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Differences in genetic origin between nodal and extranodal diffuse large B-cell lymphomas (DLBCL) exist. Using population-based data from the registry of the Danish Lymphoma Group, the present study is the first to analyse clinical implications of nodal versus extranodal presentation of DLBCL. Of 4786 newly diagnosed non-Hodgkin's lymphoma patients in a 16-year period, 1575 (33%) had DLBCL. The annual incidence rate was 2·9 per 100 000; 40% were extranodal. The clinical profile of patients with extranodal DLBCL was different from the nodal DLBCL patients. Extranodal DLBCL was associated with older age and poorer performance score, but also lower tumour burden. In extranodal DLBCL, 51% of the cases were stage I and 36% were stage IV, whereas the patients were relatively equally distributed between the four stages in nodal DLBCL. For stage I patients, extranodal DLBCL was independently associated with poor survival ( P = 0·003). In contrast, among stage IV patients those with extranodal DLBCL survived longer ( P = 0·009). We conclude that there are important clinical differences between nodal and extranodal DLBCL. The addition of these clinical results to the existing aetiological and genetic data suggests that the distinction between nodal and extranodal DLBCL is not only pathogenetically but also clinically important. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ‛cross‐decoration'. In contrast, donor liver‐derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant‐relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti‐inflammatory miRNA species. In terms of function, liver‐derived EVs were able to cross‐decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration‐dependent fashion. In terms of cytokine response, the addition of 1 × 109 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF‐α, IL‐10 and IFN‐γ. In conclusion, we determined physiologically produced liver‐derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron‐dependent cell death form that initiates lipid peroxidation (LPO) in tumors. In recent years, there has been growing interest on ferroptosis, but how to propel it forward translational medicine remains in mist. Although experimental ferroptosis inducers such as RSL3 and erastin have demonstrated bioactivity in vitro, the poor antitumor outcome in animal model limits their development. In this study, we reveal a novel ferroptosis inducer, oxaliplatin–artesunate (OART), which exhibits substantial bioactivity in vitro and vivo, and we verify its feasibility in cancer immunotherapy. For mechanism, OART induces cytoplasmic and mitochondrial LPO to promote tumor ferroptosis, via inhibiting glutathione‐mediated ferroptosis defense system, enhancing iron‐dependent Fenton reaction, and initiating mitochondrial LPO. The destroyed mitochondrial membrane potential, disturbed mitochondrial fusion and fission, as well as downregulation of dihydroorotate dehydrogenase mutually contribute to mitochondrial LPO. Consequently, OART enhances tumor immunogenicity by releasing damage associated molecular patterns and promoting antigen presenting cells maturation, thereby transforming tumor environment from immunosuppressive to immunosensitive. By establishing in vivo model of tumorigenesis and lung metastasis, we verified that OART improves the systematic immune response. In summary, OART has enormous clinical potential for ferroptosis‐based cancer therapy in translational medicine. [ABSTRACT FROM AUTHOR]

This paper describes a procedure for analysing multiple antibody reactivities that explores a commercially available immunoblot system, and is based on a double staining of nitrocellulose membranes, revealing both antibody reactivities and the migration position of the blotted proteins in the membrane. Quantification of both stainings by densitometry allowed the accurate superposition of the immunoreactivity and total protein profiles of each lane. Moreover, the protein stainings of the different lanes could be adjusted with a simple-scale transformation algorithm, correcting for possible distortions during electrophoretic migration, and allowing for the precise comparison of the immunoreactivity profiles in different lanes. The procedure is discriminatory enough to identify unique reactivity patterns in random pools of 104 activated B cells, and to define strain-specific natural antibody repertoires. The utility of this immunoblot method as an assay for simultaneously scoring multiple reactivities to hundreds of antigens in complex mixtures of antibodies, and thus defining antibody repertoires in a global manner, is discussed. [ABSTRACT FROM AUTHOR]

Presents an overview of articles featured in the 2003 special issue of "APMIS," on dendritic cells (DC). Papers on the aspects of dendritic cell biology; Role of DC in the balance between T-cell immunity and tolerance; Functions and activities of DC.

Self-adjuvanting vaccines, consisting of recombinant protein antigens and covalently attached Toll-like receptor (TLR) agonists, have the ability to simultaneously and efficiently deliver antigen and TLR adjuvant to antigen presenting cells (APCs). Here, an enzyme-mediated ligation approach was used to overcome difficulties in producing homogeneous, molecularly defined self-adjuvanting vaccine products under native conditions. This process was optimized to allow the incorporation of the lipopeptide TLR2 agonist fibroblast-stimulating lipopeptide (FSL)-1 onto the N- or C-termini of recombinant protein antigens, employing the enzyme Staphylococcus aureus sortase A (SrtAsa) penta mutant. In addition, because SrtAsamediated ligations are reversible, a tryptophan zipper derived sequence was introduced into both reactants, which was demonstrated to improve ligation efficiency through the formation of a β-hairpin structure that hinders the reverse reaction. Finally, it was demonstrated that N- or C-terminal conjugation, and the incorporation of the β-hairpin structure, did not affect the TLR2-agonist activities of protein antigen TLR agonist conjugates. Overall, this SrtAsa-mediated ligation platform enabled production of antigen TLR2 agonist conjugates with enhanced ligation efficiency, with the conjugates demonstrating potent TLR2 signaling activation (EC50<1nM). [ABSTRACT FROM AUTHOR]

ABSTRACT Skin sensitization is a key endpoint for cosmetic ingredients, with a forthcoming ban for animal testing in Europe. Four alternative tests have so far been submitted to ECVAM prevalidation: (i) MUSST and (ii) h-Clat assess surface markers on dendritic cell lines, (iii) the direct peptide reactivity assay (DPRA) measures reactivity with model peptides and (iv) the KeratinoSensTM assay which is based on detection of Nrf2-induced luciferase. It is anticipated that only an integrated testing strategy (ITS) based on a battery of tests might give a full replacement providing also a sensitization potency assessment, but this concept should be tested with a data-driven analysis. Here we report a database on 145 chemicals reporting the quantitative endpoints measured in a U937- test, the DPRA and KeratinoSensTM . It can serve to develop data-driven ITS approaches as we show in a parallel paper and provides a view as to the current ability to predict with in vitro tests as we are entering 2013. It may also serve as reference database when benchmarking new molecules with in vitro based read-across and find use as a reference database when evaluating new tests. The tests and combinations thereof were evaluated for predictivity, and overall a similar predictivity was found as before on three-fold smaller datasets. Analysis of the dose-response parameters of the individual tests indicates a correlation to sensitization potency. Detailed analysis of chemicals false-negative and false-positive in two tests helped to define limitations in the tests but also in the database derived from animal studies. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Although the roles of each low-frequency immunocompetent cells such as dendritic cells (DCs), γδT cells, and Treg cells in induction of acute or chronic graft versus host disease (GVHD) have been discussed in several reports, there are few papers dealing with an evaluation of these immunocompetent cells together and simultaneously in patients with hematopoietic stem cell transplantation (HSCT) and explored the kinetics of these cells in association with GVHD. In the present study, we assessed the number of plasmacytoid DCs (pDCs), myeloid DCs (mDCs), γδT cells and Treg cells serially in patients who received allogeneic HSCT and analyzed the relationship of these cells with acute or chronic GVHD (cGVHD) by using flow cytometry. The percentages and numbers of pDCs, mDC1s and γδT cells were significantly lowered in the patients with acute GVHD (aGVHD) compared with those with no GVHD. On the contrary, the percentages and numbers of Treg cells were significantly elevated in the patients with aGVHD compared with those with no GVHD. As to the association with cGVHD, Treg cells were elevated in the patients with cGVHD, compared with those with no GVHD. The present study revealed an association of pDCs, mDCs, γδT cells and Treg cells with induction or treatment of GVHD. [ABSTRACT FROM AUTHOR]

• Introduction - Early history of the aortic ring model - Morphology of the angiogenic response - Source of microvessels in aortic cultures - Stimulatory effect of angiogenesis on cancer spread - Regulation of angiogenesis by the extracellular matrix - Role of integrin receptors in aortic angiogenesis - Paracrine regulation of angiogenesis: role of endogenous growth factors - Paracrine regulation of angiogenesis: role of resident macrophages and inflammatory cytokines and chemokines - Expression and function of neural related genes - Signal transduction pathways - Pericyte origin and recruitment mechanisms - Role of proteolytic enzymes in angiogenesis and vascular regression - Influence of genetic background and aging on angiogenic response - Adaptation of the aortic ring model to different species and vessel types - Limitations of the aortic ring assay • Summary and conclusion The aortic ring model has become one of the most widely used methods to study angiogenesis and its mechanisms. Many factors have contributed to its popularity including reproducibility, cost effectiveness, ease of use and good correlation with in vivo studies. In this system aortic rings embedded in biomatrix gels and cultured under chemically defined conditions generate arborizing vascular outgrowths which can be stimulated or inhibited with angiogenic regulators. Originally based on the rat aorta, the aortic ring model was later adapted to the mouse for the evaluation of specific molecular alterations in genetically modified animals. Viral transduction of the aortic rings has enabled investigators to overexpress genes of interest in the aortic cultures. Experiments on angiogenic mechanisms have demonstrated that formation of neovessels in aortic cultures is regulated by macrophages, pericytes and fibroblasts through a complex molecular cascade involving growth factors, inflammatory cytokines, axonal guidance cues, extracellular matrix (ECM) molecules and matrix-degrading proteolytic enzymes. These studies have shown that endothelial sprouting can be effectively blocked by depleting the aortic explants of macrophages or by interfering with the angiogenic cascade at multiple levels including growth factor signalling, cell adhesion and proteolytic degradation of the ECM. In this paper, we review the literature in this field and retrace the journey from our first morphological descriptions of the aortic outgrowths to the latest breakthroughs in the cellular and molecular regulation of aortic vessel growth and regression. [ABSTRACT FROM AUTHOR]

Obesity is becoming one of the most serious public health problems in industrialized societies, due to the profound changes in lifestyle, and notably in nutrition. Beside diabetes, cardiovascular diseases or hypertension, increased susceptibility to infection is one of the pathological consequences of being overweight. In this paper, we have assessed the influence of a high-fat diet (HFD) rich in saturated fatty acids on the immune system of DO11.10 mice, which are transgenic for a T-cell receptor specifically recognizing a peptide of ovalbumin. We showed that the specific T-cell immune response was impaired by high-fat feeding, and that the expression of this defect is different depending on whether T cells are naive or Ag experienced. Indeed, on in vitro ovalbumin stimulation, spleen T cells from naive HFD-fed transgenic mice showed proliferation similar to that of cells from standard diet (SD)-fed mice, but exhibited a strong inflammatory profile as shown by the markedly increased IFN- γ/IL-4 ratio. Inversely, spleen T cells from ovalbumin-immunized HFD mice were impaired in their Ag-dependent proliferation compared to cells from SD mice. By co-culture experiments, we showed that both T cells and antigen-presenting cells were involved in this impairment. Moreover, in ovalbumin-immunized HFD animals, a trend towards Th2 response was noted, compared to immunized SD mice. This data implies that naive T cells could participate actively in the low-grade systemic inflammation observed in overweight patients. Moreover, the impaired activity of Ag-experienced T cells could have major consequences both in defence against infection and/or in vaccination protocols. [ABSTRACT FROM AUTHOR]

Problem Multiparity status has been found to bring beneficial effects both to the maintenance of pregnancy and to the offspring; however, these effects have not been fully explained. We have previously reported that placentae obtained from multiparous females belonging to a syngeneic mouse crossbreeding showed an important increase in the number of placental macrophages, suggesting that they might constitute a protective subpopulation. Taking into account that macrophage-colony stimulating factor (M-CSF) and granulocyte-colony stimulating factor (G-CSF) have proved to modulate macrophage activity and that both factors and/or their receptors have been found at feto–maternal interface, in this paper we analyzed the presence of M-CSF and G-CSF in placental tissue employing the same multiparity mouse model in order to investigate the influence of parity status on local immunoregulation factors of macrophage activity. Method of study Three groups of mice (CBA/J × CBA/J) were analyzed: Primiparous Young, 3.0 ± 0.5 months old (PY); Primiparous Old, 8.5 ± 0.5 months old (PO) and Multiparous Old, 8.5 ± 0.5 months old, with three to four previous pregnancies (MO). The presence of M-CSF and G-CSF in placental tissue was analyzed by immunohistochemistry. Cytokeratin (CK) and vimentin (VIM) expression and PAS staining were also studied. Results The three groups showed a similar immunostaining pattern for M-CSF in the whole placental trophoblast, while the expression of G-CSF was significantly higher only in the spongy zone in the MO group. Furthermore, all the MO placentae showed 5–11 layers of cells adjacent to the decidua, where G-CSF and M-CSF were highly detected. Conversely, they constituted a thin layer in PY and PO placentae. These cells were proved to be CK(+) and VIM(−) thus demonstrating their trophoblast origin. In addition, the layers closer to the decidua were also PAS+ suggesting that they could be interstitial cells, a type of invading trophoblast. Conclusions In our mouse model, we observed an increase in the expression of G-CSF in placental spongiotrophoblast cells in multiparous females, which have been previously proposed as progenitors of the interstitial cells. Furthermore, this is the first report that indicates that parity status increases trophoblast invasion inducing a proliferative effect of the invading cells on the maternal tissue. We suggest that M-CSF and G-CSF secreted by these invading cells could favor the recruitment of macrophages to the trophoblast and might modulate their activity inducing a switch to a protective, non-inflammatory population. [ABSTRACT FROM AUTHOR]

By substituting the heavy chain constant region of IgM and IgD with that of IgG, IgA or IgE, immunoglobulin class switching endows antibodies with novel effector functions that enhance the ability of the immune system to effectively clear invading pathogens. Plasmacytoid dendritic cells critically link innate immunity with adaptive immunity by producing massive amounts of type 1 IFN in response to viruses. We have recently found that type 1 IFN triggers class switching by inducing myeloid dendritic cells to upregulate the expression of BAFF and APRIL, two powerful B cell-activating molecules. In this paper, we propose that IFN-producing plasmacytoid dendritic cells modulate class switching by activating B cells through both T cell-dependent and T cell-independent pathways. A better understanding of these pathways may facilitate the development of novel antiviral vaccine strategies and aid in identifying new therapies for antibody-mediated autoimmune disorders, such as lupus. [ABSTRACT FROM AUTHOR]

Aim: The pathophysiology of perinatal brain lesions is probably complex and multifactorial. The development and characterization of distinct yet complementary animal models should help to unravel the cellular and molecular mechanisms underlying perinatal brain lesions. This paper reviews experimental data obtained in animal models of neonatal excitotoxic brain lesions that closely mimic some of the lesions found in human cerebral palsy.Conclusion: Available data point to a key role for brain macrophages and oligodendrocytes in neonatal rodent excitotoxic brain lesions and underline the impact of cytokines on these lesions. [ABSTRACT FROM AUTHOR]

The epithelium is thought to serve an important barrier function in the airways. However, growing evidence now supports the notion that the respiratory epithelium plays a key role in host responses to infectious and allergenic stimuli. The epithelium functions to produce a variety of proinflammatory cytokines during the inflammatory response. More recently, the epithelium has been shown to express a variety of receptors that can recognize microorganisms, such as toll-like receptors(TLRs), as well as complement and acute phase proteins. Additionally, the cell surface of epithelial cells have also been shown to express a variety of costimulatory molecules which may be involved in regulating the activation of antigen-specific T cells in the airways. This paper reviews the novel ways by which the epithelium may function in both the innate and adaptive immune responses of the airways. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are potent antigen-presenting cells that likely play multiple roles in human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) pathogenesis. This paper describes the effects of pathogenic SIV infection on the networks of DCs in rhesus macaque (Macaca mulatta) intestinal tissues. Intestinal tissues were obtained from macaques at different stages of disease following infection with the pathogenic SIV/DeltaB670 isolate. The patterns and levels of expression of SIV and DC-associated mRNAs were examined and quantitated directly in intestinal tissue sections. In situ hybridization was performed for SIV, DC-specific ICAM3-grabbing non-integrin (DC-SIGN), DC-specific lysosome-associated membrane glycoprotein (DC-LAMP), DC-specific C-type lectin 1 (DECTIN-1), CC chemokine receptor 6 (CCR6), CCR7, and macrophage inflammatory protein 3α (MIP-3α/CCL20) mRNAs and quantitative image analysis was performed to measure mRNA expression levels. To identify the cell types productively infected by SIV, simultaneous in situ hybridization and immunohistochemical staining were performed. The DC networks in macaque intestinal tissues were found to be extensive and although they generally remained intact during the course of SIV infection, there were alterations in the expression of markers for immature DCs. One alteration was an increase in the expression in intestinal submucosa of DC-SIGN, a molecule that binds to HIV-1/SIV and increases its infectivity. Concomitant with this increase, it was found that during AIDS, the population of productively infected cells included DCs, based on co-expression of DC-SIGN and DECTIN-1 mRNAs. These data indicate that SIV infection affects subpopulations of macaque intestinal DCs, including productive infection of DC-SIGN+ DCs, the consequences of which are likely to be ongoing viral propagation and decreased immunostimulatory function. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

During the last decade use of dendritic cells (DC) has moved from murine and in vitro studies to clinical trials as adjuvant in cancer immunotherapy. Here they function as delivery vehicles for exogenous tumor antigens, promoting an efficient antigen presentation. The development of protocols for large-scale generation of dendritic cells for clinical applications has made possible phase I/II studies designed to analyze the toxicity, feasibility and efficacy of this approach. In clinical trials, DC-based vaccination of patients with advanced cancer has in many cases led to immunity and in selected patients to tumor regression. However, the majority of clinical trials are still in phase I, and interpretations are hampered by pronounced variation in study design related to technical aspects of DC preparation, treatment and schedule, monitoring of immune response, and clinically relevant endpoints, including toxicity and response evaluation. This paper aims to review the technical aspects and clinical impact of vaccination trials, focusing on the generation of DC-based vaccines, evaluation of immunologic parameters and design of clinical trials necessary to meet the need for good laboratory and clinical practice. [ABSTRACT FROM AUTHOR]

In this paper the phenomenon of suppression of proliferation in vitro of 14 day primed, West Nile Virus (WNV)-specific, murine CD4+ T cells by large numbers of antigen-presenting macrophages and B cells has been investigated. Suppression was apparently not mediated by prostaglandins, as the use of indomethacin in cultures at four times the usual concentration did not reverse suppression. Experiments were designed to evaluate the contribution of major histocompatibility complex (MHC) Class II and nominal WNV antigens in causing suppression of T cell proliferation. Listeria- or thioglycollate-induced macrophages from CBA/H (H-2k) mice, when treated with heat-killed Listeria in vitro for 1 h to maintain or increase, respectively, MHC Class II levels before the addition of alloreactive Iak-specific T cells caused inverse dose-responses; the highest T cell proliferation occurred at a stimulator to responder (S:R) ratio of 0.25 and profound suppression at a S:R ratio of 1 or 2. In contrast, untreated thioglycollate-induced macrophages, which express low MHC Class II levels, gave a direct dose-response with increasing T cell proliferation as antigen-presenting cell (APC) numbers increased. Addition of anti-Ia antibodies (or their Fab fragments) to cultures caused a significant reversal of suppression of anti-WNV T cells imposed by high numbers of Listeria-induced macrophages or 14 day WNV-primed B cell APC. Suppression was also reversed by reducing the concentration of WNV antigen. These observations support the notion that the suppression of T cell proliferation observed at high S:R ratios was due to high concentrations of ligand (WNV-derived peptide complexed with Class II MHC) on APC. [ABSTRACT FROM AUTHOR]

Recent studies have provided considerable insight into the mechanism of BCR-mediated B-cell activation, but the inhibitory signals transferred by FcγRs leading to down-regulation of BCR-activated B lymphocytes are not clarified yet. In the present paper the authors give an overview on new findings regarding BCR structure and signal transduction mechanisms induced by the B-cell antigen receptor complex and outline, partly based on their own observations, the possible mechanisms resulting in FcγR-mediated inhibition of B cells. [ABSTRACT FROM AUTHOR]

Given that the associative recognition of antigen (two signal) model permits a certain level of 'autoreactivity'. Faro & Carneiro argue that this unavoidable "autoreactivity" is required as part of the regulation of the general physiology of the animal. This paper gives the author's reply pointing out two facets of the functioning of the immune system. (I) Under an associative recognition of antigen model, the scenarios of B-cell activation postulated by them are ruled out. (2) There is no way to use a destructive ridding effector function to regulate the self/non-self discrimination because autoimmune reactivity would accompany any postulated regulatory mechanism. [ABSTRACT FROM AUTHOR]

This paper describes a model for investigation of the functional implications of B-cell activation for antigen presentation. Mixed lymphocyte cultures were used to assess the ability of freshly isolated B cells, mitogen-activated B cells and Epstein Burr virus (EBV)-transformed B-cell lines to stimulate the activation and proliferation of allogeneic T cells under a variety of experimental conditions. It was found that resting B cells presented antigen poorly, while activated cells were highly immunogenic. Paraformaldehyde fixation completely eliminated antigen presentation by resting B cells, despite constitutive expression of class II MHC antigens. However, fixation had little effect on antigen presentation by activated B cells that expressed B7-1 and B7-2 in addition to class II major histocompatibility complex (MHC) molecules. Arrest of B-cell activation by serial fixation after treatment with F(ab′)2 fragments of goat anti-human IgM produced cells with variable antigen-presenting capacity. Optimal antigen presentation was observed for cells fixed 72hr after the initiation of B-cell activation. Although both BT-1 and B7-2 antigen expression increased after B-cell activation, it was found that the rate of T-cell proliferation correlated most closely with B7-2 expression. Stimulation of T cells by fixed activated B lymphocytes could be blocked by antibodies directed at class II MHC molecules, indicating involvement of the T-cell antigen receptor. In addition, T-cell proliferation was inhibited by antibodies specific for B7-1 and B7-2 and by the fusion protein CTLA4-Ig, demonstrating a requirement for CD28 signal transduction. The sole requirement of B7 family expression for antigen presentation by B lymphocytes was shown by demonstration of T-cell stimulation by fixed resting B cells in the presence of CD28 antibody as a source of artificial costimulation. [ABSTRACT FROM AUTHOR]

This paper demonstrates that epidermal cells in culture produce an activity which can increase the frequency of Ia[sup+] epidermal Langerhans cells (LC). This was achieved by treating mice topically with a mixture containing supernatant derived from primary culture of murine epidermis (ES) and a synthetic corticosteroid, triamcinolone acetonide (TAC). The presence of the supernatant in the mixture partially protected the Ia[sup+] LC from depletion by the steroid. The la[sup+] LC frequency increasing activity was measured as the difference between the Ia [sup+] LC frequency due to treatment with steroid mixed with supernatant and the Ia[sup+] LC frequency due to treatment with steroid mixed with negative control medium. The mean frequency of Ia[sup+] LC in epidermis treated with TAC mixed with ES was 6O6(SD 43) cells/mm[sup2], as compared with 486 (SD 68) cells/mm[sup2] in the epidermis treated with TAC mixed with control medium. The activity appeared to be caused by (a) proteinaceous factor(s). A fraction of ES which was retained above a ≥ 10 KDa molecular weight cut-off membrane was capable of partially protecting Ia[sup+] LC frequency from TAC depletion. Supernatants from cultured lymph nodes, dermis as well as the squamous cell carcinoma lines T7 and T79, but not the human osteosarcoma cell-line 143B, also contained similar activities. We demonstrate that GM-CSF also increased the number of Ia epidermal LC when applied topically to mouse skin in this system. Therefore, using this Ia[sup+] LC frequency modulation system, we propose that GM-CSF is one example of a cytokine which may he involved in the regulation of Ia[sup+] LC numbers in epidermis and that epidermal cells produce factors which can increase the number of Ia[sup+] LC. [ABSTRACT FROM AUTHOR]

Dr. Gül and Dr. Öztürk accuse the letter by Dr. Polykretis of being "misinforming" and of containing some "basic errors", arguing on the definitions of genetic vaccines and autoimmunity. Rational harm-benefit assessments by age group are required for continued COVID-19 vaccination We read with interest the letter by Dr. Gül and Dr. Öztürk,[1] which comments about the previous letter by Dr. Polykretis.[2] The letter by Dr. Polykretis aimed to underline the differences between the genetic vaccines against COVID-19 and vaccines based on inactivated or attenuated viruses in terms of immunization mechanism. [Extracted from the article]

Wnt pathways are important for the modulation of tissue homeostasis, and their deregulation is linked to cancer development. Canonical Wnt signaling is hyperactivated in many human colorectal cancers due to genetic alterations of the negative Wnt regulator APC. However, the expression levels of Wnt‐dependent targets vary between tumors, and the mechanisms of carcinogenesis concomitant with this Wnt signaling dosage have not been understood. In this study, we integrate whole‐genome CRISPR/Cas9 screens with large‐scale multi‐omic data to delineate functional subtypes of cancer. We engineer APC loss‐of‐function mutations and thereby hyperactivate Wnt signaling in cells with low endogenous Wnt activity and find that the resulting engineered cells have an unfavorable metabolic equilibrium compared with cells which naturally acquired Wnt hyperactivation. We show that the dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and the mitochondrial phenotype of a given cell type in a context‐dependent manner. These findings illustrate the impact of context‐dependent genetic interactions on cellular phenotypes of a central cancer driver mutation and expand our understanding of quantitative modulation of oncogenic signaling in tumorigenesis. Synopsis: Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely capable of inducing primary immune responses. Although tumour cells may directly inhibit DC maturation, exposure to tumour products may also result in their activation. Fusions of cancer cells and DCs are being explored as cancer vaccines. The effect of tumour cell fusion on DC maturation and their functional characteristics has not been defined. In the present study, immature and mature DC generated from human CD34+ and peripheral blood precursors were fused to multiple myeloma cells in the presence of polyethylene glycol. Fusion of both immature and mature DCs with tumour cells resulted in an activated phenotype. In this regard, fusion cells expressed interleukin-12, a cytokine essential for the induction of T-helper cell type 1 immunity. In contrast to immature DCs, fusion cells also strongly expressed CC-chemokine receptor R7, which is responsible for DC migration to draining lymph nodes. Fusions generated with both immature and mature DCs also potently stimulated T-cell expression ofγ-interferon and cytotoxic T lymphocyte killing of tumour targets. These findings demonstrate that tumour cell fusion induces DC maturation and the development of an activated phenotype necessary for their effectiveness as cancer vaccines. [ABSTRACT FROM AUTHOR]

In this paper the authors propose an immune network which considers B cell interactions based on the immune response network of an organism. The authors modeled a network based on an immune mechanism which uses B cell interactions for an immune response network with interactions between B cells and T cells in an organism. They then created an immune network. Finally, the authors describe the validity of pattern recognition using their immune network by performing simulations on the proposed network. © 2001 Scripta Technica, Syst Comp Jpn, 32(10): 31–41, 2001 [ABSTRACT FROM AUTHOR]

Accurate recognition of antigens by specific T cells is crucial for adaptive immunity to work properly. The activation of a T‐cell antigen‐specific response by an antigen‐presenting cell (APC) has not been clearly measured at a single T‐cell level. It is also unknown whether the cell‐extrinsic environment alters antigen recognition by a T cell. To measure the activation probability of a single T cell by an APC, we performed a single‐cell live imaging assay and found that the activation probability changes depending not only on the antigens but also on the interactions of other T cells with the APC. We found that the specific reactivity of single naïve T cells was poor. However, their antigen‐specific reactivity increased drastically when attached to an APC interacting with activated T cells. Activation of T cells was suppressed when regulatory T cells interacted with the APC. These findings suggest that although the ability of APCs to activate an antigen‐specific naïve T cell is low at a single‐cell level, the surrounding environment of APCs improves the specificity of the bulk response. [ABSTRACT FROM AUTHOR]

Exercise‐released exosomes have been identified as novel players to mediate cell‐to‐cell communication in promoting systemic beneficial effects. This review aimed to systematically investigate the effects of exercise on exosome release and cargo, as well as provide an overview of their physiological implications. Among the 436 articles obtained in the database search (WOS, Scopus, and PubMed), 19 articles were included based on eligibility criteria. Results indicate that exercise promotes the release of exosomes without modification of its vesicle size. The literature has primarily shown an exercise‐driven increase in exosome markers (Alix, CD63, CD81, and Flot‐1), along with other exosome‐carried proteins, into circulation. However, exosome isolation, characterization, and phenotyping methodology, as well as timing of sample recovery following exercise can influence the analysis and interpretation of findings. Moreover, a large number of exosome‐carried microRNAs (miRNAs), including miR‐1, miR‐133a, miR‐133b, miR‐206, and miR‐486, in response to exercise are involved in the modulation of proliferation and differentiation of skeletal muscle tissue, although antigen‐presenting cells, leukocytes, endothelial cells, and platelets are the main sources of exosome release into the circulation. Collectively, with the physiological implications as evidenced by the ex vivo trials, the release of exercise‐promoted exosomes and their cargo could provide the potential therapeutic applications via the role of intercellular communication. [ABSTRACT FROM AUTHOR]

Alkylglycerols, inflammation products of cancerous tissues, are potent macrophage activating agents. A brief in vitro treatment (30 mm) of mouse peritoneal cells with a low concentration (50 ng/mL) of dodecylglycerol (DDG) in 10% foetal calf serum supplemented RPMI-1640 medium (FCS medium) activates macrophages for Fc-receptor mediated ingestion activity. A serum factor(s) was shown to be required for the activation of macrophages. When non-adherent cells were treated with rac-sn-1(3)-dodecylglycerol (DDG) in a serum free-0.1% egg albumin supplemented RPM1 medium (EA medium) for 30 mm and cultured in FCS medium for 2 h, the resultant conditioned medium contained a signal factor able to activate macrophages (macrophage activating factor). A conditioned medium prepared with electrophoresed serum α ₂-globulin fraction in EA medium markedly enhanced activation of macrophages. Incubation of DDG-treated non-adherent cell ghosts in EA medium containing α₂-globulin also produced the macrophage activating signal factor. Therefore, it is concluded that a serum factor in α ₂-globulin fraction is processed by pre-existing functions or enzymes of DDG-treated non-adherent cell membrane to yield a macrophage activating signal factor. [ABSTRACT FROM AUTHOR]

T-cell receptor stimulation induces the convergence of multivesicular bodies towards the microtubule-organizing centre (MTOC) and the polarization of the MTOC to the immune synapse (IS). These events lead to exosome secretion at the IS. We describe here that upon IS formation centrosomal area F-actin decreased concomitantly with MTOC polarization to the IS. PKCδ-interfered T cell clones showed a sustained level of centrosomal area F-actin associated with defective MTOC polarization. We analysed the contribution of two actin cytoskeleton-regulatory proteins, FMNL1 and paxillin, to the regulation of cortical and centrosomal F-actin networks. FMNL1 β phosphorylation and F-actin reorganization at the IS were inhibited in PKCδ-interfered clones. F-actin depletion at the central region of the IS, a requirement for MTOC polarization, was associated with FMNL1 β phosphorylation at its C-terminal, autoregulatory region. Interfering all FMNL1 isoforms prevented MTOC polarization; nonetheless, FMNL1 β re-expression restored MTOC polarization in a centrosomal area F-actin reorganization-independent manner. Moreover, PKCδ-interfered clones exhibited decreased paxillin phosphorylation at the MTOC, which suggests an alternative actin cytoskeleton regulatory pathway. Our results infer that PKCδ regulates MTOC polarization and secretory traffic leading to exosome secretion in a coordinated manner by means of two distinct pathways, one involving FMNL1 β regulation and controlling F-actin reorganization at the IS, and the other, comprising paxillin phosphorylation potentially controlling centrosomal area F-actin reorganization. Ab, antibody; AICD, activation-induced cell death; AIP, average intensity projection; APC, antigen-presenting cell; BCR, B-cell receptor for antigen; C, centre of mass; cent2, centrin 2; cIS, central region of the immune synapse; CMAC, CellTracker™ Blue (7-amino-4-chloromethylcoumarin); cSMAC, central supramolecular activation cluster; CTL, cytotoxic T lymphocytes; DAG, diacylglycerol; DGKα, diacylglycerol kinase α; Dia1, Diaphanous-1; dSMAC, distal supramolecular activation cluster; ECL, enhanced chemiluminescence; ESCRT, endosomal sorting complex required for traffic; F-actin, filamentous actin; Fact-low cIS, F-actin-low region at the centre of the immune synapse; FasL, Fas ligand; FMNL1, formin-like 1; fps, frames per second; GFP, green fluorescent protein; HBSS, Hank's balanced salt solution; HRP, horseradish peroxidase; ILV, intraluminal vesicles; IS, immune synapse; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; MIP, maximal intensity projection; MVB, multivesicular bodies; MTOC, microtubule-organizing centre; NS, not significant; PBL, peripheral blood lymphocytes; PKC, protein kinase C; PKCδ, protein kinase C δ isoform; PLC, phospholipase C; PMA, phorbol myristate acetate; Pol. Index, polarization index; pSMAC, peripheral supramolecular activation cluster; PSF, point spread function; ROI, region of interest; SD, standard deviation; shRNA, short hairpin RNA; SEE, Staphylococcus enterotoxin E; SMAC, supramolecular activation cluster; TCR, T-cell receptor for antigen; T-helper (Th); TRANS, transmittance; WB, Western blot. [ABSTRACT FROM AUTHOR]

Summary of main observation and conclusion: Herein, we report on a tumor nanovaccine LMNP@CM that enhances the process of antigen‐presenting by stimulating the immune system to uptake tumor antigens actively. The nanovaccine is comprised of polyethylene glycol modified liquid metal nanoparticles (LMNP) and tumor cell membranes (CM) as antigens. Under 808 nm irradiation, the photothermal conversion effect of injected LMNP can cause mild local inflammation, and subsequently induces antigen‐presenting cells active recruitment and facilitates cellular uptake of tumor antigens. Meanwhile, because of the immune adjuvant effect of metal materials, the nanovaccine LMNP@CM promotes the maturation and activation of antigen‐presenting cells and induces anti‐tumor immune response effectively. By priming the host immune recognition of tumor antigens, this nanovaccine displays prophylactic effects and significantly suppresses tumor growth in a mouse breast tumor model. The nanovaccine LMNP@CM represents a novel strategy of utilizing light‐controlled means to actively induce anti‐tumor immune processes, showing advanced therapeutic potentials and robust adaptability for treating multiple tumors by changing the loaded antigens. [ABSTRACT FROM AUTHOR]

CD279 is a cell surface protein predominantly expressed on T cells. Its ligands CD273 and CD274 are expressed on antigen‐presenting cells and tumors. CD279 has been shown to act as an important immune check point by inhibiting CD8 T cell activation, and antibodies against CD279 enhance T cell‐mediated cytotoxic function. However, whether CD279 has other functions in CD4 T cell homeostasis or in mediating T cell interactions with antigen‐presenting cells remains unclear. In the present study, we show that antibody‐mediated inhibition of CD279 reduces T cell survival in bone marrow in vivo. Unexpectedly, CD279 blockade also compromised regulatory T cell and macrophage interactions by reducing their contact time. The observation that the CD273 antagonist had little effect suggests that CD274 (the second ligand of CD279) plays a more central role in contact between conventional T cells (Tcon) and macrophages. The results of the present study suggest that both CD279 ligands contribute to the interaction length between T cells and macrophages as a mechanism of maintaining Treg homeostasis. Furthermore, CD273 and CD274 are not redundant ligands because CD274 may have unique effects on Tcon in this complex immune axis. Therefore, ligand selection for check point blockade as a tool for cancer immunotherapy has important implications with respect to anti‐tumor T cell activation and the avoidance of side effects. [ABSTRACT FROM AUTHOR]

Modulation of T‐cell immune functions by blocking key immune checkpoint protein interactions using monoclonal antibodies (mAbs) has been an innovative immunotherapeutic strategy. T‐cells are regulated by different checkpoint proteins at the immunological synapse including the B7 ligands (B7‐1 or CD80 and B7‐2 or CD86), which is discussed in this review. These ligands are typically expressed on antigen presenting cells and interact with CD28 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) receptors on T‐cells. Their interactions with CD28 trigger a costimulatory signal that potentiates T‐cell activation, function and survival in response to cognate antigen. In addition, their interactions with CTLA‐4 can also inhibit certain effector T‐cell responses, particularly in response to sustained antigen stimulation. Through these mechanisms, the balance between T‐cell activation and suppression is maintained, preventing the occurrence of immunopathology. Given their crucial roles in immune regulation, targeting B7 ligands has been an attractive strategy in cancer and autoimmunity. This review presents an overview of the essential roles of B7‐1, highlighting the therapeutic benefits of modulating this protein in immunotherapy, and reviewing earlier and state‐of‐the‐art efforts in developing anti‐B7‐1 inhibitors. Finally, we discuss the challenges facing the design of selective B7‐1 inhibitors and present our perspectives for future developments. [ABSTRACT FROM AUTHOR]

A novel myeloid antigen presenting cell can be generated through in vitro haematopoiesis in long‐term splenic stromal cocultures. The in vivo equivalent subset was recently identified as phenotypically and functionally distinct from the spleen subsets of macrophages, conventional (c) dendritic cells (DC), resident monocytes, inflammatory monocytes and eosinophils. This novel subset which is myeloid on the basis of cell surface phenotype, but dendritic‐like on the basis of cell surface marker expression and antigen presenting function, has been tentatively labelled "L‐DC." Transcriptome analysis has now been employed to determine the lineage relationship of this cell type with known splenic cDC and monocyte subsets. Principal components analysis showed separation of "L‐DC" and monocytes from cDC subsets in the second principal component. Hierarchical clustering then indicated a close lineage relationship between this novel subset, resident monocytes and inflammatory monocytes. Resident monocytes were the most closely aligned, with no genes specifically expressed by the novel subset. This subset, however, showed upregulation of genes reflecting both dendritic and myeloid lineages, with strong upregulation of several genes, particularly CD300e. While resident monocytes were found to be dependent on Toll‐like receptor signalling for development and were reduced in number in Myd88‐/‐ and Trif‐/‐ mutant mice, both the novel subset and inflammatory monocytes were unaffected. Here, we describe a novel myeloid cell type closely aligned with resident monocytes in terms of lineage but distinct in terms of development and functional capacity. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 16-year-old White female from Ukraine who had been suffering from severe pruritic inflammatory dermatosis that affected her back and posterior neck area. It notes that the patient's histological examination revealed heterogeneity of morphological features, reflecting three distinct phases of Prurigo pigmentosa.

The major histocompatibility complex (MHC; 6p21.3) contains the most polymorphic genes, the most gene dense parts, and the highest diversity of functional gene clusters of the human genome. The clusters form haplotypes, which differ in linkage disequilibrium and show large variations in strength and extent between populations. Haplotype cis‐ and trans‐expression quantitative trait loci have increased the knowledge of regulatory interactions between multiple MHC genes. The detailed haplotype data offer a reference for future studies in immune‐mediated diseases and may unravel disease associations in conditions traditionally considered not to be immunologic. This article aims to describe the structural and functional variations of the MHC genes and haplotypes and their role on selected immune‐mediated diseases. In immune‐/inflammation‐mediated complex diseases, hundreds of common variants influence the development of the disease trait, but the individual variants have small effects on the disease phenotypes as seen in genome‐wide association studies. The genetic influence may still be significant on the cellular or molecular level. Nonetheless, the HLA alone is not sufficient as a susceptible genetic background to deduce the disease. For a comprehensive insight of the disease mechanisms, both immunological and genome assays methods are required. [ABSTRACT FROM AUTHOR]

Summary: Major histocompatibility complex class II (MHC‐II) molecules are expressed on the surface of professional antigen‐presenting cells where they display peptides to T helper cells, which orchestrate the onset and outcome of many host immune responses. Understanding which peptides will be presented by the MHC‐II molecule is therefore important for understanding the activation of T helper cells and can be used to identify T‐cell epitopes. We here present updated versions of two MHC–II–peptide binding affinity prediction methods, NetMHCII and NetMHCIIpan. These were constructed using an extended data set of quantitative MHC–peptide binding affinity data obtained from the Immune Epitope Database covering HLA‐DR, HLA‐DQ, HLA‐DP and H‐2 mouse molecules. We show that training with this extended data set improved the performance for peptide binding predictions for both methods. Both methods are publicly available at www.cbs.dtu.dk/services/NetMHCII-2.3 and www.cbs.dtu.dk/services/NetMHCIIpan-3.2. [ABSTRACT FROM AUTHOR]

Background Allergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Dendritic cells ( DCs) initiate immune responses to common aeroallergens, and ADAM10 has been demonstrated to be important for the development of adaptive responses. This study's objective was to understand the role of ADAM10 on DCs in the development of allergic and anaphylactic responses. Methods In this study, we used mouse models of allergic airway inflammation (house dust mice and Alternaria alternata) and OVA-induced models of active anaphylaxis to determine the DC-specific function of ADAM10 and Notch signaling. To examine TH1 and TH17 immunity infection with Anaplasma phagocytophilum and Citrobacter rodentium respectively, were used. Results Mice, which have ADAM10 deleted from DCs, have dramatic reductions in IgE production and do not develop significant TH2 immune responses. Further, ADAM10 DC−/− mice are resistant to IgE-mediated anaphylaxis. This response is selective for TH2 immunity as TH1 and TH17 immunity is largely unaffected. Notch1, a known ADAM10 substrate, when knocked out of DCs (Notch1 DC−/−) demonstrated a similar reduction in anaphylaxis and IgE. Without ADAM10 and Notch1 signaling, DCs were unable to make cytokines that stimulate TH2 cells and cytokines. Anaphylaxis and allergic lung inflammation were restored in ADAM10 DC−/− with the overexpression of the Notch1-intracellular domain, confirming the role of Notch signaling. Conclusions Targeting ADAM10 and Notch1 on DCs represent a novel strategy for modulating TH2 immune responses and IgE production. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors, including those targeting CTLA-4/B7 and the PD-1/ PD-L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell-mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the 'don't-eat me' signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter-receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47- SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47- SIRPα axis may also promote antigen-presenting cell function and thereby stimulate adaptive T cell-mediated anti-cancer immunity. The development of CD47- SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47- SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47- SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field. [ABSTRACT FROM AUTHOR]

Aims We recently identified the presence of Rosai-Dorfman-type histiocytes ( RDH) in sinonasal tissue removed from individuals with eosinophilic chronic rhinosinusitis ( ECR). We sought to determine their clinical significance. Methods and results Sinonasal biopsies from 10 individuals (index cases) with classical features of ECR and the additional finding of RDH were collected during a two-and-a-half-year period. Twenty-one sinonasal biopsies with a diagnosis of ECR accrued during a 6-month period were reviewed at one institution to assess the presence of this phenomenon in archived material. Five of the 10 index cases were recurrent; in four of these in which archival material was available, three had RDH on review. Of the 21 review cases, 52% contained RDH. Six of the review cases represented recurrent disease and in five of these RDH were demonstrable. Archival material was available from five cases that recurred, RDH being demonstrable in three. RDH were seen to persist across multiple recurrences. Conclusions The presence of RDH within ECR samples is associated highly with recurrence. RDH have properties of antigen-presenting cells and may play a hitherto unrecognized role in the initiation and persistence of ECR. [ABSTRACT FROM AUTHOR]

Blastic plasmacytoid dendritic cell neoplasm ( BPDCN) is a rare haematological malignancy derived from the precursors of plamacytoid dendritic cells, with an aggressive clinical course and high frequency of cutaneous and bone marrow involvement. Neoplastic cells express CD4, CD43 (also termed SPN), CD45 RA and CD56 (also termed NCAM1), as well as the plasmacytoid dendritic cell-associated antigens CD123 (also termed IL3 RA), BDCA-2 (also termed CD303, CLEC4E) TCL1 and CTLA1 (also termed GZMB). The median survival is only a few months as the tumour exhibits a progressive course despite initial response to chemotherapy. The best modality of treatment remains to be defined. Generally, patients receive acute leukaemia-like induction, according to acute myeloid leukaemia ( AML)-type or acute lymphoid leukaemia ( ALL)-type regimens. The frequent neuromeningeal involvement indicates systematic pre-emptive intrathecal chemotherapy in addition to intensive chemotherapy. Allogeneic haematopoietic stem cell transplantation ( HSCT), particularly when performed in first remission, may improve the survival. Preliminary data suggest a potential role for immunomodulatory agents and novel targeted drugs. Herein epidemiology, clinical manifestations, diagnosis and management of BPDCN will be presented. In detail, this review focuses on the therapeutic aspects of BPDCN, proposing a treatment algorithm for the management of the disease, including induction chemotherapy, allogeneic HSCT and intrathecal prophylaxis at different steps of treatment, according to compliance, biological and clinical characteristics of patients. [ABSTRACT FROM AUTHOR]

Relapsed or refractory (R/R) diffuse large B-cell lymphoma ( DLBCL) in those unfit or ineligible for autologous stem cell transplantation is associated with a poor outcome and new treatment approaches are needed. Pixantrone is a novel aza-anthracenedione which is structurally similar to anthracyclines and is licenced in R/R DLBCL and National Institute for Health and Care Excellence ( NICE)-approved following the PIX301 trial. No data exist post- NICE approval. We performed a UK-wide retrospective multi-centre study of 92 R/R DLBCL who received pixantrone. Eighty-five per cent had refractory disease and 72% had an international prognostic index ( IPI) 3-5 at commencement of pixantrone. The median progression-free survival ( PFS) was 2·0 months (95% confidence interval ( CI) 1·5-2·4) and the median overall survival was 3·4 months (95% CI 2·7-4·5). The overall response rate was 24% (complete response 10%; partial response 14%). We demonstrate that pixantrone has limited activity in a cohort of high risk, predominantly refractory DLBCL. Multivariate Cox regression revealed that patients who relapsed >12 months after first line treatment, those with fewer prior lines of therapy and relapsed (non-refractory) DLBCL had improved PFS. The major population of unmet need are those with refractory DLBCL who are poorly represented within trials and in whom pixantrone appears less efficacious compared to relapsed DLBCL. [ABSTRACT FROM AUTHOR]

Paediatric B-cell non-Hodgkin lymphoma (B- NHL) compromises a heterogeneous group of histological entities of which Burkitt lymphoma is the most common. In resource-rich countries, the expected cure rate is in excess of 85% with application of risk-adapted short intensive chemotherapy. In recent years, large paediatric cooperative group trials have sought to improve upon outcomes by decreasing the intensity of cytotoxic treatment as well as introducing targeted therapies, such as rituximab. These efforts have resulted in excellent outcomes, however there remains a group of high-risk patients for whom novel treatment approaches are needed. In this review, we will summarize the recent paediatric clinical trials in B- NHL as well as compare treatment approaches across the major cooperative groups. We will also highlight our current understanding of the molecular biology of paediatric B- NHL with a focus on how this may help guide future rational targeted therapy. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies are essential therapeutics and diagnostics in a large number of diseases. Moreover, they are essential tools in all sectors of life sciences. Although the great majority of monoclonal antibodies currently in use are of mouse origin, the use of human B cells to generate monoclonal antibodies is increasing as new techniques to tap the human B cell repertoire are rapidly emerging. Cloned lines of immortalized human B cells are ideal sources of monoclonal antibodies. In this review, we summarize our studies to the regulation of the replicative life span, differentiation, and maturation of B cells that led to the development of a platform that uses immortalization of human B cells by in vitro genetic modification for antibody development. We describe a number of human antibodies that were isolated using this platform and the application of the technique in other species. We also discuss the use of immortalized B cells as antigen-presenting cells for the discovery of tumor neoantigens. [ABSTRACT FROM AUTHOR]

Mycosis fungoides ( MF) starts as an indolent disease, progresses from a patch stage to confluent plaques and ultimately develops skin tumors. Tumor-associated macrophages ( TAMs) play roles in maintaining the tumor microenvironment in MF. The purpose of this study was to elucidate the involvement of TAMs in the lesional skin of different stages of MF. First, we immunohistologically examined the percentage of CD163+ macrophages and CD206+ cells, as well as the levels of periostin and IL-4 in cancer stroma. The percentage of CD206+ cells increased in parallel with tumor progression, while there was no significant difference in the percentage of CD163+ cells. Periostin was prominent in the stromal area at the patch and plaque stages but decreased at the tumor stage. In contrast, IL-4 was prominently stained at both plaque and tumor stages. To further elucidate the molecular mechanisms of the effects of these stromal factors on TAMs, we examined their effects on mRNA expression in monocyte-derived macrophages in vitro. Based on microarray analysis and gene ontology, we examined a series of chemokines and MMPs whose expression was strongly connected with periostin stimulation. The DNA microarray results were verified in M2 macrophages using real-time PCR. We further examined the mRNA expression of these chemokines and MMPs in the presence of periostin and IL-4 to simulate the advanced stages of MF and validated their protein expression by ELISA. Our present report suggests possible roles of periostin on TAMs in establishing the tumor microenvironment in MF. [ABSTRACT FROM AUTHOR]

The lymphatic system works in close collaboration with the cardiovascular system to preserve fluid balance throughout the body and is essential for the trafficking of antigen-presenting cells and lymphocytes to lymphoid organs. Recent findings have associated lymphatic dysfunction with the pathogenesis of cardiovascular-related diseases such as atherosclerosis, inflammation and obesity. Whether lymphatic dysfunction is a cause or a consequence of these diseases, as well as how, is under intensive investigation. Extracellular vesicles (EVs) are submicron vesicles released by diverse cell types upon activation or apoptosis and are considered important biomarkers for several inflammatory diseases. Thus, it is critical to characterize the presence of EVs in various biological tissues and fluids to delineate their origins and, subsequently, their functions. In the past few years, new techniques allowing the quantitative and qualitative analysis of EVs have emerged, thus facilitating the onset of studies bridging these vesicles to the lymphatic system. Using several state-of-the-art approaches, this article reports the presence of diverse EVs inclusively derived from red blood cells and platelets in lymph of healthy animals. Our results suggest that lymph from atherosclerotic mice displays a higher concentration of EVs, bringing forward the concept that EVs contained in lymph could either be a biomarker for lymphatic dysfunction or, conversely, for inflammatory disease progression. [ABSTRACT FROM AUTHOR]

Sixty-three dogs with newly diagnosed lymphoma underwent complete staging and received the same chemotherapy. Diffuse large B-cell lymphoma was the leading histotype (44.4%), followed by peripheral T-cell lymphoma (20.6%). Indolent lymphomas accounted for 30.2% of cases. Most dogs with aggressive B-cell lymphoma had stage IV disease. Dogs with indolent and aggressive T-cell lymphoma had more often stage V disease and were symptomatic. Liver and bone marrow were predominantly involved in B-cell and T-cell lymphoma, respectively. The clinical stage was significantly related to substage, sex and total lactic dehydrogenase ( LDH) levels. Aggressive B-cell lymphomas were more likely to achieve remission. Median survival was 55 days for aggressive and indolent T-cell lymphoma, 200 and 256 days for indolent and aggressive B-cell lymphoma, respectively. The prognosis of advanced indolent lymphoma does not appear to be appreciably different from that of aggressive disease. Familiarity with the various histotypes is critical to make the correct diagnosis and drive therapy. [ABSTRACT FROM AUTHOR]

Self-amplifying mRNAs ( SAM®) are a novel class of nucleic acid vaccines, delivered by a non-viral delivery system. They are effective at eliciting potent and protective immune responses and are being developed as a platform technology with potential to be used for a broad range of targets. However, their mechanism of action has not been fully elucidated. To date, no evidence of in vivo transduction of professional antigen-presenting cells ( APCs) by SAM vector has been reported, while the antigen expression has been shown to occur mostly in the muscle fibres. Here we show that bone-marrow-derived APCs rather than muscle cells are responsible for induction of MHC class-I restricted CD8 T cells in vivo, but direct transfection of APCs by SAM vectors is not required. Based on all our in vivo and in vitro data we propose that upon SAM vaccination the antigen is expressed within muscle cells and then transferred to APCs, suggesting cross-priming as the prevalent mechanism for priming the CD8 T-cell response by SAM vaccines. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase ( IDO) is expressed in antigen-presenting cells and exerts immunosuppressive effects on CD4+ T cells. One mechanism is through the inhibition of aerobic glycolysis. Another prerequisite for T-cell proliferation and differentiation into effector cells is increased fatty acid ( FA) synthesis. The effect of IDO on enzymes involved in FA synthesis was evaluated in primary human cells both in mixed lymphocyte reactions in the presence or not of the IDO inhibitor 1- dl-methyl-tryptophan, and in stimulated CD4+ T cells in the presence or not of the general control non-derepressible 2 ( GCN2) kinase activator tryptophanol ( TRP). IDO or TRP inhibited cell proliferation. By assessing the level of GCN2 kinase or mammalian target of rapamycin complex 1 substrates along with a kynurenine free system we showed that IDO exerts its effect mainly through activation of GCN2 kinase. IDO or TRP down-regulated ATP-citrate lyase and acetyl coenzyme A carboxylase 1, key enzymes involved in FA synthesis. Also, IDO or TRP altered the expression of enzymes that control the availability of carbon atoms for FA synthesis, such as lactate dehydrogenase-A, pyruvate dehydrogenase, glutaminase 1 and glutaminase 2, in a way that inhibits FA synthesis. In conclusion, IDO through GCN2 kinase activation inhibits CD4+ T-cell proliferation and down-regulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD4+ T-cell proliferation and differentiation into effector cell lineages. [ABSTRACT FROM AUTHOR]

There are three questions under re-examination here that have been inspired by Bretscher's 'Two-step, Two-signal' model. First, what is the nature of the steps required in order for antigen-responsive cells to become effectors? Second, how does the immune system get started? Third and the most troublesome, what is the mechanism that relates the delivery of the two signals? To answer the first question, Bretscher proposes a pathway that I will place in another context by comparing it with what had been envisaged under the Associative Recognition of Antigen (ARA) model. The second question, how does the immune system gets started, is crucial to our understanding of the self-non-self discrimination. This problem boils down to, what is the origin of the first effector T helper (eTh) cells required to activate all antigen-responsive cells including the T helpers themselves (the primer problem)? To deal with this question, I proposed an antigen-independent pathway to primer eTh. Bretscher presents us with an antigen-dependent pathway to primer eTh. As competing models are precious in clarifying thinking and in guiding experimentation, I felt it important to reanalyse the two models and look for ways to decide between them. The third question deals with the requirement for and the mechanism of associative (linked) recognition of antigen (ARA). The concept of ARA is so compelling at both the experimental and theoretical levels that to save it, a new perspective will be introduced. [ABSTRACT FROM AUTHOR]

Filarial infection in humans is initiated when a mosquito deposits third-stage parasite larvae (L3) in the skin. Langerhans cells ( LCs) and dermal dendritic cells ( DDCs) are the first cells that the parasite encounters, and L3s must evade these highly effective antigen-presenting cells to establish infection. To assess LC and DDC responses to L3 in human skin, we employed three models of increasing physiologic relevance: in vitro-generated LCs, epidermal blister explants and full-thickness human skin sections. In vitro-generated LCs expressed TLR1-10 and robustly produced IL-6 and TNF-α in response to PolyI:C, but pre-exposure to L3s did not alter inflammatory cytokine production or TLR expression. L3s did not modulate expression of LC markers CDH1, CD207, or CD1a, or the regulatory products TSLP or IDO in epidermal explants or in vitro-generated LC. LC, CD14+ DDC, CD1c+ DC and CD141+ DC from human skin sections were analysed by flow cytometry. While PolyI:C potently induced CCL22 production in LC, CD1c+ DC, and CD141+ DC, and IL-10 production in LC, L3s did not modulate the numbers of or cytokine production by any skin DC subset. L3s broadly failed to activate or modulate LCs or DDCs, suggesting filarial larvae expertly evade APC detection in human skin. [ABSTRACT FROM AUTHOR]