Journal of Immunotoxicology最新文献

The aim of this study was to assess the relationship between the expression of the CD23 molecule on B-cells and the levels of specific IgE against allergens and molecular components of storage mites (Gly d 2, Lep d 2), dog (Can f 1, Can f 2), cat (Fel d 1), shrimp (Pen m 2), molds (Asp f 6, Mala s 11, Alt a 6, Alt a 1, Mala s 6, Cla h), and German cockroach (Bla g 9) in atopic dermatitis (AD) patients (with and without dupilumab therapy). Here, 46 patients with AD were included (26 without dupilumab treatment, 20 with dupilumab treatment). Serum levels of specific IgE were measured using the component-resolved diagnostic microarray ALEX2 Allergy Xplorer, and the expression of the CD23 molecule on B-cells was evaluated using flow cytometry. For statistical analysis, a Spearman's rank correlation was used. The data indicated there was a higher correlation between CD23 expression on B-cells and specific IgE against molecular components of storage mites Bla g 9 (up to 27%), cat Fel d 1 (22.7%), and allergen extract Cla h (Cladosporium herbarum) up to 38.9% in AD patients treated with dupilumab. These results regarding the higher association suggested a significant role in the non-inflammatory clearance and uptake of these specific IgE antibodies.

Immunotherapeutics targeting immune checkpoint receptors or their ligands (i.e., immune checkpoint inhibitors), have been groundbreaking in the field of oncology, radically changing the approach to treatment and improving the clinical outcomes of an ever-expanding list of solid tumors and hematological malignancies. However, immune checkpoint inhibitors (ICI) are not devoid of side effects, collectively regarded as immune-related adverse events (irAE); they are not easily uncovered in preclinical immunotoxicological investigations and are often due to the very low expression of their targets in immunologically-unchallenged non-clinical species. We have characterized expression of a broad range of immune checkpoint receptors in peripheral blood mononuclear cell (PBMC) subpopulations from cynomolgus monkeys and healthy human volunteers, under resting and T-cell stimulatory conditions by multicolor flow cytometry to inform appropriate species selection for modeling potential irAE in immunotherapeutic preclinical research. Focusing on the response of the main lymphocyte populations to interleukin (IL)-2 alone, or in combination with anti-CD3 and anti-CD28 antibodies, checkpoints with shared similarities and key differences between the two species were identified. The results of this first study provide a database for the expression and response to stimulation for immune checkpoint receptors and can help guide future model selection in the design of preclinical studies involving immunotherapeutics directed against these targets.

Unwanted immunogenicity of therapeutic proteins arises through the combination of many factors, with the route of administration considered a significant contributor. Contrary to historic data on vaccine delivery, analysis of various therapeutic protein products indicates that the subcutaneous route is not a systematic risk. However, individual product assessments may identify factors specific to the circumstance of their use. Preclinical in vivo studies may add additional information to the comparative immunogenicity risk assessment of intravenous versus subcutaneous administrations. Moreover, immunogenicity risk assessment of new biotherapeutic modalities, such as bispecific antibodies and antibody-linked cytokines, may benefit from a full analysis of risk factors, including preclinical in vivo data. The study here provides immunogenicity analysis of an IgG, two CD3 bispecific antibodies, and two Fc-linked immunocytokines administered intravenously and subcutaneously, aiming to highlight similarities and differences between these administration routes. The current results suggest that the development of anti-drug antibodies does not solely depend on the route of administration but is influenced by multiple risk factors, which should be addressed on a case-by-case basis. This paper reflects on the challenges of interpreting the data and propose standards for improving sample and data collection to aid future analysis.

Immune mechanisms associated with normal pregnancy have only been being substantively investigated since the early 1990s. In parallel with the progress in that area of research, in the past few years it has become increasingly clear that several xenobiotics - including a variety of environmental chemicals, pharmaceuticals, and metals are considered to be both generally immunotoxic and specifically able to affect pregnancy. Among these, there is intense interest regarding potential effects from synthetic cannabinoids, immune checkpoint inhibitors, nanometals, and microplastics, with immunotoxic events that impact on pregnancy being shown for these agents. For instance, phytocannabinoids have been shown to interfere with reproduction in mice through effects on the endocannabinoid system. Because of effects of immune enhancement, as a requirement for regulatory submission, co-inhibitory immune checkpoint molecule inhibitors were also evaluated for effects on pregnancy. Similarly, because of increasing use and concerns about incidental environmental exposures, nanometals, and micro-plastics have also been examined for effects. Several studies in humans or mice showed that exposures to each during gestation increased the risk/rate of fetal loss, in part, by disruption of the placenta-associated immune system. Furthermore, signaling by endogenous danger molecules and/or impairment of physiological intercellular mediators may have contributed to the pregnancy loss. As there are clearly a variety of immunotoxic effects that can impact on a pregnancy, this review attempts to briefly introduce immune mechanisms associated with pregnancy as well as reasons for its loss, and proposes that 'immunotoxicological disruption of pregnancy' be accepted as a new research area in immunotoxicology.

The aim of the study here was to evaluate the association between expression of CD23 molecule on B-lymphocytes and the level of specific IgE to molecular components of birch, Bermuda grass, hazel pollen, timothy, and rye grass in atopic dermatitis (AD) patients (with and without dupilumab therapy). A total of 46 patients suffering from AD were included: 26 without dupilumab treatment and 20 with dupilumab treatment. Serum levels of specific IgE were measured by the components resolved diagnostic assay ALEX2 Allergy Xplorer, the expression of CD23 molecule on B-lymphocytes was evaluated with flow cytometry. For the statistical analysis, the Spearman's rank correlation coefficient was used. In patients treated with dupilumab, the higher association was observed between the expression of CD23 on B-lymphocytes and specific IgE to molecular components Bet v 1, Cor a 1.0103, Cor a 1.0401, and Phl p 1. This study demonstrated that the relationship between CD23 expression on B-lymphocytes and specific IgE to pollen molecular components varies depending on whether the patient was treated with dupilumab and the type of molecular component involved.

It was previously reported that half of the anaphylaxis cases occurring after intra-articular administration of diclofenac etalhyaluronate (DEH) - developed as SI-613/ONO-5704 and marketed as JOYCLU^® - were induced by IgE-mediated mechanisms; mechanisms for the remaining cases remain unclear. In this study, we investigated the relationship of DEH-induced anaphylaxis to non-IgE-mediated mechanisms in vitro. Assays were carried out based on the production of downstream products of the complement cascade, calcium influx due to Mas-related G protein-coupled receptor-X2 (MRGPRX2) activation, mast cell degranulation, and expression of basophil activation markers. Human plasma, CHO-K1 cells stably expressing MRGPRX2, the human mast cell line LAD2, and the human basophil leukemia cell line KU812 were used for these evaluations. No effect of DEH treatment was found on complement activation, MRGPRX2 agonist activity, direct mast cell activation, or direct basophil activation. From this it could be concluded that DEH-induced anaphylaxis is unlikely to involve complement activation or direct activation of mast cells and basophils. However, the possibility remains that the anaphylaxis might be a non-immunological hypersensitivity reaction due to inhibition of cyclooxygenase-1 by non-steroidal anti-inflammatory drugs (NSAID). Further investigation into the relationship between the non-immunological hypersensitivity and anaphylaxis following DEH administration is warranted.

Plantago asiatica L., a perennial herb in the family Plantaginaceae, has been shown to impart several pharmacologic activities, including anti-oxidative, anti-inflammatory, and diuretic effects. In the study here, the anti-gout(y) arthritis (GA) effects of a crude extract from P. asiatica L. (PAE) were investigated in a rat GA model. For this, PAE was prepared by ethanol extraction and analyzed for phytochemicals by RP-HPLC and Q-TOF-MS. Thereafter, potential therapeutic effects of the PAE were investigated in rats; Wistar rats (male, 8 wk-of-age) were randomly allocated into four groups (n = 9/group) and intra-articularly injected with 3 mg monosodium urate (MSU) in saline solution to establish a GA model. For the study, rats received oral dosings of 0.3 mg colchicine/kg or 1 g PAE/kg (w/w) before and after gout was established. At fixed times after the treatments, assessment of joint swelling ratios and pathological changes in the joints, as well as of select cytokine expression in the blood, was done. RP-HPLC results showed the PAE contained at least 8 'active' ingredients, with plantamajoside, verbascoside, and cymaroside being the most abundant. In comparison to in control rats, MSU induced joint space narrowing, ankle joint swelling, and increased levels of pro-inflammatory interleukin (IL)-1β, IL-17a, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, and reductions in anti-inflammatory IL-10 in the blood. PAE treatment significantly reversed patho- genic joint space narrowing and swelling, reversed the MSU-induced changes in inflammatory factors, and in general imparted effects very similar to those seen with colchicine (COL; known non-steroidal anti-inflammatory drug for clinical treatment of GA). Collectively, these findings provide experimental evidence supporting the potential applicability of PAE to treat gouty arthritis.

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China, leading to the global Coronavirus Disease pandemic. The rapid spread of SARS-CoV-2 highlighted the urgent need for effective vaccines. However, the high cost, cold storage requirements, and scalability challenges associated with mRNA vaccines have necessitated alternative vaccine technologies. In the study, the safety of a plant-based vaccine was evaluated. The vaccine, an emulsion of the SARS-CoV-2 S1 antigen and a synthetic TLR4 agonist produced and purified from Nicotiana benthamiana, was administered to Sprague-Dawley rats three times over 4 wk. Mortality, clinical signs, body weight, food consumption, vision, urinalysis, gross findings, organ weight, hematology, serum biochemistry, histopathology, and immunogenicity were evaluated. The results showed that antibodies were efficiently produced and maintained for one month following vaccination with the plant-derived receptor-binding domain (RBD) antigen of COVID-19. Furthermore, the rats showed no toxicological symptoms, with reversible changes at the injection site and minor histological alterations in the spinal cord and bone marrow, typical of vaccine responses. The plant-derived SARS-CoV-2 vaccine appears safe following repeated administration over 4 wk and represents a promising alternative for potential use in human clinical trials and clinical applications.

Efgartigimod is a human IgG₁ antibody F_c fragment that reduces IgG levels through neonatal F_c receptor blockade. This study evaluated whether efgartigimod affects the generation of T-cell-dependent antibodies and cellular immune responses to keyhole limpet hemocyanin (KLH) immunization in non-human primates. Cynomolgus monkeys received efgartigimod or vehicle control intravenously for 11 wk, followed by a recovery phase. KLH challenges occurred during both the dosing phase and the recovery phase. No statistically significant differences emerged in anti-KLH IgM levels between the efgartigimod and control groups. Likewise, comparable KLH-specific T cell responses were observed between groups. Anti-KLH IgG titers were lower in efgartigimod-treated animals compared with controls only after the first boost of KLH, coinciding with decreases in total IgG titers in efgartigimod-treated animals, and returned to baseline levels by the end of the recovery phase. Taken together, these results indicate that efgartigimod does not suppress T-cell-dependent antibody responses or antibody class-switching. The findings of this study are consistent with efgartigimod's pharmacological mechanism of action and suggest that efgartigimod does not impair the generation of effective immune responses.

Trichloroethylene (TCE) is a volatile synthetic chemical used in various industrial processes like metal degreasing. Large amounts of TCE have been released into the environment. Exposure to TCE can occur through routes, such as inhalation for workers using TCE or ingestion of drinking water in contaminated areas. Macrophages are key immune cells in virtually all tissues in the human body, including the fetal membranes, making them a plausible target for DCVC-induced immunotoxicity. Macrophages are critical for maintaining anti-microbial defenses during pregnancy, but little data exists on TCE immunotoxicity during pregnancy. We previously showed that the TCE metabolite, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), down-regulates immune functions in fetal membranes. To gain insight into immune functions impacted by DCVC, we treated a macrophage cell model (THP-1 cells) with DCVC followed by stimulation with bacterial or fungal toxins relevant for intrauterine infections: lipopolysaccharide (LPS), lipoteichoic acid (LTA), or zymosan. DCVC inhibited toxin-stimulated release of cytokines (e.g. TNFα and IL-1β) for all three microbial toxins. We then conducted benchmark dose modeling and compared benchmark doses for DCVC cytotoxicity vs. cytokine suppression and determined that inhibition of cytokine release was the more potent endpoint compared to cytotoxicity. Finally, we analyzed a previously generated transcriptomic dataset from THP-1 cells stimulated with LPS, with or without DCVC treatment. We identified transcription factors that were enriched with DCVC and/or LPS treatment, including NF-kB and Vitamin D receptor (VDR). Our findings show that DCVC potently alters cellular and molecular macrophage immune responses involved in defense against intrauterine pathogens.