Type I interferons in systemic autoimmunity

Type I IFN (IFN-I) was firstly described in 1957 as a soluble factor responsible for viral resistance in vitro. Today, it is well known that the IFN-I family comprises a wide number of cytokines with different modulatory effects on angiogenesis, cell growth, fibrosis, and apoptosis. However, one of the most important functions of IFN-I is the capability to trigger a complex array of cellular responses that result in a host-protective antiviral response. For this reason, IFN-I can be considered a “director” of protective immune responses. The recent finding of the so-called interferon signature in patients suffering from different autoimmune diseases has underlined its possible role in the pathogenesis of these diseases. On the other hand, IFN-α/β is reported to be efficacious in the treatment of some autoimmune and infectious diseases not responsive to conventional therapy. On these occasions, the treated patients often start or increase autoantibody production supporting the role of IFN as inducer of an autoimmune response. In this review, we will underline recent acquisitions about IFN-I biology, with a focus on the relevance of the induction of some autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermato/polymiositis, and Sjogren's syndrome.     

Secretory immunoglobulin A: well beyond immune exclusion at mucosal surfaces

At mucosal surfaces, secretory IgA (SIgA) antibodies serve as the first line of defense against microorganisms through a mechanism called immune exclusion that prevents interaction of neutralized antigens with the epithelium. In addition, SIgA plays a role in the immune balance of the epithelial barrier through selective adhesion to M cells in intestinal Peyer’s patches. This mediates the transepithelial retro-transport of the antibody and associated antigens from the intestinal lumen to underlying gut-associated organized lymphoid tissue. In Peyer’s patches, SIgA-based immune complexes are internalized by underlying antigen-presenting cells, leaving the antigen with masked epitopes, a form that limits the risk of overwhelming the local immune protection system with danger signals. This translates into the onset of mucosal and systemic responses associated with production of anti-inflammatory cytokines and limited activation of antigen-presenting cells. In the gastrointestinal tract, SIgA exhibits thus properties of a neutralizing agent (immune exclusion) and of an immunopotentiator inducing effector immune responses in a noninflammatory context favorable to preserve local homeostasis.     

Autologous canine immunotherapy: short-time generated dendritic cells loaded with canine transmissible venereal tumor-whole lysate

Abstract

Objective: The aim of the present study was to evaluate the therapeutic potential of autologous DCs loaded with whole tumor cell lysate of CTVT generated under a simplified and rapid procedure in vitro production process, in a vulvar submucosal model of CTVT in dogs.

Materials and methods: We generated a model of intravulvar CTVT in dogs. A CTVT lysate antigen was prepared according to the method of 1-butanol and after administered with complete Freund's adjuvant via subcutaneous in female healthy dogs and challenge with CTVT cells to corroborate the immunogenicity. Short-time generated dendritic cell pulsed with CTVT whole-lysate was performed, and analyzed by FITC-dextran uptake assay and characterized using anti-canine monoclonal antibodies CD14, CD80, CD83, and DLAII by flow cytometry. Dendritic cell therapy was administered in a frequency of three times every 2 weeks when the CTVT had 4 months of growth and 89?±?5 cm diameter. The CD3⁺, CD4⁺ and CD8⁺ lymphocytes were determined by flow cytometry, and IFN-γ by ELISA assay.

Results and discussion: The administration of CTVT whole-lysate resulted in tumor prevention. The short-time generated dendritic cell pulsed with CTVT whole-lysate administration resulted in an efficient reduction and elimination of CTVT, probably due to the increase in lymphocyte populations (CD3⁺, CD4⁺, and CD8⁺), IFN-γ production and tumor infiltrating lymphocytes.

Conclusion: In conclusion, this study demonstrates the efficacy of immunotherapy based in short-time generated dendritic cell pulsed with CTVT whole-lysate for the treatment of CTVT, and offer veterinary oncologists new alternative therapies to treat this and another malignancy.     

G-CSF: A key regulator of neutrophil production,but that's not all!

G-CSF is a major extracellular regulator of haemopoiesis and the innate immune system. Named for its relatively specific stimulation of the growth of neutrophil progenitor cells in vitro in semi-solid cultures (Burgess and Metcalf 1980, Nicola et al. 1983), G-CSF influences the survival, proliferation and differentiation of all cells in the neutrophil lineage, from haemopoietic stem cell through to mature neutrophil. Further, G-CSF influences the function of mature neutrophils. These actions underpin its rapid uptake into clinical medicine as a drug that increases the production of neutrophils in patients with chemotherapy-induced neutropenia.

Ongoing research has uncovered initially unsuspected polyfunctionality for G-CSF. G-CSF is well recognised as a potent mobiliser of haemopoietic stem cells from the bone marrow into the blood, and now is being increasingly accepted as a regulator of immune responses. These two “new” actions of G-CSF first came to light through observations made during clinical trials of G-CSF. Subsequent investigations into the cellular and molecular basis for this polyfunctionality have generated exciting new knowledge about the biology of G-CSF. This review emphasises recent advances in knowledge about G-CSF signalling, mechanisms of G-CSF-induced stem cell mobilisation, and how G-CSF influences T-cell function and dendritic cell activation. An attempt is made to link the current issues about the biology of G-CSF with its clinical uses, both present and future.     

PSD-95 in CA1 Area Regulates Spatial Choice Depending on Age

Cognitive processes that require spatial information rely on synaptic plasticity in the dorsal CA1 area (dCA1) of the hippocampus. Since the function of the hippocampus is impaired in aged individuals, it remains unknown how aged animals make spatial choices. Here, we used IntelliCage to study behavioral processes that support spatial choices of aged female mice living in a group. As a proxy of training-induced synaptic plasticity, we analyzed the morphology of dendritic spines and the expression of a synaptic scaffold protein, PSD-95. We observed that spatial choice training in young adult mice induced correlated shrinkage of dendritic spines and downregulation of PSD-95 in dCA1. Moreover, long-term depletion of PSD-95 by shRNA in dCA1 limited correct choices to a reward corner, while reward preference was intact. In contrast, old mice used behavioral strategies characterized by an increased tendency for perseverative visits and social interactions. This strategy resulted in a robust preference for the reward corner during the spatial choice task. Moreover, training decreased the correlation between PSD-95 expression and the size of dendritic spines. Furthermore, PSD-95 depletion did not impair place choice or reward preference in old mice. Thus, our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices, old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment.SIGNIFICANCE STATEMENT It remains poorly understood how aging affects behavioral and molecular processes that support cognitive functions. It is, however, essential to understand these processes to develop therapeutic interventions that support successful cognitive aging. Our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices (i.e., choices that require spatial information), old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment. Second, the contribution of PSD-95-dependent synaptic functions in spatial choice changes with age.     

Elucidation of the Receptors in Macrophage and Plasmodium Yoelii Interactions.

Binding of hyperimmune serum opsonized merozoites of Plasmodium Yoelii nigerensis to trypsinized macrophages suggested it to be mediated by FcII receptor. Receptor blocking inhibition with monoclonal antibody 2.4G2 directed against Fc receptor for IgG1/IgG2b provided evidence that Fcγ2b on macrophage played an important role in the merozoite-macrophage interactions. In addition, a neuraminidase sensitive receptor was noted to mediate the binding of P. yeelii merozoites in the absence of serum. Binding inhibition studies with two monosaccharides, D-mannose and α-methyl mannoside, indicated the role of Mannose/Fucose receptor on macrophage in this interaction.     

Proteomic Analyses of the Effects of Drugs of Abuse on Monocyte-Derived Mature Dendritic Cells

Drug abuse has become a global health concern. Understanding how drug abuse modulates the immune system and how the immune system responds to pathogens associated with drug abuse, such hepatitis C virus (HCV) and human immunodeficiency virus (HIV-1), can be assessed by an integrated approach comparing proteomic analyses and quantitation of gene expression. Two-dimensional (2D) difference gel electrophoresis was used to determine the molecular mechanisms underlying the proteomic changes that alter normal biological processes when monocyte-derived mature dendritic cells were treated with cocaine or methamphetamine. Both drugs differentially regulated the expression of several functional classes of proteins including those that modulate apoptosis, protein folding, protein kinase activity, and metabolism and proteins that function as intracellular signal transduction molecules. Proteomic data were validated using a combination of quantitative, real-time PCR and Western blot analyses. These studies will help to identify the molecular mechanisms, including the expression of several functionally important classes of proteins that have emerged as potential mediators of pathogenesis. These proteins may predispose immunocompetent cells, including dendritic cells, to infection with viruses such as HCV and HIV-1, which are associated with drug abuse.     

Design of CD40 Agonists and Their Use in Growing B Cells for Cancer Immunotherapy

CD40 stimulation has produced impressive results in early-stage clinical trials of patients with cancer. Further progress will be facilitated by a better understanding of how the CD40 receptor becomes activated and the subsequent functions of CD40-stimulated immune cells. This review focuses on two aspects of this subject. The first is the recent recognition that signaling by CD40 is initiated when the receptors are induced to cluster within the membrane of responding cells. This requirement for CD40 clustering explains the stimulatory effects of certain anti-CD40 antibodies and the activity of many-trimer, but not one-trimer, forms of CD40 ligand (CD40L, CD154). The second topic is the use of these CD40 activators to expand B cells (“CD40-B cells”). As antigen-presenting cells (APCs), CD40-B cells are as effective as dendritic cells, with the important difference that CD40 B cells can be induced to proliferate in vitro, whereas DCs proliferate poorly if at all. As a result, the use of CD40-B cells as antigen-presenting cells (APCs) promises to streamline the generation of anti-tumor CD8⁺ T cells for the adoptive cell therapy (ACT) of cancer.     

Novel Findings in Drug-Induced Dendritic Cell Tolerogenicity

Dendritic cells (DCs) constitute a unique set of antigen-presenting cells (APCs), equipped with the potential to initiate strong immune responses as well as to critically regulate immunity. Tolerogenic or “alternatively activated” DCs show remarkable properties in regulating immune responses both in vitro and in vivo. Furthermore, tolerogenic DCs are now beginning to be tested in clinical studies. Use of pharmacological agents to induce maturation-resistant tolerogenic DCs is a popular approach. In this review, we will discuss already recognized, as well as recently discovered, potential pharmacological agents, their mechanism of action, and the way in which they induce tolerance in DCs.