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Lancet (London, England) Jul 2023T-cell-engaging bispecific antibodies (BsAbs) simultaneously bind to antigens on tumour cells and CD3 subunits on T cells. This simultaneous binding results in the... (Review)
Review
T-cell-engaging bispecific antibodies (BsAbs) simultaneously bind to antigens on tumour cells and CD3 subunits on T cells. This simultaneous binding results in the recruitment of T cells to the tumour, followed by T-cell activation and degranulation, and tumour cell elimination. T-cell-engaging BsAbs have shown substantial activity in several haematological malignancies by targeting CD19 in acute lymphoblastic leukaemia, CD20 in B-cell non-Hodgkin lymphoma, and BCMA and GPRC5D in multiple myeloma. Progress with solid tumours has been slower, in part due to the paucity of therapeutic targets with a tumour-specific expression profile, which is needed to limit on-target off-tumour side-effects. Nevertheless, BsAb-mediated recognition of a peptide fragment of gp100 presented by HLA-A2:01 molecules has shown marked activity in patients with unresectable or metastatic uveal melanoma. Cytokine release syndrome is the most frequent toxicity associated with BsAb treatment and is caused by activated T cells secreting proinflammatory cytokines. Understanding of resistance mechanisms has resulted in the development of new T cell-redirecting formats and novel combination strategies, which are expected to further improve depth and duration of response.
Topics: Humans; T-Lymphocytes; Antibodies, Bispecific; Neoplasms; Antigens, CD19
PubMed: 37271153
DOI: 10.1016/S0140-6736(23)00521-4 -
Allergology International : Official... Jul 2023The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding... (Review)
Review
The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding of how and why skin MCs are involved and different in CU. Also, novel and relevant mechanisms of MC activation in CU have been identified and characterized. Finally, the use of MC-targeted and MC mediator-specific treatments has helped to better define the role of the skin environment, the contribution of specific MC mediators, and the relevance of MC crosstalk with other cells in the pathogenesis of CU. Here, we review these recent findings and their impact on our understanding of CU, with a focus on chronic spontaneous urticaria (CSU). Also, we highlight open questions, issues of controversy, and unmet needs, and we suggest what studies should be performed moving forward.
Topics: Humans; Urticaria; Mast Cells; Chronic Urticaria; Skin
PubMed: 37210251
DOI: 10.1016/j.alit.2023.05.003 -
Seminars in Immunology Nov 2023Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed... (Review)
Review
Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation.
Topics: Humans; Neutrophils; Pyroptosis; Phagocytosis; Apoptosis
PubMed: 37939552
DOI: 10.1016/j.smim.2023.101849 -
Biological Reviews of the Cambridge... Jun 2024Neutrophils are considered 'first-line defence' cells as they can be rapidly recruited to the site of the immune response. As key components of non-specific immune... (Review)
Review
Neutrophils are considered 'first-line defence' cells as they can be rapidly recruited to the site of the immune response. As key components of non-specific immune mechanisms, neutrophils use phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to fight pathogens. Recently, immunoregulatory abilities of neutrophils associated with the secretion of several mediators, including cytokines and extracellular vesicles (EVs) containing, among other components, microRNAs (miRNAs), have also been reported. EVs are small structures released by cells into the extracellular space and are present in all body fluids. Microvesicles show the composition and status of the releasing cell, its physiological state, and pathological changes. Currently, EVs have gained immense scientific interest as they act as transporters of epigenetic information in intercellular communication. This review summarises findings from recent scientific reports that have evaluated the utility of miRNA molecules as biomarkers for effective diagnostics or even as start-points for new therapeutic strategies in neutrophil-mediated immune reactions. In addition, this review describes the current state of knowledge on miRNA molecules, which are endogenous regulators of gene expression besides being involved in the regulation of the immune response.
Topics: MicroRNAs; Neutrophils; Humans; Animals; Extracellular Vesicles
PubMed: 38148491
DOI: 10.1111/brv.13048 -
Allergology International : Official... Jul 2023Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to... (Review)
Review
Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to allergen-induced skin reactions supports that skin mast cell IgE receptor activation is also involved in CSU. Accumulating evidence also supports a role for blood basophils in disease expression. Blood basopenia is noted in active CSU disease with the recruitment of blood basophils to skin lesion sites. Blood basophils further display altered IgE receptor mediated degranulation patterns in two phenotypes that improve in remission. In active CSU subjects, changes in IgE receptor signaling molecule expression levels accompany the altered degranulation function in blood basophils. The success of therapies targeting IgE in CSU patients have also shown that altered blood basophil phenotypes and enumeration have potential use as a disease biomarker.
Topics: Humans; Basophils; Receptors, IgE; Chronic Disease; Urticaria; Chronic Urticaria
PubMed: 37221123
DOI: 10.1016/j.alit.2023.05.001 -
Developmental and Comparative Immunology Oct 2023Leukocyte immune-type receptors (LITRs) are a large family of teleost immunoregulatory receptor-types belonging to the immunoglobulin superfamily. These immune genes are... (Review)
Review
Leukocyte immune-type receptors (LITRs) are a large family of teleost immunoregulatory receptor-types belonging to the immunoglobulin superfamily. These immune genes are phylogenetically and syntenically related to Fc receptor-like protein genes (fcrls) present in other vertebrates, including amphibians, birds, mice, and man. In vitro-based functional analyses of LITRs, using transfection approaches, have shown that LITRs have diverse immunoregulatory potentials including the activation and inhibition of several innate immune effector responses such as cell-mediated killing responses, degranulation, cytokine secretion, and phagocytosis. The purpose of this mini review is to provide an overview of fish LITR-mediated immunoregulatory potentials obtained from various teleost model systems, including channel catfish, zebrafish, and goldfish. We will also describe preliminary characterization of a new goldish LITR-specific polyclonal antibody (pAb) and discuss the significance of this tool for further investigation of the functions of fish LITRs.
Topics: Mice; Animals; Zebrafish; Receptors, Immunologic; Phagocytosis; Immunity, Innate; Leukocytes
PubMed: 37414235
DOI: 10.1016/j.dci.2023.104768 -
Frontiers in Immunology 2023Chorioamnionitis, commonly referred to as intrauterine infection or inflammation, is pathologically defined by neutrophil infiltration and inflammation at the... (Review)
Review
Chorioamnionitis, commonly referred to as intrauterine infection or inflammation, is pathologically defined by neutrophil infiltration and inflammation at the maternal-fetal interface. Chorioamnionitis is the common complication during late pregnancy, which lead to a series of serious consequences, such as preterm labor, preterm premature rupture of the fetal membranes, and fetal inflammatory response syndrome. During infection, a large number of neutrophils migrate to the chorio-decidua in response to chemokines. Although neutrophils, a crucial part of innate immune cells, have strong anti-inflammatory properties, over-activating them can harm the body while also eliminating pathogens. This review concentrated on the latest studies on chorioamnionitis-related consequences as well as the function and malfunction of neutrophils. The release of neutrophil extracellular traps, production of reactive oxygen species, and degranulation from neutrophils during intrauterine infection, as well as their pathological roles in complications related to chorioamnionitis, were discussed in detail, offering fresh perspectives on the treatment of chorioamnionitis.
Topics: Female; Infant, Newborn; Pregnancy; Humans; Chorioamnionitis; Neutrophils; Inflammation; Extracellular Traps; Premature Birth
PubMed: 37475854
DOI: 10.3389/fimmu.2023.1198831 -
Current Protocols Sep 2023Neutrophils represent the first line of defense against bacterial and fungal pathogens. Indeed, patients with inherited or acquired qualitative and quantitative...
Neutrophils represent the first line of defense against bacterial and fungal pathogens. Indeed, patients with inherited or acquired qualitative and quantitative neutrophil defects are at high risk for developing bacterial and fungal infections and suffering adverse outcomes from these infections. Therefore, research aiming at defining the molecular factors that modulate neutrophil effector function under homeostatic conditions and during infection is essential for devising strategies to augment neutrophil function and improve the outcomes of infected individuals. This article describes reproducible density-gradient-centrifugation-based as well as positive and negative immunomagnetic selection protocols that can be applied in any laboratory to harvest large numbers of highly enriched and highly viable neutrophils from the bone marrow of mice. In another protocol, we also present a method that combines gentle enzymatic tissue digestion with a positive immunomagnetic selection technique or fluorescence-activated cell sorting (FACS) to harvest highly pure and highly viable preparations of neutrophils directly from mouse tissues such as the kidney, the liver, or the spleen. Mouse neutrophils isolated by these protocols can be used to examine several aspects of cellular function ex vivo, including pathogen binding, phagocytosis, and killing, neutrophil chemotaxis, oxidative burst, degranulation, and cytokine production, and for performing neutrophil adoptive transfer experiments. © 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. Basic Protocol 1: Isolation of Neutrophils from Mouse Bone Marrow Using Positive Immunomagnetic Separation Alternate Protocol 1: Purification of Neutrophils from Bone Marrow Using Negative Immunomagnetic Separation Alternate Protocol 2: Purification of Neutrophils from Bone Marrow Using Histopaque-Based Density Gradient Centrifugation Basic Protocol 2: Isolation of Neutrophils from Mouse Tissues Using Positive Immunomagnetic Separation Alternate Protocol 3: Isolation of Neutrophils from Mouse Tissues Using FACS.
Topics: Animals; Mice; Humans; Neutrophils; Phagocytosis; Adoptive Transfer; Flow Cytometry; Government Employees
PubMed: 37707422
DOI: 10.1002/cpz1.879 -
Science (New York, N.Y.) Dec 2023Current HIV vaccines designed to stimulate CD8 T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8 T...
Current HIV vaccines designed to stimulate CD8 T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8 T cells were investigated here in detail. Cytotoxic capacity was significantly lower than in HIV controllers and was not a consequence of low frequency or unaccumulated functional cytotoxic proteins. Low cytotoxic capacity was attributable to impaired degranulation in response to the low antigen levels present on HIV-infected targets. The vaccine-induced T cell receptor (TCR) repertoire was polyclonal and transduction of these TCRs conferred the same reduced functions. These results define a mechanism accounting for poor antiviral activity induced by these vaccines and suggest that an effective CD8 T cell response may require a vaccination strategy that drives further TCR clonal selection.
Topics: Humans; AIDS Vaccines; Clone Cells; HIV Infections; Receptors, Antigen, T-Cell; Cytotoxicity, Immunologic; T-Lymphocytes, Cytotoxic; Cell Degranulation
PubMed: 38096385
DOI: 10.1126/science.adg0514