Future direction in immunotoxicology: immunosuppression as key player (#773)
1 Université catholique de Louvain, Louvain centre for Toxicology and Applied Pharmacology, Brussels, Belgium
A pathogenic scenario whereby chronic inflammation governs toxicant-induced chronic diseases has been largely disclosed in mechanistic toxicology. Considerable evidence suggests that accumulated inflammatory leukocytes play a critical role in the pathological processes by generating free radical-induced damage to DNA, triggering genomic instability, producing a favorable environment for cell growth and promoting angiogenesis.
While toxicant-induced cancer, fibrosis or autoimmunity have been so far almost exclusively linked to an exacerbated inflammation, recent studies reveal a new pathophysiological pathway that involves, in contrast, immunosuppressive responses (defined as immunosuppression) initially established for limiting deleterious effects of inflammation. Much progress has been recently made in our comprehension of immunosuppression in cancer. This challenging concept has additionally modified our view of how toxicants perturb the immune system and cause chronic diseases.
In this session, participants are informed on how immunosuppression is triggered and orchestrated by chemical substances and particles. A portfolio of immunosuppressive cells will be depicted, in particular the role of type-2 macrophages (M2), regulatory lymphocytes (T and B regs) or Myeloid Derived Suppressor Cells (MDSC). Immunosuppression is not limited to immune mediators; metabolism of several essential amino acids such as tryptophan and arginine also serves for efficiently inhibiting immune responses. The consideration that immunosuppression is crucial in toxicant-related diseases provides a unique opportunity to open new horizons for discovering new key biomarkers and/or therapeutic targets.
Keywords: immunosuppression, immunosuppressive responses, metabolism, cytokines, cancer, fibrosis, particles
Pesticide-induced immunotoxicity: the experience at EFSA (#130)
1 EFSA, Pesticide, parma, Italy
The project reviewed the potential immunotoxicity of pesticide active substances evaluated in EU following the european regulation under the auspicies of the European Food Safety Authority (EFSA). Focus was to identify any new approach to the evaluation of potential immunotoxicity. Current testing guidelines and specific immunotoxicity tests have been evaluated and critical end-points identified for use in evaluating summaries of 198 active substances reviewed in the EU. Analyses have been performed to identify the number of pesticides that affect immune system end-points, the number that have a consistent pattern of effects and those that exhibit these effects at dose levels relevant to the overall risk assessment. The conclusion are that the current testing strategy for pesticides, although having some deficiecies, appears adequate to identify compounds with the potential to affect the functioning of the immune system. Proposal are made to enhance the testing strategy in the future.
Keywords: imminotoxicity, pesticides, protocols, review.
Immunotoxicology testing within the National Toxicology Program (NTP): Reflections on the Past, Present and Future (#93)
D. R. Germolec1
1 National Toxicology Program, NIEHS, Toxicology Branch, Research Triangle Park, North Carolina, United States of America
The identification of chemicals that have the potential to cause injury to the immune system is of considerable public health significance, as alterations in immune function can lead to increased incidence of hypersensitivity and autoimmune disorders, infectious diseases or neoplasias. Experimental animal data collected over the past 20 years using standardized testing panels have provided a database from which the sensitivity and predictability of tests commonly used for the screening of chemicals for immunotoxicity has been evaluated. These studies suggest that there is not a single most sensitive parameter for assessing damage to the immune system, but rather that multiple endpoints are needed to flag a compound as immunotoxic. We have used a tiered testing strategy to assess changes in immune function and continue to refine and improve the test methods. However, with the infinite number of chemcials and mixtures in the environment, we are challenged to develop streamlined strategies for more efficient examination of potential immune effects. As part of a response to assess human health risk following recent releases of polycyclic aromatic compounds (PACs) in the environment, the NTP has developed a research plan to characterize the toxicity of PACs using in vitro, alternative animal, and short-term rodent studies. We are using a streamlined approach to assess humoral immunity in B6C3F1/N mice to generate potency data for well characterized and understudied PACs. As we increase our understanding of the mechanisms that underlie immunotoxicity, we are able to model in vitro changes at the cellular level that lead to alterations in immune function. We are comparing data from assays using primary cells or cells lines with data from traditional animal models and epidemiology studies of known toxicants such as perfluoroalkyl substances, and using in vitro tools to screen classes of chemicals and mixtures that may otherwise confound with their potential variety.
Keywords: immunotoxicology, polycyclic aromatic compounds, perfluoroalkyl substances, humoral immunity, in vitro testing
Immunosuppression mediated by enzymes that degrade tryptophan (#825)
B. Van den Eynde1, 2
1 Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium
Both central and peripheral mechanisms ensure the tight regulation of the immune system that is needed to ensure efficient protection against pathogens while avoiding autoimmunity. Peripheral immune tolerance mechanisms include negative feedback pathways controlled by immune checkpoints, whose function is to shut down established immune responses and prevent excessive immune activation. These immune checkpoints normally act when the pathogen has been cleared. The immune system also attacks tumors, but the kinetics is often slower, so that immune checkpoints get activated before complete clearance of the tumor. In recent years, a better understanding of immune checkpoints has allowed the design of new cancer therapies able to sustain immune responses by blocking immune checkpoints such as PD-1 and CTLA4. Those new therapies have shown unprecedented clinical activity in a subset of patients with metastatic cancers. However, other immune checkpoints likely limit the efficacy of cancer immunotherapy in other patients. Ongoing research aims at characterizing these additional mechanisms and devising therapeutic strategies to overcome them. One of them is based on metabolic changes in the tumor microenvironment: many tumors aberrantly express enzymes able to degrade tryptophan into kynurenine. These are indoleamine-dioxygenase (IDO) and, to a lesser extent, tryptophan dioxygenase (TDO). These metabolic changes are profoundly immunosuppressive, through the combined action of tryptophan depletion and kynurenine production. Inhibitors of these enzymes increase the efficacy of cancer immunotherapy in preclinical models and are currently in clinical development. The exact mechanisms responsible for IDO/TDO-induced immunosuppression remain unclear. Different pathways have been proposed, including a GCN2-mediated integrated stress response or a deactivation of mTOR, both triggered by tryptophan shortage, and the induction of an AHR response by kynurenine or its derivatives.
Keywords: IDO, Cancer immunosuppression, AHR, mTOR, GCN2
The Aryl Hydrocarbon Receptor in Immuno(toxicity): the new, the old, the unexpected (#791)
1 IUF - Leibniz Research Institute of Environmental Medicine, Immunotoxicology, Düsseldorf, Germany
The aryl hydrocarbon receptor (AHR) and its ligand-driven transcriptional activity was originally discovered as a master regulator for genes coding for xenobiotic metabolizing enzymes. Thus, AhR´s functional role seemed clear: metabolize and degrade a range of structurally similar chemicals. However, AhR activation by a number of these chemicals, namely xenobiotic pollutants such as polycyclic aromatic hydrocarbons (PAHs) or halogenated PAHs, can result in toxicity. For instance, cancerogenicity can be caused by benzo[a]pyrenes or immunotoxicity by TCDD. The resulting bad reputation of AHR as the mediator of toxicity by its ligands found in environmental pollutants seems to contrast with the recently discovered important roles of AHR for adaptive cell differentiation and specific cellular functions, for instance in the immune system. It was shown that “natural” ligands found in plants or generated endogenously are necessary and relevant for many such functions. In the diet indole-derivatives, glucosinolates, or flavonoids can act as ligands. Other AHR activators are tryptophan-derivatives generated by sun-light in the skin or bacteria in the gut. I will discuss major research findings regarding the immunological outcome of AHR-activation and look at two areas of future immunological / immunotoxicological concern, (i) the AHR-microbiome axis and (ii) the issue of participation of AHR in the adverse immune effects of airborne particulate matter. They showcase the surprises that AHR signaling still has to offer for basic biology and for its relevance in global health concerns.
Keywords: immunotoxicology, dioxin, air pollution, microbiome, aryl hydrocarbon receptor, ahr