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The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers pubished in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers published in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. [ABSTRACT FROM AUTHOR]

[Display omitted] The recent ongoing outbreak of coronavirus disease 2019 (COVID-19), still is an unsolved problem with a growing rate of infected cases and mortality worldwide. The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is targeting the angiotensin-converting enzyme 2 (ACE2) receptor and mostly causes a respiratory illness. Although acquired and resistance immunity is one of the most important aspects of alleviating the trend of the current pandemic; however, there is still a big gap of knowledge regarding the infection process, immunopathogenesis, recovery, and reinfection. To answer the questions regarding "the potential and probability of reinfection in COVID-19 infected cases" or "the efficiency and duration of SARS-CoV-2 infection-induced immunity against reinfection" we critically evaluated the current reports on SARS-CoV-2 immunity and reinfection with special emphasis on comparative studies using animal models that generalize their finding about protection and reinfection. Also, the contribution of humoral immunity in the process of COVID-19 recovery and the role of ACE2 in virus infectivity and pathogenesis has been discussed. Furthermore, innate and cellular immunity and inflammatory responses in the disease and recovery conditions are reviewed and an overall outline of immunologic aspects of COVID-19 progression and recovery in three different stages are presented. Finally, we categorized the infected cases into four different groups based on the acquired immunity and the potential for reinfection. In this review paper, we proposed a new strategy to predict the potential of reinfection in each identified category. This classification may help to distribute resources more meticulously to determine: who needs to be serologically tested for SARS-CoV-2 neutralizing antibodies, what percentage of the population is immune to the virus, and who needs to be vaccinated. [ABSTRACT FROM AUTHOR]

• We first described the S.maltophilia immunosuppressive effect on T cells and it is meaningful for immunosuppressed patients or co-infections. • T cells stimulated by S.maltophilia with CD4 and CD8 degraded via PD-1/PD-L1 pathway, which led to the massive apoptosis of T cells. • T cells were stimulated by S. maltophilia to secrete IFN-γ. Blocking the PD-1/PD-L1 pathway, apoptosis was suppressed. • S.maltophilia down-regulates host immunity by inhibiting immune cells. Smalotrophomonas maltophilia (S. maltophilia) is common in nosocomial infections. However, few studies have revealed the effect of S. maltophilia on cellular immunity in the host's immune system up to now. In clinical work, we accidentally discovered that S. maltophilia directly stimulated T cells to secrete IFN-γ. S. maltophilia was co-cultured with PBMCs to detect secretion of cytokines (IFN-γ, TNF-α and IL-2) and expression of cell surface molecules (CD3, CD4, CD8, CD69, CD147 and CD152) of T cells. We used light microscopy and electron microscopy to observe the cell morphology and subcellular structure of S. maltophilia co-cultured with lymphocytes. Flow cytometry and Western Blot were used to detect the expression of PD-1/PD-L1 and annexin V in cells. T cells stimulated by S. maltophilia secreted a large amount of IL-2, IFN-γ, and TNF-α. The expression of CD4 and CD8 on the cell surface were declined, accompanied by the activation of the PD-1/PD-L1 pathway, which eventually led to the massive apoptosis of T cells. Electron microscopy showed that cells showed significant apoptotic morphology. Blocking the PD-1/PD-L1 pathway can inhibit the apoptosis-inducing effect of S. maltophilia on T cells. These indicates that T cells are inhibited after being stimulated by S. maltophilia , and then accelerated to induce death without the initiation of an immunologic cascade. This paper demonstrates for the first time the inhibitory effect of S. maltophilia on cellular immunity, and the immunosuppressive effect induced by infection of S. maltophilia should be considered. [ABSTRACT FROM AUTHOR]

Despite the clinical success of immune checkpoint blockade, only a subset of people exhibits durable responses, suggesting that an alternative immunotherapeutic strategy is required. This paper reported a two-in-one cancer vaccine that targets programmed death ligand 1 (PDL1) that blocks the PD1/PDL1 pathway and also activates antitumor immune response. The PDL1- NitraTh vaccine, which consists of the extracellular domain of PDL1 and nitrated T cell epitope, effectively broke the immune tolerance of PDL1 and elicited PDL1-specific humoral and cellular immunity. The treatment of PDL1-NitraTh exhibited potent antitumor activity. Moreover, immunization of PDL1 vaccine increased the infiltration of tumor lymphocytes and decreased the proportion of Treg cells in tumor tissues, suggesting that the vaccine may remodel the tumor microenvironment. The upregulation of PDL1 in tumor tissues was induced by PDL1-NitraTh vaccine but not in spleen and lymphomas. This upregulation of PDL1 is beneficial to the antitumor activity of PDL1-specific humoral and cellular immunity induced by PDL1-NitraTh. In summary, PDL1-targeted vaccine exhibits potent antitumor activity and may provide an alternative immunotherapy strategy for patients who are not sensitive to PDL1 antibody drugs. [ABSTRACT FROM AUTHOR]

Nocardia affects immunocompromised human host exhibiting an altered cell-mediated immunity. Infectious risk after allogeneic hematopoietic cell transplantation (AHCT) is significantly correlated to the recovery status of donor-derived immune system, especially CD4+ T-cells reconstitution and thymopoiesis. The purpose of this paper is to highlight a lack of cell-mediated immunity recovery for patients presenting a nocardiosis compared to a control cohort. This is a case control retrospective monocentric study. We retrospectively analyzed a monocentric cohort of 15 cases of nocardiosis after AHCT and we explored the degree of patients' immunosuppression by phenotyping circulating lymphoid subpopulations, including NK cells, CD8+ T-cells, CD4+ T-cells and CD19+ B-cells. We focused on CD4+ T-cell subsets to appreciate thymic output, especially on naive CD4+ T-cells (NTE, CD45RA+/RO− CD4+ T-cells) and recent thymic emigrants (RTE, CD4+CD45RA+/RO−/CD31+). Infected patients were paired with a control cohort of patients with identical transplantation characteristics screened on hematological disease, AHCT conditioning, primary graft- versus -host disease (GHVD) prophylaxis, graft type, sex, age, and season at the AHCT and data concerning immunological reconstitution were compared. At onset of nocardiosis, circulating lymphocytes and CD4+ T-cells means count were respectively 730/μL and 162/μL. CD8+ T-cells, CD56+ NK cells and CD19+ B-cells means count were respectively 362/μL, 160/μL, 112/μL. CD4+ T-cells subpopulations, naïve CD4+ T-cells production was impaired with NTE and RTE means count at 26/μL and 11/μL respectively. Comparison between nocardiosis cohort and control cohort over time highlight significant lower cellular count for lymphocytes, CD4+ T-cells, NTE and RTE with p = 0.001, p < 0.001, p < 0.001, p < 0.001 respectively. Immune recovery monitoring follow-up after AHCT is of particular importance to identify patients susceptible to develop Nocardiosis. Efficient microbiological investigations toward Nocardia such PCR should be used in case of compatible clinical presentation. [ABSTRACT FROM AUTHOR]

[Display omitted] One of the most significant species that are present in large quantities in biological cells is reactive oxygen species (ROS). They are essential for cell motility, cell differentiation, and cellular immunity. In this paper, we introduce that (E)-1-methyl-4-(4-(propionyloxy)styryl)pyridin-1-ium (MPSPI) is an "on" type fluorescent probe regulated by the ICT mechanism. After the addition of hydrogen peroxide, the fluorophore (E)-4-(4-hydroxystyryl)-1-methylpyridin-1-ium (HMI-OH) is released. The simple probe MPSPI not only exhibited good selectivity and low cytotoxicity, but also demonstrated a detection limit as low as 35 nM and reaction times as quick as 20 s. Moreover, it has been successfully applied to the imaging of hydrogen peroxide in RAW 264.7 cells. [ABSTRACT FROM AUTHOR]

Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By inference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell-mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN-γ, TNFα and IL-1β, induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, inflammation, mitochondrial dysfunction, cytotoxicity, excitotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant inflammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the detection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pathophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases. [ABSTRACT FROM AUTHOR]

Direct cell-to-cell transmission of HIV-1 is proved to be a more efficient means of virus infection than virus-to-cell transmission. In this paper, we incorporate both virus-to-cell and cell-to-cell transmissions into an HIV-1 virus model, which also contains intracellular delay and humoral immunity. By analyzing the characteristic equations, the local stability of feasible equilibria is established. By using Lyapunov functionals and LaSalle’s invariance principle, it is verified that global threshold dynamics of the model can be explicitly described by immune-inactivated reproduction rate and immune-activated reproduction rate. Numerical simulations are carried out to illustrate the corresponding theoretical results. [ABSTRACT FROM AUTHOR]

Highlights: [•] The manuscript describes our view on hemocyte subsets, lineages and compartments. [•] The paper details the plasticity of plasmatocyte/macrophage lineages. [•] One of the main points of the paper is the regulation of the cell mediated immunity. [•] Phenotypic and functional changes upon effector cell differentiation are described. [•] The ontogenesis of the hematopoietic compartments is presented. [ABSTRACT FROM AUTHOR]

The goal of this paper is to study the threshold dynamics of an HIV-1 viral infection model with cell-mediated immune responses and direct cell-to-cell transmission mechanism. The model demonstrates global threshold dynamics with respect to the reproductive numbers for viral infection ℜ 0 and for CTL immune response ℜ 1 . The proofs of main results come from suitable uses of analyzing the characteristic equation and constructing Lyapunov functionals. Specifically, if ℜ 0 < 1, the infection-free equilibrium E 0 is locally and globally asymptotically stable, and the viruses are cleared. If ℜ 1 < 1 < ℜ 0 , the CTL-inactivated equilibrium E 1 is locally and globally asymptotically stable, and the infection becomes chronic but without persistent CTLs response. If ℜ 1 > 1, the CTL-activated equilibrium E 2 is locally and globally asymptotically stable, and the infection is chronic with persistent CTLs response. Numerical simulations are performed to support our results. [ABSTRACT FROM AUTHOR]

The immune repertoire (IR) refers to the sum of B cells and T cells with functional diversity in the circulatory system of one individual at any given time. Immune cells, which reside within microenvironments and are responsible for protecting the human body, include T cells, B cells, macrophages, and dendritic cells. These dedicated immune cells have a characteristic structure and function. T and B cells are the main lymphocytes and are responsible for cellular immunity and humoral immunity, respectively. The T cell receptor (TCR) and B cell receptor (BCR) are composed of multiple peptide chains with antigen specificity. The amino acid composition and sequence order are more diverse in the complementarity-determining regions (including CDR1, CDR2 and CDR3) of each peptide chain, allowing a vast library of TCRs and BCRs. IR research is becoming increasingly focused on the study of CDR3 diversity. Deep profiling of CDR3s using high-throughput sequencing is a powerful approach for elucidating the composition and distribution of the CDR3s in a given sample, with in-depth information at the sequence level. Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. To identify novel biomarkers for diagnosis and drug targets for therapeutic interventions, several groups attempted to describe immune repertoire characteristics of the liver in the physiological environment or/and pathological conditions. This paper reviews the recent progress in IR research on human diseases, including hepatocellular carcinoma, attempting to depict the relationships between hepatocellular carcinogenesis and the IR, and discusses the possibility of IR as a potential biomarker and therapeutic for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Evidence is accumulating that exposure to human immunodeficiency virus (HIV) can lead to an increased resistance or immunity to subsequent infection. A multirisk model that permits either induced immunity or infection to develop after heterosexual inoculation with HIV is shown to be compatible with a wide spectrum of disparate male-to-female transmission data.When the model is applied to time-dependent, HIV-seroprevalence data, the probability that an unexposed woman would remain unexposed after an unprotected contact with an infected man was estimated to be greater than 0.95 on the average. Thus, it would require at least 14 unprotected sexual contacts with HIV-infected men for 50% of an unexposed cohort of women to become exposed to the virus. This suggests that there is a low probability that HIV virions will be found to have penetrated the mucosal barriers of the reproductive tract after a contact.The model also predicts, that the average woman whose mucosal barriers have been breached by HIV has a significant probability of developing immunity to the virus rather than infection. Modelling data for a cohort of unexposed Nairobi women leads to the prediction that the probability of acquiring induced immunity per contact is about 60% of the probability of acquiring the disease per contact.The modelling results also predict that those who had developed resistance to HIV run the small, but significant risk of becoming infected nonetheless by continuing high-risk behavior. For the common contact rate of ten per month, the modelling predicts that the HIV-transmission risk per contact for unexposed women in the Nairobi cohort is SHAPE="SOL" ALIGN="C" STYLE="S">1178 while the transmission risk for the cohort''s immunized women is SHAPE="SOL" ALIGN="C" STYLE="S">11548. These numbers suggest that HIV infection is difficult to transmit through heterosexual intercourse on the average and that male-to-female HIV-transmission risk per contact for African women lies between SHAPE="SOL" ALIGN="C" STYLE="S">1178 and SHAPE="SOL" ALIGN="C" STYLE="S">11548.Direct confirmation of the predictions in the last paragraph has been subsequently observed in two completely independent studies. The Nairobi research team recently reported that a notable number of Nairobi prostitutes previously identified to be members of the HIV-resistant group became infected nonetheless. Second, in a study of 174 sexually monogamous, discordant couples in Rakai, Uganda reporting contacts rates of nine to ten per month, the male-to-female HIV-transmission risk per contact was found to be SHAPE="SOL" ALIGN="C" STYLE="S">1769 by direct measurement, a value that falls between the above limits of SHAPE="SOL" ALIGN="C" STYLE="S">1178 and SHAPE="SOL" ALIGN="C" STYLE="S">11548 predicted by the modelling. Thus, a second major prediction of this paper has been directly confirmed, and induced immunity to HIV is limited and not absolutely protective.Circumstantial evidence suggests that the induced immunity to HIV predicted by the model could be generated and/or initiated by nonspecific innate immune responses, specific immunological responses, including IgA-mediated mucosal immunity and cytotoxic T lymphocytes (CTL) immunity, or some combination of the above. It is suggested here, that a decrease in the ability of HIV virions to penetrate the protective mucus layer of the reproductive tract may be a prerequisite, cofactor, or the principle cause of the induced immunity or resistance demonstrated to exist in this paper. The value of the probability that induced immunity to HIV will develop after a contact is shown to be a sensitive function of the woman''s human leucocyte antigen (HLA) supertype profile. [Copyright &y& Elsevier]

Emerging evidence reveals the controversial role of B cells in antitumor immunity, but the underlying mechanisms have to be explored. Three latest articles published in the issue 521 of Nature in 2015 reconfirmed the puzzling topic and put forward some explanations of how B cells regulate antitumor T-cell responses both positively and negatively. This paper attempts to demonstrate that different B-cell subpopulations have distinct immunological properties and that they are involved in either antitumor responses or immunosuppression. Recent studies supporting the positive and negative roles of B cells in tumor development were summarized comprehensively. Several specific B-cell subpopulations, such as IgG(+), IgA(+), IL-10(+), and regulatory B cells, were described in detail. The mechanisms underlying the controversial B-cell effects were mainly attributed to different B-cell subpopulations, different B-cell-derived cytokines, direct B cell-T cell interaction, different cancer categories, and different malignant stages, and the immunological interaction between B cells and T cells is mediated by dendritic cells. Promising B-cell-based antitumor strategies were proposed and novel B-cell regulators were summarized to present interesting therapeutic targets. Future investigations are needed to make sure that B-cell-based pharmacological strategies benefit cancer immunotherapy substantially. [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CP) is a cytotoxic drug that can suppress both humoral and cellular immunity. Combining traditional medicinal herbs and chemotherapy drugs are used to improve immunity and quality of life performance status. In this paper, the effects of plant extracts, active components and their derivatives on immunosuppression of CP are discussed. Appropriate keywords were used to search through PubMed, Google Scholar, and Sciverse. All relevant results published from 1990 to date were chosen for final review. Over 50 references were found in which plant extracts, active components and their derivatives have been tested for their immune protective effects against CP-induced immune toxicity. Although there are several plants shown to be effective in animal models, no study was carried out on human subjects. According to the results; we can claim that plants and their active ingredients are good candidates for alternative adjuvant chemotherapy in reducing the immunotoxicity of CP. [ABSTRACT FROM AUTHOR]

The study of fundamental mechanisms of autoimmunity has been instrumental to clinical progress in the diagnosis and treatment of a range of immune-mediated inflammatory disorders. Dutch immunology has made major contributions to these developments, ranging from fundamental studies on immune cells, antibodies and cytokines to translational and clinical studies with targeted therapies in patients. In this paper we illustrate the progress made in our understanding of autoimmunity and the translational implications for human disease management by focusing on three areas: the autoantibody response in rheumatoid arthritis (RA), T-B cell interactions in Sjögren's syndrome (SS), and cytokine targeting in spondylarthritis (SpA). [ABSTRACT FROM AUTHOR]

Podosomes and invadopodia (collectively known as invadosomes) are small, F-actin-rich protrusions that are located at points of cell-ECM contacts and endow cells with invasive capabilities. So far, they have been identified in human or murine immune (myelomonocytic), vascular and cancer cells. The overarching reason for studying invadosomes is their connection to human disease. For example, macrophages and osteoclasts lacking Wiskott–Aldrich syndrome protein (WASp) are not able to form podosomes, and this leads to altered macrophage chemotaxis and defective bone resorption by osteoclasts. In contrast, the ability of cancer cells to form invadopodia is associated with high invasive and metastatic potentials. While invadosome composition, dynamics and signaling cascades leading to their assembly can be followed easily in in vitro assays, studying their contribution to pathophysiological processes in situ remains challenging. A number of recent papers have started to address this issue and describe invadosomes in situ in mouse models of cancer, cardiovascular disease and angiogenesis. In addition, in vivo invadosome homologs have been reported in developmental model systems such as C. elegans , zebrafish and sea squirt. Comparative analyses among different invasion mechanisms as they happen in their natural habitats, i.e. , in situ , may provide an outline of the invadosome evolutionary history, and guide our understanding of the roles of the invasion process in pathophysiology versus development. [ABSTRACT FROM AUTHOR]

• The Omicron variant diminishes the neutralizing capability of the antibodies. • Omicron can easily bypass an individual's humoral immune response. • The Omicron variant has more than 50 mutations. • CD8 + T-cell response may show promise against the Omicron variant. The million-dollar question that has been the talk of the day is how effective the COVID 19 vaccines are against the Omicron variant. Still, there is no clear-cut answer to this question but several studies have concluded that this Variant of Concern (VOC) successfully weakens the neutralizing capability of the antibodies acquired from the COVID 19 vaccines and prior infections, which indicates that Omicron can easily bypass an individual's humoral immune response. However, the most significant confusion revolves around cell-mediated immunity tackling the Omicron variant. This paper aims to provide a clear idea about the status of the body's immune surveillance concerning the infection caused by the Omicron variant by producing the effectivity of the humoral and cell-mediated immunity in handling the same. This work also provides complete detail of the various characteristics of the Omicron variant and how it may be a blessing in disguise. The effectiveness of the current vaccines, the transmissibility rate of the variant compared to the other variants, and the importance of administering a booster dose to prevent the spread of this variant are also discussed. Finally, this work aims to bridge the gap between the past and the current status of the Omicron infection and sheds light on the hypothetical idea that herd immunity developed from the SARS-COV2 infection may help tackle other dangerous variants. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic and debilitating disorder affecting up to 5-10% of women in reproductive age. Investigators have described deficiency in cellular immunity in women suffering from endometriosis, and in the recent years endometriosis has been linked to other diseases, allergic disease being one of them. The objective of this paper is to systematically review the existing literature on the possible association between endometriosis and allergic disease. This review is based on the recommendations by the preferred reporting of systematic reviews and meta-analysis (PRISMA) statement. PubMed and Embase were searched for studies on women diagnosed with endometriosis and with manifestations of allergic disease who were compared to a reference group. Out of 316 articles screened, 6 were reviewed and 5 ultimately met the inclusion criteria. Four out of the five studies reported a positive correlation between endometriosis and allergic manifestations, including hay fever, sinus allergic rhinitis, and food intolerance/sensitivities (food allergy). Investigators reported an odds ratio (OR) as high as 4.28 (95% CI: 2.93-6.27) for a positive history of allergy among women suffering from endometriosis. Equivocal results were found on asthma prevalence in women with endometriosis. Due to the heterogeneity of the included studies, no meta-analyses could be performed. The available literature clearly indicates that women with endometriosis are at an increased risk of allergic disorders compared to controls, but due to the lack of a concise definition of allergic disease and therefore diagnostic criteria, further studies are needed in order to draw firm conclusions on the association between endometriosis and allergic disease. [ABSTRACT FROM AUTHOR]

Abstract: The effectiveness of influenza vaccines is still controversial, and the role of adjuvants in such vaccines is briefly reviewed in this paper. Inactivated whole virus vaccines may include components that function as adjuvants, meaning that additive adjuvants are often not required. MF59 and AS03 showed higher adjuvanticity than aluminum salts in several clinical studies. Recent research has suggested that immune cell recruitment is the main mechanism underlying adjuvant actions in general, and that aluminum salts induce this recruitment via inflammation at the injected site. The aspect of how oil-based adjuvants, such as MF59 and AS03, recruit immune cells remains to be clarified. [Copyright &y& Elsevier]

The bursa of Fabricius, the acknowledged central humoral immune organ, plays a vital role in B lymphocyte differentiation. However, there are few reports of the molecular basis of the mechanism on immune induction and potential antitumor activity of bursal-derived peptides. In this paper, a novel bursal-derived pentapeptide-II (BPP-II, MTLTG) was isolated and exerted immunomodulatory functions on antibody responses in vitro. Gene microarray analyses demonstrated that BPP-II regulated expression of 2478 genes in a mouse-derived hybridoma cell line. Immune-related gene ontology functional procedures were employed for further functional analysis. Furthermore, the majority of BPP-II-regulated pathways were associated with immune responses and tumor processes. Moreover, BPP-II exhibited immunomodulatory effects on antigen-specific immune responses in vivo, including enhancement of avian influenza virus (H9N2 subtype)-specific antibody and cytokine production and modification of T cell immunophenotypes and lymphocyte proliferation. Finally, BPP-II triggered p53 expression and stabilization and selectively inhibited tumor cell proliferation. These data identified the multifunctional factor, BPP-II, as a novel biomaterial representing an important linking between the humoral central immune system and immune induction, including antitumor. Information generated in this study elucidates further the mechanisms involved in humoral immune system and represents the potential basis of effective immunotherapeutic strategies for treating human tumors and immune improvement. [ABSTRACT FROM AUTHOR]

Abstract: Tumor growth models subject to virotherapy treatment are analyzed and compared in this paper. Tumor growth conditions are obtained for each model type based on the virus infection rate and immune suppressive drug delivery. Equilibrium conditions resulted into quadratic functions for which the tumor radius remained constant during virotherapy. An irrigation tumor model for virotherapy treatment was also proposed. This model consists of irrigation layers distributed radially along the tumor and attached to a common blood circulation compartment. The irrigation model has similar dynamic and steady state characteristics to the diffusion model, which has been supported by experimental results. The irrigation model considers the immune system cell generation and consumption outside the tumor boundary but inside the blood circulation compartment. These characteristics provide a great potential for advanced cancer treatment applications because therapy dose delivery and immune system measurements can be made at the blood compartment level of the irrigation model. [Copyright &y& Elsevier]

Abstract: Establishment of a leukemia plasmacytoid dendritic cell line (PMDC05) and intra-lineage transformation from pDCs to mDCs in PMDC05 has been reported. In this paper, we show the applicability of PMDC05 for cellular immunotherapy. By stimulation with LPS, PMDC05 showed enhancement in expression of antigen presentation-associated surface molecules and production of cytokines (IL-12p70 and TNF-α). The antigen presenting ability was markedly increased in PMDC05 stimulated with LPS. By co-culturing of CD8+ T cells with LPS-stimulated and WT1/CMVpp65 peptide-pulsed PMDC05, WT1/CMVpp65 tetramer+ cytotoxic T lymphocytes were efficiently generated. These findings reveal the applicability of PMDC05 in cellular immunotherapy for tumor and severe viral infections. [Copyright &y& Elsevier]

Hepatitis C virus (HCV) is a blood borne disease estimated to chronically infect 3% of the worlds’ population causing significant morbidity and mortality. Current medical therapy is curative in approximately 50% of patients. While recent treatment advances of genotype 1 infection using directly acting antiviral agents (DAAs) are encouraging, there is still a need to develop vaccine strategies capable of preventing infection. Moreover, vaccines may also be used in future in combination with DAAs enabling interferon-free treatment regimens. Viral and host specific factors contribute to viral evasion and present important impediments to vaccine development. Both, innate and adaptive immune responses are of major importance for the control of HCV infection. However, HCV has evolved ways of evading the host’s immune response in order to establish persistent infection. For example, HCV inhibits intracellular interferon signalling pathways, impairs the activation of dendritic cells, CD8+ and CD4+ T cell responses, induces a state of T-cell exhaustion and selects escape variants with mutations CD8+ T cell epitopes. An effective vaccine will need to produce strong and broadly cross-reactive CD4+, CD8+ T cell and neutralising antibody (NAb) responses to be successful in preventing or clearing HCV. Vaccines in clinical trials now include recombinant proteins, synthetic peptides, virosome based vaccines, tarmogens, modified vaccinia Ankara based vaccines, and DNA based vaccines. Several preclinical vaccine strategies are also under development and include recombinant adenoviral vaccines, virus like particles, and synthetic peptide vaccines. This paper will review the vaccines strategies employed, their success to date and future directions of vaccine design. [ABSTRACT FROM AUTHOR]

Abstract: The first findings that depression is characterized by cell-mediated immune activation and inflammation were published between 1990–1993 (Maes et al.). Recently, it was reported that – based on meta-analysis results – depression is an inflammatory disorder because the plasma levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2 and interferon-(IFN)γ levels are not altered in depression, suggesting that there is no T cell activation in that illness. The present paper reviews the body of evidence that depression is accompanied by cell-mediated immune activation. The findings include: increased serum levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule; increased numbers and percentages of T cells bearing T cell activation markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels; induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of plasma tryptophan and increased levels of tryptophan catabolites along the IDO pathway (TRYCATs); and glucocorticoid resistance in immune cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and IFNα-induced activation of T cells, IDO activity and TRYCAT formation are related to the development of IFNα-induced depressive symptoms. Animal models of depression show that a cell-mediated immune response is related to the development of depression-like behavior. Antidepressants and mood stabilizers suppress different aspects of cell-mediated immunity and rather specifically target IFNγ production. This review shows that inflammation and cell-mediated immune activation are key factors in depression. [Copyright &y& Elsevier]

Abstract: This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well. [Copyright &y& Elsevier]

Abstract: Safe and efficient vaccination is important for rabies prevention in domestic animals. Replicative vectors expressing the rabies virus glycoprotein, derived from canine adenovirus have been reported to be promising vaccines in various animal models. In this paper we compare the potential of a replicative and a non-replicative vector, both based on canine adenovirus type 2 and expressing the rabies glycoprotein. Upon inoculation in sheep, immune responses against the rabies virus protein elicited by recombinant vectors were monitored. All immunised sheep produced a rapid and potent neutralizing antibody response against rabies virus after a single inoculation of either replicative or non-replicative recombinant canine adenovirus type 2. In addition, the non-replicative vector expressing the rabies glycoprotein stimulated antigen-specific CD4+ and CD8+ lymphocyte proliferation as well as IFN-γ production. These results suggest that vectors derived from canine adenovirus 2 could be considered for the development of promising vaccines in the ruminant species. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) matured with helminth-derived molecules that promote Th2 immune responses do not follow conventional definitions of DC maturation processes. While a number of models of DC maturation by Th2 stimuli are postulated, further studies are required if we are to clearly define DC maturation processes that lead to Th2 immune responses. In this study, we examine the interaction of Th2-inducing molecules from the parasitic helminth Ascaris lumbricoides with the maturation processes and function of DCs. Here we show that murine bone marrow-derived DCs are partially matured by A. lumbricoides pseudocoelomic body fluid (ABF) as characterised by the production of IL-6, IL-12p40 and macrophage inflammatory protein 2 (MIP-2) but no enhanced expression of cluster of differentiation (CD)-14, T-cell co-stimulatory markers CD80, CD86, CD40, OX40L and major histocompatibility complex class II was observed. Despite these phenotypic characteristics, ABF-stimulated DCs displayed the functional hallmarks of fully matured cells, enhancing DC phagocytosis and promoting Th2-type responses in skin-draining lymph node cells in vivo. ABF activated Th2-associated extracellular signal-regulated kinase-1 and nuclear factor-kB intracellular signalling pathways independently of toll-like receptor 4. Taken together, we believe this is the first paper to demonstrate A. lumbricoides murine DC-Th cell-driven responses shedding further light on DC maturation processes by helminth antigens. [Copyright &y& Elsevier]

Abstract: Women pregnant with a male fetus often generate cellular and humoral immune responses against male-specific minor histocompatibility (HY) antigens—however, the importance of these responses for pregnancy outcome is unclear. Epidemiologic studies have shown that the birth of a boy compared with a girl prior to a series of miscarriages significantly reduces the chance of a subsequent live birth and pregnancies with boys have an increased risk of placental abruption. This paper aims to review the current knowledge about the impact of anti-HY immunity on pregnancy outcome in terms of miscarriage and placental abruption. Our knowledge primarily comes from studies of the impact on pregnancy outcome of HLA class II alleles known to restrict CD4 T cell mediated anti-HY responses among 358 secondary recurrent miscarriage (SRM) patients and 203 of their children born prior to the miscarriages and investigation of these HLA alleles in 8 patients with recurrent severe placental abruptions. The chance of a subsequent live birth in SRM patients with firstborn boys compared to firstborn girls was significantly lower in women with HY-restricting HLA class II alleles [OR: 0.17 (0.1–0.4), p =0.0001]. Most patients with recurrent placental abruptions had firstborn boys and significantly more of these patients carried HLA haplotypes with HY-restricting class II alleles compared with controls (p =0.009). These findings are strongly indicative of aberrant maternal immune reactions against fetal HY antigens playing a role in recurrent miscarriage and placental abruption. We propose pathogenetic pathways for these conditions that in our view best explain the findings. [Copyright &y& Elsevier]

Two recent papers published in Immunity and Cell Host & Microbe underline the great importance of B cells and of antibodies (Abs) in orchestrating crucial T helper cell type 2 (Th2) protective immune responses to gastrointestinal nematodes. The findings in animal models now raise major questions as to how B cells and Abs carry out these functions in humans. Here we discuss recent technological advances in humanizing animal models at the level of both Abs and their Fc-receptors, that might provide some answers. [Copyright &y& Elsevier]

Abstract: Sheep are important to the economy of many countries because they are a source of food for humans Sheep are commonly infected with the protozoan parasite, Toxoplasma gondii. Infection with the parasite may cause early embryonic death and resorption, fetal death and mummification, abortion, stillbirth, and neonatal death. Severity of infection is associated with the stage of pregnancy at which the ewe becomes infected, the earlier in gestation, the more severe the consequences. Infected sheep meat is a source of T. gondii infection for humans and carnivorous animals. Most sheep acquire T. gondii infection after birth, and less than 4% of persistently infected sheep transmit the parasite vertically to the next generation. Recent studies by a group of researchers in England reported that repeat ovine transmission of T. gondii may be more common than previously believed but these findings are soley based on PCR data and require additional data using other techniques to verify the findings. Following infection with T. gondii, sheep develop humoral and cell-mediated immune responses against the parasite that provides effective protection against disease in subsequent pregnancies. A commercial vaccine is available, comprising a live, incomplete strain of T. gondii. The vaccine is administered to sheep prior to mating to protect against lamb losses due to toxoplasmosis. In the present paper, information on the prevalence, transmission, and control of ovine toxoplasmosis in the last 20 years is reviewed. [Copyright &y& Elsevier]

Abstract: The natural immune system provides an effective defense mechanism against foreign substances via complex interactions among various cells and molecules. Jerne introduced the immune network theory to model the relation between immune cells and molecules. The immune system like the neural system is able to learn from experience. In this paper, a multi-epitopic immune network model is proposed. The proposed model is hybridized with Learning Vector Quantization (LVQ) and fuzzy set theory to present a new supervised learning method. The new method is called Hybrid Fuzzy Neuro-Immune Network based on Multi-Epitope approach (HFNINME). To evaluate the performance of the proposed method several experiments on benchmark classification problems are carried out and the results are compared with two prominent immune-based classifiers as well as several versions of the LVQ algorithm. The results of the experiments reveal that the proposed method yields a parsimonious classifier that can classify data more accurately and more efficiently. [Copyright &y& Elsevier]

Abstract: Early results have recognized that influenza virus infects the innate and adaptive immune cells. The data presented in this paper demonstrated that influenza virus labeled with fluorescent dye not only retained the ability to infect and replicate in host cells, but also stimulated a similar human immune response as did unlabeled virus. Influenza virus largely infected the innate and activated adaptive immune cells. Influenza B type virus was different from that of A type virus. B type virus was able to infect the immature lymphocytes, but in lower amounts when compared to activated lymphocytes. Protection from influenza is tightly associated with cellular immunity. Traditional methods of cellular immunity assay had limitations to imitate the natural human cell-mediated responses to influenza virus. Labeled viruses could be used in the assay of virus-specific cytotoxicity, which might reflect the natural process more closely. Furthermore, human immune cells activated by one influenza subtype virus could kill the cells infected by other subtype virus. These results implied the human immune cells could directly handle and remove free virus using similar mechanism that was used to remove virus-infected non immune cells, which might help to simplify the design and production of influenza vaccine, thereby reduce the cost. [Copyright &y& Elsevier]

Abstract: Interferons (IFNs) are cytokines with important immunomodulatory activity in vertebrates. Although type I IFNs and interleukins (IL) 29 and 28a (type III IFNs) bind to different cellular receptors and have distinct structures, most of their biological activities are redundant. Apeu virus (APEUV) is a member of the Bunyaviridae family isolated from the Brazilian rain forest. In this paper we evaluated the antiviral activity of type I and type III IFNs against APEUV. All tested IFNs were able to induce an antiviral state against the virus in a dose-dependent way. The activity of type III IFNs did not need the presence of type I IFNs. Mixing both types of IFNs did not improve the biological activity of each type alone. The tested IFNs were also able to protect human peripheral blood mononuclear cells from infection. IFN alpha2, IFN beta, IL-29 and IL-28a induced the expression of 2′,5′-oligoadenylate synthetase (2′5′OAS) and 6–16 genes. Although MxA gene was related to antiviral activity against Bunyaviruses, there was no induction of MxA in our model. We were able to show activity of type I and type III IFNs against a RNA virus, and that this activity is not dependent on MxA gene. [Copyright &y& Elsevier]

Abstract: LEI/L-DNase II is the key protein of a caspase-independent pathway activated by serine proteases. LEI (Leukocyte elastase inhibitor), L-DNase II precursor, is a member of the clade B serpins (also called serpin b1). In its native conformation it inhibits several intracellular proteases and has an anti-apoptotic activity. Following a metabolic stress and the increase of protease activity in the cell, LEI is cleaved and transformed into L-DNase II (LEI-derived DNase II). This transformation is due to a conformational modification that exposes a nuclear localization signal and an endonuclease active site. In this paper we show that LEI can bind the exportin Crm1, and we identify on LEI a nuclear export signal involved in the control of LEI/L-DNase II nuclearization in healthy cells. Point mutation of this site increases the accumulation of the molecule in the nucleus and triggers cell death. [Copyright &y& Elsevier]

Abstract: The essentiality of zinc for humans was recognized only 40 years ago. Zinc deficiency was suspected to occur in Iranian patients with growth retardation, hypogonadism in males, hepato-splenomegaly, rough and dry skin, geophagia and severe iron deficiency anemia. Later we documented zinc deficiency in similar patients in Egypt. The diet of these patients consisted of mainly cereal proteins which contained high phytate and this led to decreased availability of iron and zinc. These patients had severe immune dysfunctions, inasmuch as they died of intercurrent infections by the time they were 25 years of age. In our studies in experimental human model of zinc deficiency, we documented decreased serum testosterone level, oligospermia, severe immune dysfunctions mainly affecting T helper cells, decreased serum thymulin activity hyperammonemia, neuro-sensory disorders and decreased lean body mass. The basic mechanisms of zinc action on immune cells have been reviewed in this paper. Our studies showed that the activation of many zinc dependent enzymes and transcription factors were affected adversely due to zinc deficiency. The gene expression and production of Th1 cytokines were affected adversely due to zinc deficiency. Zinc is also an antioxidant and has anti-inflammatory actions. We have reported decreased plasma zinc, increased plasma oxidative stress markers and increased generation of inflammatory cytokines in the elderly subjects which were corrected by zinc supplementation. In cell culture studies, we have observed that zinc induces A20 which inhibits NF-κB activation resulting in decreased generation of inflammatory cytokines. [Copyright &y& Elsevier]

Abstract: Exciting complexity of natural phenomena can be based on rather simple biophysical principles. For example, the genetic code is based on a double-helix of DNA formed by planar geometry of weak hydrogen bounds. On the examples of cytokine networks, immune synapse, psychoneuroimmunology and systems biology, this review paper attempts to show how molecular networks both in brain and immunity can be studied using common principles of protein–protein interactions. [Copyright &y& Elsevier]

Abstract: The aim of the current paper was to determine the chorion''s contribution to complement synthesis in the placenta and its regulation by cytokines. Biosynthetic labeling followed by immunoprecipitation with polyclonal antibodies was performed in chorionic tissue and chorion-derived cells. Eight complement proteins, factor B, C3, C1r, C1s, C1 inhibitor, factor H, C4 and C2 were detected in chorionic tissue and were secreted extracellularly. In chorion-derived cells, IL-1β stimulated factor B synthesis but had no effect on C1r, C1 inhibitor, C1s, factor H and C4. TNFα had no stimulative effect on any of the complement proteins tested. In contrast, both IL-1β and TNFα highly induced IL-6 secretion in chorion-derived cells, demonstrating the overall responsiveness of these cells to these stimuli. Interestingly, IFN-γ increased the synthesis of C1s, C1r, C1 inhibitor, C4 and factor H in chorion-derived cells. The fact that the latter two complement proteins have opposing effects on immune activation of the complement cascade demonstrates the complex balance required to both maintain an ability to ward off infections but simultaneously suppress the immune response to enable tolerance of the allograft fetus. [Copyright &y& Elsevier]

Dietary fish oil has immunomodulatory effects that are partly mediated by its effects on cytokine secretion. In this paper, we examine whether dietary fish oil has different effects on cytokine secretion by T cells and macrophages. Female BalbC mice were fed diets supplemented with 18% fish oil + 2% corn oil or 20% corn oil. Concanavalin A (ConA)- and LPS-induced TNF-alpha and IL-10 secretion by splenocytes was examined using ELISA. Dietary fish oil decreased ConA induced-, but increased LPS-induced, TNF-alpha and IL-10 secretion by total murine splenocytes. Dietary fish oil increased the number of splenocytes secreting TNF-alpha and IL-10, following stimulation with LPS, by 123 and 38%, respectively, but did not affect cytokine secretion by each cell, as determined using enzyme-linked immunospot. Spleens from mice fed the fish oil diet had over 2-fold higher proportion of macrophages with high expression of CD11b than spleens from mice fed the corn oil diet. In addition, fish oil increased the proportion of total and CD11b(+) splenocytes that expressed the LPS receptor complex molecules, CD14 and toll-like receptor (TLR)4/myeloid differentiation factor-2 (MD-2), by 85 and 28%, respectively. The increased proportion of macrophages expressing the LPS receptor complex molecules, CD14 and TLR4/MD-2, in spleens from mice fed the fish oil diet may explain the increased number of cells that secreted the cytokines after LPS stimulation. [ABSTRACT FROM AUTHOR]

In post-natal life the inflammatory response is an inevitable consequence of tissue injury. Experimental studies established the dogma that inflammation is essential to the establishment of cutaneous homeostasis following injury, and in recent years information about specific subsets of inflammatory cell lineages and the cytokine network orchestrating inflammation associated with tissue repair has increased. Recently, this dogma has been challenged, and reports have raised questions on the validity of the essential prerequisite of inflammation for efficient tissue repair. Indeed, in experimental models of repair, inflammation has been shown to delay healing and to result in increased scarring. Furthermore, chronic inflammation, a hallmark of the non-healing wound, predisposes tissue to cancer development. Thus, a more detailed understanding in mechanisms controlling the inflammatory response during repair and how inflammation directs the outcome of the healing process will serve as a significant milestone in the therapy of pathological tissue repair. In this paper, we review cellular and molecular mechanisms controlling inflammation in cutaneous tissue repair and provide a rationale for targeting the inflammatory phase in order to modulate the outcome of the healing response.Journal of Investigative Dermatology (2007) 127, 514–525. doi:10.1038/sj.jid.5700701 [ABSTRACT FROM AUTHOR]

Abstract: This paper reports the cloning and sequencing of two pro-inflammatory cytokines, interleukin (IL)-1β and IL-8, in haddock (Melanogrammus aeglefinus) by homology cloning. The complete transcript of the haddock IL-1β was sequenced and contained 1043bp, including a 762bp open reading frame. The 3′ end of the gene includes a polyadenylation signal 13bp upstream of the poly(A) tail, along with 10 instability motifs. The predicted protein of 253aa revealed the presence of the IL-1 family signature and the absence of an ICE cut site. The cDNA of the chemokine IL-8 was sequenced in haddock and contained 903bp of which 306bp are the open reading frame. Interestingly, the predicted protein sequence of 101aa, contains an ELR motif preceding the CXC signature, common in all vertebrate IL-8 molecules but absent in all teleost genes sequenced to date. The expression of both haddock cytokines was studied in four different tissues: head kidney, spleen, liver and gill. Tissues were obtained from both healthy fish and fish stimulated in vivo with four commercial serotypes of LPS, namely Escherichia coli 026:B6, 055:B5, 0111:B4 and 0127:B8 and PMA. Haddock IL-1β was not constitutively expressed and expression was only observed following stimulation. However, this expression was stimulant dependent and only PMA and LPS 026:B6 induced high levels of expression in the head kidney. The haddock IL-8 gene on the other hand, showed a constitutive expression, that could be up or down-regulated depending on the immunostimulant used, although to a lesser extent than IL-1β. [Copyright &y& Elsevier]

Abstract: Hydroxyapatite (HA) is widely used to coat metal parts in order to improve their biocompatibility. Analysis of retrieved tissues associated with failed implants, suggest that phagocytosis of HA wear debris by monocytes/macrophages might provide a potent stimulus for the release of a variety of cytokines. Phagocytosis involved a large variety of cellular receptors like toll-like receptors that results in activation of the transcriptional nuclear factor-κB (NF-κB) via a cell-signalling pathway. In the present paper, we aimed to evaluate the role of the toll-like receptor 4 (TLR4) in the production of inflammatory cytokines induced by HA particles using TLR4+ and TLR4− peritoneal macrophages. We investigated the production of TNF-α and the activation of the nuclear transcription factor NF-κB. Our data clearly show for the first time that the production of TNF-α by macrophages exposed to HA particles was TLR4 dependent but not the activation of NF-κB. All these results open future therapies to reduce the inflammatory response induced by HA biomaterials. [Copyright &y& Elsevier]

Abstract: Uncaria tomentosa, commonly known as cat''s claw, is a medicinal plant native to Peru, which has been used for decades in the treatment of various inflammatory disorders. Uncaria tomentosa can be used as an antioxidant, has anti-apoptotic properties, and can enhance DNA repair, however it is best know for its anti-inflammatory properties. Treatment with Uncaria tomentosa extracts inhibits the production of the pro-inflammatory cytokine, TNF-α, which is a critical mediator of the immune response. In this paper, we showed that treatment of THP-1 monocyte-like cells with Uncaria tomentosa extracts inhibited the MAP kinase signaling pathway and altered cytokine expression. Using ELISA assays, we showed that treatment with Uncaria tomentosa extracts augmented LPS-dependent expression of IL-1β by 2.4-fold, while inhibiting the LPS-dependent expression of TNF-α by 5.5-fold. We also showed that treatment of LPS-stimulated THP-1 cells with Uncaria tomentosa extracts blocked ERK1/2 and MEK1/2 phosphorylation in a dose-dependent manner. These data demonstrate that treatment of THP-1 cells with Uncaria tomentosa extracts has opposite effects on IL-1β and TNF-α secretion, and that these changes may involve effects on the MAP kinase pathway. [Copyright &y& Elsevier]

Abstract: α-Galactosyl-ceramide (1) has been identified as a powerful modulator of immunological processes through its capacity to bind CD1d molecules and specifically activate invariant natural killer (NK)-like T cells (iNKT cells). This paper describes the synthesis of 1, the analogous α-galactosyl-ceramide 3, and its short chain analogue ‘OCH’ (2), by use of the 4,6-di-O-tert-butylsilylene (DTBS) protecting group to produce a powerful α-galactosylating agent. In vivo experiments confirmed these compounds to be potent and selective activators of iNKT cells in a CD1d-dependent manner, each inducing a unique profile of cytokine release. This synthesis strategy will permit the generation of novel derivatives for use in the study of the mechanism of iNKT cell activation. [Copyright &y& Elsevier]

Abstract: Phospholipases A2 (PLA2s) are responsible for releasing the fatty acid moiety from the sn-2 position of phospholipids. These enzymes are virtually ubiquitous proteins known from all major biological taxa. Various PLA2s act in a wide array of biological processes, including digestion of dietary lipids, cellular homeostasis, intra- and intercellular signaling, host defense and at least a few ecological interactions. PLA2 activities have been recorded in a small number of insect species, which can be taken to represent the broad group, Insecta. Within insects, PLA2s act in functions expected from the background on these enzymes. So far, we know PLA2s act in lipid digestion, cellular host defense signaling, reproduction and in organismal-level metabolism. Additional PLA2 actions are certain to emerge. This is the first article devoted to assembling the known information on insect PLA2s. I review the scant information available on the biological actions of PLA2s in insects, relate new findings on insect pathogens that disrupt insect immune functions by inhibiting PLA2s and mention the few reports of sequence information on insect PLA2s. Finally, I offer a brief prospectus on future research into insect PLA2s. There are two overarching points in this paper. One, there remains a great deal to learn about insect PLA2s and two, some of the findings on insect PLA2s will have meaningful practical significance. [Copyright &y& Elsevier]

Abstract: Infections with gastrointestinal nematodes represent a major problem for human health and animal health and production. The physical size of the parasite, its changing life-cycle stages and the relative inaccessibility to host cells pose unique challenges to the immune system, which has evolved specialized strategies for parasite control. This paper reviews the work performed in the authors’ laboratories to identify components that are involved in the natural rejection response against ruminant gastrointestinal nematode parasites, in particular Haemonchus contortus in sheep. The results of these studies indicate that stage-specific antibodies act in concert with effector cells, in particular globular leukocytes (intraepithelial mast cells) and eosinophils, appropriately activated/primed by type 2 (T2) cytokines, to initiate different mechanisms of parasite expulsion and killing. In addition, other molecules, in particular carbohydrate binding galectins, may be involved in strengthening the final effector phase of the rejection response. [Copyright &y& Elsevier]

Abstract: Macrophage migration inhibitory factor (MIF), a long known proinflammatory cytokine exhibits perplexing enzymatic activities: tautomeric conversion of d-dopachrome and phenylpyruvate. Whether these catalytic activities bear functional relevance regarding MIF''s multifaceted roles is under current scrutiny. Nevertheless, intense search has already started for pharmacological agents that target MIF''s tautomerase activity. We have probed several antiinflammatory compounds against keto–enol (enolase) and enol–keto (ketonase) conversion of phenylpyruvate by MIF with spectrophotometry. We have identified acidic CH groups as markers of inhibitor potency toward MIF phenylpyruvate tautomerase. Among simple model molecules with strong acidic CH groups we found acetylacetone the best inhibitor particularly against the ketonase activity. Ketones of physiological importance – ketone bodies – also feature acidic CH groups and have been reported to exert certain anti-inflammatory effects. In this paper we report that ketone bodies inhibit preferentially the ketonase activity of MIF in vitro. Future studies should address whether such an interaction might operate in vivo and delineate its possible relevance concerning cytokine and non-cytokine roles of MIF. [Copyright &y& Elsevier]

Abstract: The hallmark of fibrosis is the excessive accumulation of collagen. The deposited collagen contains increased pyridinoline cross-link levels due to an overhydroxylation of lysine residues within the collagen telopeptides. Lysyl hydroxylase 2b (LH2b) is the only lysyl hydroxylase consistently up-regulated in several forms of fibrosis, suggesting that an enhanced LH2b level is responsible for the overhydroxylation of collagen telopeptides. The present paper reports the effect of profibrotic cytokines on the expression of collagen, lysyl hydroxylases and lysyl oxidase in normal human skin fibroblasts, as well as the effect on pyridinoline formation in the deposited matrix. All three isoforms of TGF-β induce a substantial increase in LH2b mRNA levels, also when expressed relatively to the mRNA levels of collagen type I α2 (COL1A2). The TGF-β isoforms also clearly influence the collagen cross-linking pathway, since higher levels of pyridinoline cross-links were measured. Similar stimulatory effects on LH2b/COL1A2 mRNA expression and pyridinoline formation were observed for IL-4, activin A, and TNF-α. An exception was BMP-2, which has no effect on LH2b/COL1A2 mRNA levels nor on pyridinoline formation. Our data show for the first time that two processes, i.e., up-regulation of LH2b mRNA levels and increased formation of pyridinoline cross-links, previously recognized to be inherent to fibrotic processes, are induced by various profibrotic cytokines. [Copyright &y& Elsevier]

Abstract: This paper describes the cloning and sequence analysis of the cDNAs encoding the T helper (Th) 2 cytokines of llama including interleukin-4 (IL-4), IL-10 and IL-13. The cDNAs encoding for IL-4, IL-10 and IL-13 were amplified using specific primers designed from reported sequences of bovine cytokine genes. The cDNAs for llama IL-4, IL-10 and IL-13 were found to be 402, 537 and 411bp in length, with open reading frames encoding 133, 178 or 136 amino acids, respectively. Homology analyses of nucleotide and deduced amino acid sequences of llama IL-4, IL-10 and IL-13 and phylogenetic analysis based on their nucleotide sequences indicated the close relationship in these cytokine genes between llama and eutherian mammalian order Artiodactyla (pig, cattle) and Perissodactyla (horse). [Copyright &y& Elsevier]

Abstract: During inflammatory responses in the brain, the expression of cytochrome P450 isoforms in the CNS are modulated and the capacity of the brain to metabolize drugs and to synthesize or degrade certain endogenous chemicals and drugs is diminished. While this response can be attributed in part, to the production and action of cytokines within the brain, it is also likely that other inflammatory mediators play an integral role. This paper investigates a potential role for nitric oxide (NO) in the loss of cytochrome P450 (CYP1A) in the brain during inflammation. Escherichia coli lipopolysaccharide (LPS), a commonly used proinflammatory endotoxin, was incubated with cultured rat astrocytes to provide a model of inflammation in the CNS. CYP1A activity was significantly decreased in cultured astrocytes incubated with LPS for 24 h. This loss in enzyme activity was accompanied by a substantial production of nitric oxide (NO) by these cells. Immunohistochemical examination demonstrated an upregulation of inducible nitric oxide synthase (iNOS) expression following the exposure of astrocytes to LPS. The addition of a selective iNOS blocker (1400W) caused a partial but significant reversal of the LPS-mediated loss in CYP1A. The incubation of astrocytes with the NO-generating compound (DETA NONOate) resulted in a loss of CYP1A. Taken together, these observations suggest that NO plays a pivotal role in the inflammation mediated loss in CYP1A activity in the brain. [Copyright &y& Elsevier]