP approach compared to DP, both in terms of costs and an enhanced flexibility during the network design process.

R. Audi e J. Habermas, nonostante le reciproche differenze, condividono l'obiettivo di ripensare il rapporto fra discorso pubblico e appartenenze religiose, allo scopo di superare le inadeguatezze dello schema liberale tradizionale. Entrambi si occupano del tema dal punto di vista di una possibile etica della cittadinanza e ritengono sia cruciale la posizione epistemica che il discorso religioso occupa nella sfera pubblica. La proposta di Audi articola i confini normativi di un'etica pubblica degli argomenti politici di natura religiosa, in una prospettiva liberale ma moderatamente inclusiva. La riflessione di Habermas sembra più persuasiva nelle sue premesse, in quanto mette radicalmente in questione le condizioni epistemologiche del discorso pubblico nelle democrazie liberali. R. Audi and J. Habermas share, despite their mutual differences, the goal of rethinking the relationship between public discourse and religious inspirations in a new way, with the aim of overcoming the inadequacy of traditional liberal schemes. Both focus on the issue at stake from the point of view of a possible ethics of citizenship and find a key point in the epistemological position of religious discourse inside the public sphere. Audi’s proposal effectively offers normative boundaries to a public ethics of political arguments of religious nature, within a liberal but fairly inclusive perspective. Habermas’ reflection looks more persuasive at the level of premises, as it radically questions the epistemological issue behind public discourse in liberal democracies.

OBJECTIVE-Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4(+)CD25(+)FOXP3(+) T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs. RESEARCH DESIGN AND METHODS-nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation. RESULTS-We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4(+) CD25(-) effector T-cells compared with that before treatment. CONCLUSIONS-These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function. OBJECTIVE—Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4CD25FOXP3 T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs. RESEARCH DESIGN AND METHODS—nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation. RESULTS—We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4 CD25 effector T-cells compared with that before treatment. CONCLUSIONS—These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function. Diabetes 57:2341–2347, 2008

Immature monocyte-derived dendritic cells (DC) strongly express the endocytic mannose receptor (MR). Addition of a specific anti-MR mAb (clone PAM-1) for 24 h to cultures of immature DC induced phenotypical and functional maturation of the cells, assessed as up-regulation of costimulatory molecules and CD83, and chemotactic response to CCL19. A different isotype-matched anti-MR mAb (clone 19.2) had no significant effect. Engagement of MR with mAb PAM-1 induced the production of the anti-inflammatory cytokines IL-10, IL-1R antagonist, and of the nonsignaling IL-1R type II. In contrast IL-1β, TNF, and IL-12 were not produced. PAM-1-treated DC were unable to polarize Th1 effector cells and did not secrete the chemokines CXCL10 and CCL19; in turn, they produced large amounts of CCL22 and CCL17, thus favoring the amplification of Th2 circuits. T cells cocultured with PAM-1-matured DC initially proliferated but later became anergic and behaved as suppressor/regulatory cells. Natural ligands binding to MR had differential effects. MUC III (a partially purified mucin), biglycan (a purified complex proteoglycan), and mannosylated lipoarabinomannan from Mycobacterium tuberculosis affected cytokine production with high IL-10, IL-1R antagonist, IL-1R type II, and inhibition of IL-12. In contrast, mannan, dextran, and thyroglobulin had no significant effect. In conclusion, the appropriate engagement of the MR by mAb PAM-1 and selected natural ligands elicit a secretory program in mono-derived DC characterized by a distinct profile of cytokines/chemokines with the ability to dampen inflammation and to inhibit the generation of Th1-polarized immune responses.

We studied the effects of 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) on differentiation, maturation, and functions of dendritic cells (DC) differentiated from human monocytes in vitro in the presence of GM-CSF and IL-4 for 7 days. Recovery and morphology were not affected by 1α,25-(OH)2D3 up to 100 nM. DC differentiated in the presence of 10 nM 1α,25-(OH)2D3 (D3-DC) showed a marked decrease in the expression of CD1a, while CD14 remained elevated. Mannose receptor and CD32 were significantly increased, and this correlated with an enhancement of endocytic activity. Costimulatory molecules such as CD40 and CD86 were slightly decreased or nonsignificantly affected (CD80 and MHC II). However, after induction of DC maturation with LPS or incubation with CD40 ligand-transfected cells, D3-DC showed marginal increases in MHC I, MHC II, CD80, CD86, CD40, and CD83. The accessory cell function of D3-DC in classical MLR was also inhibited. Moreover, allogeneic T cells stimulated with D3-DC were poor responders in a second MLR to untreated DC from the same or an unrelated donor, thus indicating the onset of a nonspecific hyporesponsivity. In conclusion, our data suggest that 1α,25-(OH)2D3 may modulate the immune system, acting at the very first step of the immune response through the inhibition of DC differentiation and maturation into potent APC.

We have investigated the effect of glucocorticoids (GC) on antigen uptake molecule expression and on endocytic activity of human dendritic cells (DC). Human monocyte-derived DC were differentiated in vitro for 7 days with granulocyte macrophage colony stimulating factor and IL-4 in the presence or absence of dexamethasone 10(-8) M (Dex). Dex-treated DC showed an enhancement of mannose receptor (MR)-mediated endocytosis (measured as uptake of FITC-dextran) and of fluid-phase endocytosis [measured as uptake of Lucifer yellow (LY)] The effect was dose dependent and correlated with the length of exposure to Dex. The expression of receptors involved in antigen capture was investigated by FACS analysis. Dex up-regulates MR, CD16 and CD32 expression on DC. After maturation with tumor necrosis factor-alpha or CD40 ligand in Dex-treated DC, despite a reduction induced by maturation the endocytic activity of FITC-dextran and LY, the expression of MR, CD16 and CD32 remained higher than in control DC. In view of the fact that antigen capture was increased in cells cultured with Dex, we evaluated the ability to present soluble antigen that needs to be taken up and processed. Cells differentiated in the presence of Dex showed much lower efficiency in presenting tetanus toxin to specific autologous T cell lines. In conclusion our data suggest a new mechanism by which GC may influence immune responses. In fact with the increase in endocytic activity, Dex favors the scavenging of antigen from the external milieu, decreasing antigen concentration and availability, and simultaneously inhibiting the capacity to stimulate T cells.

The immunoregulatory function of NKT cells is crucial for prevention of autoimmunity. The prototypical NKT cell Ag α-galactosylceramide is not present in mammalian cells, and little is known about the mechanism responsible for NKT cell recruitment and activation. Up-regulation of CD1d, the NKT cell restriction molecule, expressed on mononuclear cells infiltrating the target organ, could represent the physiological trigger for NKT cells to self-contain T cell immunity and to prevent autoimmune disease. Recognition of CD1d, either by itself or bound to self-ligands (selfCD1d), could drive NKT cells toward an immunoregulatory phenotype. Hence, ineffective NKT cell-mediated immunoregulation in autoimmune-prone individuals including nonobese diabetic (NOD) mice could be related to defective signals that regulate CD1d expression at time and site of autoimmunity. To test this hypothesis, we transgenically overexpressed CD1d molecules under the control of the insulin promoter within the pancreatic islets of NOD mice (insCD1d). Recognition of overexpressed CD1d molecules rescued NKT cell immunoregulatory function and prevented autoimmune diabetes in insCD1d transgenic NOD mice. Protection from diabetes was associated with a biased IL-4-secreting cytokine phenotype of NKT cells and alteration of the cytokine microenvironment in the pancreatic lymph nodes of transgenic mice. The net effect was a reduced development of the autoimmune T cell repertoire. Our findings suggest that up-regulation of CD1d expression during inflammation is critical to maintain T cell homeostasis and to prevent autoimmunity.

There are a large number of stable pancreatic ductal carcinoma cell lines (PDCL) that are used by researchers worldwide. Detailed data about their differentiation status and genetic alterations are present in the literature, but a systematic correlation with cell biological behavior is often lacking. PDCL ( n=12) were clustered by source of tumor cell (ascites, primary tumor, metastasis), and the data of functional cell biology were correlated with the reported structural and genetic profiles. Major histocompatibility complex expression, chemosensitivity and aneuploidia appeared to be related to the source of PDCL, and proliferative capacity appeared to be related to the grade of differentiation. No correlation between genetic/structural features of PDCL and biological behavior was found. All the cell lines appeared generally insensitive to in vitro treatment with 5-fluorouracil and showed variable degrees of susceptibility to gemcitabine, raltitrexed and oxaliplatin. All the PDCL showed resistance to Fas-mediated apoptosis but were significantly sensitive to the pro-apoptotic effect of inflammatory cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha and interferon gamma]. PDCL were characterized for the secretion of several factors relevant to the tumor-immune cross talk. Vascular endothelial growth factor, CCL2, CCL5 and transforming growth factor beta were the factors most frequently released; less frequent was the secretion of CXCL8, CCL22, IL-6 and sporadically CXCL12, IL-10 and hepatocyte growth factor. The cytokines IL-1beta and TNFalpha were always undetectable. In conclusion, a clear correlation between structural/genetic features and function could not be detected, suggesting the weakness of a "morphological" classification for the in vitro studies of pancreatic cancer.