Journal of Immunotoxicology最新文献

Nanoparticles are commonly used in diagnostics and therapy. They are also increasingly being implemented in cancer immunotherapy because of their ability to deliver drugs and modulate the immune system. However, the effect of nanoparticles on immune cells involved in the anti-tumor immune response is not well understood. The study reported here showed that nickel-doped maghemite nanoparticles (FN NP) are differentially cytotoxic to cultured mouse and human cancer cell lines, causing their death without negatively impacting the subsequent anticancer immune response. It also found that FN NP induced cell death in the mouse colorectal cancer cell line CT26 and human prostate cancer cell line PC-3, but not in the human prostate cancer cell line LNCaP. The induced cancer cell death did not affect the phenotype and responsivity of the isolated mouse peritoneal macrophages, or ex vivo-generated mouse bone marrow-derived, or human monocyte-derived dendritic cells. Additionally, the induced cancer cell death did not prevent the ex vivo-generated mouse or human dendritic cells from stimulating lymphocytes and enriching cell cultures with cancer cell-reactive T-cells. In conclusion, this study shows that FN NP could be a valuable platform for targeting cancer cells without causing immunosuppressive effects on the subsequent anticancer immune response.

Per- and polyfluoroalkyl substances (PFAS) are anthropogenic organofluorine compounds that persist indefinitely in the environment and bioaccumulate throughout all trophic levels. Biomonitoring efforts have detected multiple PFAS in the serum of most people. Immune suppression has been among the most consistent effects of exposure to PFAS. PFAS often co-occur as mixtures in the environment, however, few studies have examined immunosuppression of PFAS mixtures or determined whether PFAS exposure affects immune function in the context of infection. In this study, mixtures containing two or four different PFAS and a mouse model of infection with influenza A virus (IAV) were used to assess immunotoxicity of PFAS mixtures. PFAS were administered via the drinking water as either a binary mixture of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) or quaternary mixture of PFOS, PFOA, perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). The results indicated that the binary mixture affected the T-cell response, while the quaternary mixture affected the B-cell response to infection. These findings indicate that the immunomodulatory effects of PFAS mixtures are not simply additive, and that the sensitivity of immune responses to PFAS varies by cell type and mixture. The study also demonstrates the importance of studying adverse health effects of PFAS mixtures.

Per- and polyfluoroalkyl substances (PFAS) are a large group of synthetic surfactants of over 12,000 compounds that are incorporated into numerous products for their chemical and physical properties. Studies have associated PFAS with adverse health effects. Although there is a high potential for dermal exposure, these studies are lacking. The present study evaluated the systemic and immunotoxicity of subchronic 28- or 10-days of dermal exposure, respectively, to PFHpS (0.3125-2.5% or 7.82-62.5 mg/kg/dose) or PFOS (0.5% or 12.5 mg/kg/dose) in a murine model. Elevated levels of PFHpS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. PFHpS induced significantly increased relative liver weight, significantly decreased relative spleen and thymus weight, altered serum chemistries, and altered histopathology. Additionally, PFHpS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen of genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells and CD11b⁺ monocyte and/or macrophages in the spleen along with decreases in eosinophils and dendritic cells in the skin. These findings support PFHpS absorption through the skin leading to liver damage and immune suppression.

Infections caused by the influenza virus lead to both epidemic and pandemic outbreaks in humans and animals. Owing to their rapid production, safety, and stability, DNA vaccines represent a promising avenue for eliciting immunity and thwarting viral infections. While DNA vaccines have demonstrated substantial efficacy in murine models, their effectiveness in larger animals remains subdued. This limitation may be addressed by augmenting the immunogenicity of DNA-based vaccines. In the investigation here, protein expression was enhanced via codon optimization and then mouse cytotoxic T-lymphocyte antigen 4 (CTLA-4) was harnessed as a modulatory adjunct to bind directly to antigen-presenting cells. Further, the study evaluated the immunogenicity of two variants of the hemagglutinin (HA) antigen, i.e. the full-length and the C-terminal deletion versions. The study findings revealed that the codon-optimized HA gene (pcHA) led to increased protein synthesis, as evidenced by elevated mRNA levels. Codon optimization also significantly bolstered both cellular and humoral immune responses. In cytokine assays, all plasmid constructs, particularly pCTLA4-cHA, induced robust interferon (IFN)-γ production, while interleukin (IL)-4 levels remained uniformly non-significant. Mice immunized with pcHA displayed an augmented presence of IFNγ⁺ T-cells, underscoring the enhanced potency of the codon-optimized HA vaccine. Contrarily, CTLA-4-fused DNA vaccines did not significantly amplify the immune response.

Per- and polyfluoroalkyl substances (PFASs) are a large class of compounds used in a variety of processes and consumer products. Their unique chemical properties make them ubiquitous and persistent environmental contaminants while also making them economically viable and socially convenient. To date, several reviews have been published to synthesize information regarding the immunotoxic effects of PFASs on the adaptive immune system. However, these reviews often do not include data on the impact of these compounds on innate immunity. Here, current literature is reviewed to identify and incorporate data regarding the effects of PFASs on innate immunity in humans, experimental models, and wildlife. Known mechanisms by which PFASs modulate innate immune function are also reviewed, including disruption of cell signaling, metabolism, and tissue-level effects. For PFASs where innate immune data are available, results are equivocal, raising additional questions about common mechanisms or pathways of toxicity, but highlighting that the innate immune system within several species can be perturbed by exposure to PFASs. Recommendations are provided for future research to inform hazard identification, risk assessment, and risk management practices for PFASs to protect the immune systems of exposed organisms as well as environmental health.

Diclofenac etalhyaluronate, an active pharmaceutical ingredient in JOYCLU^® (JCL), serves as a joint function improvement agent in knee and hip osteoarthritis patients. However, frequent cases of anaphylaxis induced by JCL administration have been reported. Recent clinical research suggests the potential utility of the basophil activation test (BAT) in predicting JCL-induced anaphylaxis. Nonetheless, the BAT is deemed impractical for routine diagnostic testing due to complex procedures involving whole blood stimulation and flow cytometry-based analyses. In the study reported here, an IgE crosslinking-induced luciferase expression (EXiLE) test which uses patient sera without complicated procedures, was performed with patients who had received JCL, with or without subsequent anaphylactic symptoms. The results of this test were then compared with those of the BAT reported in a clinical research study. Of the six BAT-positive JCL-induced anaphylaxis-experienced patients, four were positive in the EXiLE test and all non-experienced patients were negative in both the BAT and EXiLE tests, thus illustrating a high concordance rate of 92.3%. Further validation of testing conditions is expected to improve these rates. Notably, complement inactivation treatment led to a positive EXiLE result in a BAT-negative patient. In conclusion, it appears that the EXiLE test exhibits promise as an alternative to BAT for predicting JCL-induced anaphylaxis, and in so doing offers a simpler diagnostic approach.

The skin is the organ most often affected by adverse drug reactions. Although these cutaneous adverse drug reactions (CADRs) often are mild, they represent a major burden for patients. One of the drugs inducing CADRs is aldesleukin, a recombinant interleukin-2 (recIL-2) originally approved to treat malignant melanoma and metastatic renal cell carcinoma which frequently led to skin rashes when applied in high doses for anti-cancer therapy. Skin rashes and other side effects, together with poor efficacy led to a drawback of the therapeutic, but modified recIL-2 molecules are on the rise to treat both cancer and inflammatory diseases such as autoimmunity. Still, pathophysiological mechanisms of recIL-2-induced skin rashes are not understood. In the study reported here, a hypothetical literature-based immune-related adverse outcome pathway (irAOP) was developed to identify possible key cells and molecules in recIL-2-induced skin rash. Using this approach, a hypothesis was formed that the induced immune response predominantly is Type 2-driven by T-helper and innate lymphoid cells, leading to the occurrence of cutaneous side effects during recIL-2 therapy. This paper further discusses mechanisms beyond the proposed irAOP which might add to the pathology but currently are less-studied. Together, this hypothetic irAOP forms a basis to clarify possible cellular and molecular interactions leading to recIL-2-induced skin rash. This might be used to adapt existing or develop new test systems to help predict and prevent cutaneous side effects in future IL-2-based or similar therapies.

This work focuses on the need for modeling and predicting adverse outcomes in immunotoxicology to improve nonclinical assessments of the safety of immunomodulatory therapies. The integrated approach includes, first, the adverse outcome pathway concept established in the toxicology field, and, second, the systems medicine disease map approach for describing molecular mechanisms involved in a particular pathology. The proposed systems immunotoxicology workflow is illustrated with chimeric antigen receptor (CAR) T cell treatment as a use case. To this end, the linear adverse outcome pathway (AOP) is expanded into a molecular interaction model in standard systems biology formats. Then it is shown how knowledge related to immunotoxic events can be integrated, encoded, managed, and explored to benefit the research community. The map is accessible online at https://imsavar.elixir-luxembourg.org via the MINERVA Platform for browsing, commenting, and data visualization. Our work transforms a graphical illustration of an AOP into a digitally structured and standardized form, featuring precise and controlled vocabulary and supporting reproducible computational analyses. Because of annotations to source literature and databases, the map can be further expanded to match the evolving knowledge and research questions.

The chances and opportunities in modern biology inspired devising new therapeutics are mind blowing. The promises reach from successfully treating so-far incurable diseases like cancer and certain infections, to modulating and fine tuning the immune response to prolong the lifespan by inhibiting aging. However, as underlying therapies become more and more complex and sophisticated, it becomes increasingly difficult to find ways to ensure and predict the safety of these new therapeutics. The ICH guideline S6 (R1) from June 2011 EMA/CHMP/ICH/731268/ 1998 Committee for Medicinal Products for Human Use (CHMP) already stated "Conventional approaches to toxicity testing of pharmaceuticals may not be appropriate for biopharmaceuticals due to the unique and diverse structural and biological properties of the latter that may include species specificity, immunogenicity, and unpredicted pleiotropic activities" and is committed to a "flexible, case-by-case, science-based approach to preclinical safety evaluation". Initial approaches to this are described in the OECD Test Guidelines for new approach methods (NAM) with the newest update released in 2023 and alternative non-animal test guidelines (https://www.icapo.org/test-guidelines) provided from the International Council on Animal Protection in OECD Programmes (ICAPO; https://www.icapo.org). Beyond that, the European Union-funded innovative medicine initiative project Immune Safety Avatar (imSAVAR) decided to develop a systematic and holistic framework for non-clinical safety assessment of biopharmaceuticals and Advanced Therapy Medicinal Products (ATMP); thereby, the consortium focuses on immuno-regulatory therapeutics. Science-based approaches, such as the mechanistic description of adverse outcomes would be essential to demonstrate the safety of a particular new immuno-therapeutic agent. Here, we re-use the concept of adverse outcome pathways (AOP) to capture immune-related adverse outcomes (irAO), which are aimed to guide us to the use of relevant test systems and experiments. Thus, the focus within imSAVAR is on the use and (further) develop-ment of human and alternative models.

Innovative therapeutics like biologicals that modulate the immune system are on the rise. However, their immune-modulating characteristics can also lead sometimes to the induction of adverse effects, by triggering unintended immune reactions. Due to the complexity and target-specificity of such therapeutics, these drug-induced adverse events could remain undetected during non-clinical development, if the test systems are, for example, animal-based, and only emerge in clinical development when tested in humans and subsequently lead to discontinuance of otherwise promising drug candidates. To identify adverse effects on the human immune system at an early stage, new approaches, assays, and technologies are needed. The Innovative Medicine Initiative (IMI) cooperation Immune Safety Avatar (imSAVAR) project aims to develop a tool for integrated non-clinical safety assessment for immune-modulatory new therapeutic drugs and clinical trial applications. To achieve this goal, imSAVAR has relied on the Adverse Outcome Pathway (AOP) framework to gather knowledge in a structured approach and to design, select or develop, when needed, appropriate test systems for prediction of the immune-related adverse outcomes. So far, the imSAVAR consortium has identified the "mode of action" for certain classes of drugs that needed improved risk assessment, including chimeric antigen receptor T cells (CAR T cells), immune checkpoint inhibitors (ICIs), and recombinant proteins (e.g. interleukin [IL]-2), has linked those to their immune-related adverse outcomes and has formulated literature-based immune-related AOPs (irAOPs). Models to measure those immune-specific perturbations were selected, adjusted, or newly developed. The imSAVAR work described in this special issue of The Journal of Immunotoxicology supports our understanding of immune-mediated adverse effects and their early discovery during development to improve the safety of innovative biomedicals.