immunosuppression

/Tag:immunosuppression

Evaluation and Prevalidation of an Immunotoxicity Test Based on Human Whole-blood Cytokine Release

Ingrid Langezaal, Sebastian Hoffmann, Thomas Hartung, & Sandra Coecke

Immunotoxicology is a relatively new field in toxicology, and is one of emerging importance, because immunotoxicity appears to contribute to the development of cancer, autoimmune disorders, allergies and other diseases. At present, there is a lack of human cell-based immunotoxicity assays for predicting the toxicity of xenobiotics toward the immune system in a simple, fast, economical and reliable way. Existing immunotoxicity tests are mainly performed in animals, although species differences favour humanbased testing. Whole-blood cytokine release models have attracted increasing interest, and are broadly used for pharmacological in vitro and ex vivo studies, as well as for pyrogenicity testing. We have adapted those methods for immunotoxicity testing, to permit the potency testing of immunostimulants and immunosuppressants. Following stimulation with a lipopolysaccharide or staphylococcal enterotoxin B, monocytes and lymphocytes release interleukin-1β and interleukin-4, respectively. Thirty-one pharmaceutical compounds, with known effects on the immune system, were used to optimise and standardise the method, by analysing their effects on cytokine release. The in vitro results were expressed as IC50 values for immunosuppression, and SC4 (fourfold increase) values for immunostimulation, and compared with therapeutic serum concentrations of the compounds in patients, and in vivo LD50 values from animal studies. The in vitro results correlated well with the in vivo data, so the test appears to reflect immunomodulation. Results were reproducible (CV = 20 ± 5%), and the method could be transferred to another laboratory (r2 = 0.99). We therefore propose this method for further validation and for use in immunotoxicity testing strategies.
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Immunotoxicology: Opportunities for Non-animal Test Development

Emanuela Corsini and Erwin L. Roggen

At present, several animal-based assays are used to assess immunotoxic effects such as immunosuppression and sensitisation. The use of whole animals, however, presents several secondary issues, including expense, ethical concerns and relevance to human risk assessment. There is a growing belief that non-animal approaches can eliminate these issues without impairing human safety, provided that biological markers are available to identify the immunotoxic potentials of new chemicals to which humans may be exposed. Driven by the 7th Amendment to the EU Cosmetics Directive, the new EU policy on chemicals (the REACH system), proposals to update the European legislation on the protection of animals used in research, and emerging visions and strategies for predicting toxicity, such in vitro methods are likely to play a major role in the near future. The realisation that the immune system can be the target of many chemicals, resulting in a range of adverse effects on the host’s health, has raised serious concerns from the public and within the regulatory agencies. Hypersensitivity and immunosuppression are considered the primary focus for developing in vitro methods in immunotoxicology. However, in vitro assays to detect immunostimulation and autoimmunity are also needed. This review of the state-of-the-art in the field of in vitro immunotoxicity, reveals a lack of cell-based immunotoxicity assays for predicting the toxicity of xenobiotics toward the immune system in a simple, fast, economical and reliable way.
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