Journal of Immunotoxicology最新文献

This review was undertaken because it is known that high doses of atrazine activate the HPA axis, leading to increased corticosterone secretion, which could result in immunosuppression.  The mammalian immunotoxicity of atrazine was evaluated based on in vitro and in vivo studies and the association between chlorotriazine use and the risk of cancer in humans based on epidemiological studies. In vitro studies reported that μM concentrations of atrazine may adversely affect cytokine production, lymphocytes, and dendritic cell function. However, there were no consistent patterns of effects of the chlorotriazines on the developing or mature immune system in sub-chronic, chronic, and lifetime animal studies. In a detailed immunotoxicity study on atrazine in rats, there were no effects of atrazine treatment on T-cell-dependent, IgM antibody production or natural killer cell activity. Based on the compendium of toxicology data reviewed, it was concluded that atrazine is unlikely to be immunotoxic at any dose to which humans might realistically be exposed. This conclusion was supported by epidemiological studies indicating that there was no consistent association between occupational exposure to atrazine and cancers of the immune system.

Exposure to environmental agents has been linked to inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD) in humans. In these studies, we describe a modification of an experimental model used historically in the pharmaceutical industry to help identify therapies for the treatment of IBD to facilitate its use for identification of environmental agents that have the potential to accelerate, exacerbate, and/or impair recovery from IBD. In this model, female C57BL/6 mice were exposed to low levels of dextran sodium sulfate (DSS) for 7 consecutive days in drinking water to allow for a modest level of colon inflammation and pathology as measured by a battery of clinical, pathological, toxicological endpoints (water consumption, body weights, colon length, body temperature, stool consistency, and hematochezia), and cytokine/chemokine production in the serum and colon. Treatment with DSS for 7 d showed a clear dose-response with 1% DSS producing minimal changes in the colon and 3% DSS inducing severe damage with IBD. A concentration of 2% DSS in drinking water for 7 d was selected for investigating disease recovery and exacerbation by an environmental agent as it induced mild colon inflammation that showed nearly complete resolution within 21 d following cessation of DSS exposure. Cytokine and chemokine profiles showed a Type 1 predominant immune response in the colon and serum that is consistent with inflammation observed in human IBD. The model was used to determine the impact of administration of a high salt diet (HSD) on DSS IBD progression, severity, and recovery. While administration of HSD by itself had no effect on indicators of colon damage or inflammation, co-administration of HSD with DSS, produced marked exacerbation and persistence of disease supporting the potential of the model for identifying environmental agents that can affect IBD.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by impaired skin barrier function, persistent inflammation, and increased vulnerability to environmental irritants. Chronic inflammation in AD can also contribute to premature skin aging by promoting collagen degradation, wrinkle formation, and reduced skin elasticity. Conventional treatments, including topical corticosteroids, may lead to adverse effects with long-term use, underscoring the need for safer, sustainable alternatives. Glycomacropeptide (GMP), a bioactive peptide derived from κ-casein during cheese production, has attracted interest for its anti-inflammatory, antioxidant, and skin barrier-supporting properties. Evidence from in vitro, in vivo, and limited clinical studies suggests that GMP may modulate inflammatory responses, attenuate oxidative stress, support collagen integrity, and promote wound healing. Its amphiphilic nature also enables its use as a natural emulsifier in topical formulations. In addition, the utilization of GMP contributes to sustainable development by valorizing dairy byproducts. This narrative review synthesizes current literature on GMP's dermatological potential, with a focus on its applicability in AD management and skin aging mitigation, while identifying research gaps and directions for future clinical evaluation.

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.