The Experts below are selected from a list of 15123 Experts worldwide ranked by ideXlab platform
Jacques Descotes - One of the best experts on this subject based on the ideXlab platform.
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Immunotoxic effects of cyclophosphamide and cyclosporine in the dog
Journal of immunotoxicology, 2012Co-Authors: Jean-jacques Legrand, Caroline Bouchez, Cecile Mimouni, Armelle Nguyen, Johanne Bouchard, Thibault Ameller, Jacques DescotesAbstract:Limited non-clinical Immunotoxicity data are available in the dog, although this is a major non-rodent species in regulatory safety studies. The present study aimed to test whether widely accepted Immunotoxicity endpoints including lymphocyte subset immunophenotyping, the anti-KLH TDAR assay, and histological examination of the main lymphoid organs were reliable to detect immunosuppression induced by cyclosporine and cyclophosphamide in dogs and could, therefore, be used for non-clinical Immunotoxicity evaluation in this species. Male and female Beagle dogs were treated orally from Day 1 for 4 weeks with 25 mg/kg cyclosporine daily, or with 2 mg/kg cyclophosphamide on 4 consecutive days each week, or the same volume of drinking water daily. Blood samples were withdrawn pre-test and on Days 11, 18, and 23 to measure standard hematology parameters and analyze lymphocyte subsets. All animals received an intramuscular injection of 5 mg KLH on Day 11. Sandwich ELISA assays were used to quantify anti-KLH IgM an...
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Pharmaceutical Sciences Encyclopedia - Safety Assessment Studies: Immunotoxicity
Pharmaceutical Sciences Encyclopedia, 2010Co-Authors: Jacques DescotesAbstract:The clinical shift from immunology to toxicology resulted in the introduction of toxicological concepts in Immunotoxicity evaluation. Current procedures for assessing the immunotoxicological safety of medicinal products have some shortcomings. Nonclinical Immunotoxicity evaluation is currently limited to unintended immunosuppression. This article discusses various safety factors related to Immunotoxicity, including preclinical assessment of immunosuppression and models of IgE mediated hypersensitivity reactions. Keywords: Immunotoxicity; toxicology; immunosuppression; IgE-mediated hypersensitivity; drug safety
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Immunotoxicity of monoclonal antibodies.
mAbs, 2009Co-Authors: Jacques DescotesAbstract:Monoclonal antibodies (mAbs) are large molecules intended to bind to specific targets often expressed on the immune system, and to treat various immunopathological conditions. Therefore, mAbs can be considered to have a high potential for Immunotoxicity, which is reflected in the clinical experience accumulated on mAbs-induced adverse effects related to immunosuppression, immunostimulation, and hypersensitivity (immunogenicity). So far, non clinical Immunotoxicity studies have been inadequate to address all safety issues in relation to the possible Immunotoxicity of mAbs, because they are fraught with limitations and pitfalls primarily related to the lack of relevant animal species. In addition, clinical studies rarely include validated end-points dedicated to the prediction of Immunotoxicity. With the ongoing development of mAbs as novel therapeutic strategies for a wide variety of diseases, efforts should be paid to improve our understanding of mAbs-induced immunotoxic effects and design dedicated strat...
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Immunotoxicology
Drug Safety, 2005Co-Authors: Jacques DescotesAbstract:The immunotoxic effects of drugs are divided into immunosuppression, immunostimulation, hypersensitivity and autoimmunity. The major adverse consequences of immunosuppression are infectious complications and virus-induced malignancies. Flu-like reactions, more frequent autoimmune diseases and hypersensitivity reactions to unrelated allergens, and inhibition of drug-metabolising enzymes are the adverse effects related to immunostimulation. Hypersensitivity reactions are the most frequent immunotoxic effects of drugs. They include immune-mediated (‘allergic’) and non immune-mediated (‘pseudoallergic’) reactions. Drug-induced autoimmune reactions, either systemic or organ-specific, are seemingly rare. A review of drug-induced immunotoxic effects demonstrates that Immunotoxicity is a significant cause of morbidity and even mortality. As immunotoxicologists have long focused on immunosuppression, the nonclinical Immunotoxicity safety assessment of unexpected immunosuppression is based on a number of relatively well standardised and validated animal models and assays. However, there is no general consensus regarding the minimal requirement for this assessment. Many different assays can be used to extend the assessment case by case. Few animal models and assays have been validated for use in the nonclinical safety assessment of unexpected immunostimulation. The situation is worse regarding the prediction of hypersensitivity and autoimmune reactions. Our limited understanding of the molecular and cellular mechanisms of Immunotoxicity accounts, at least partly, for this situation. Recent guidelines for the Immunotoxicity safety assessment of drugs, even though conflicting on several points, will serve as an impetus not only to refine current animal models and assays, but also to search for better alternatives. The new data generated will have to be interpreted and extended to animal species other than just rodents. Likewise, animal results will have to be compared with findings in humans. The search for immunological endpoints that can be used in several animal species and in humans will therefore become essential. Specific endpoints and clinical criteria that can be included in clinical trials to further investigate the potential for Immunotoxicity of new drugs will have to be defined. Because Immunotoxicity plays a key role in drug-induced adverse effects, the role of immunotoxicology in drug safety assessment is indisputable and the systematic nonclinical as well as clinical Immunotoxicity assessment of every new drug is deemed essential.
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Immunotoxicology: role in the safety assessment of drugs.
Drug safety, 2005Co-Authors: Jacques DescotesAbstract:The immunotoxic effects of drugs are divided into immunosuppression, immunostimulation, hypersensitivity and autoimmunity. The major adverse consequences of immunosuppression are infectious complications and virus-induced malignancies. Flu-like reactions, more frequent autoimmune diseases and hypersensitivity reactions to unrelated allergens, and inhibition of drug-metabolising enzymes are the adverse effects related to immunostimulation. Hypersensitivity reactions are the most frequent immunotoxic effects of drugs. They include immune-mediated ('allergic') and non immune-mediated ('pseudoallergic') reactions. Drug-induced autoimmune reactions, either systemic or organ-specific, are seemingly rare. A review of drug-induced immunotoxic effects demonstrates that Immunotoxicity is a significant cause of morbidity and even mortality. As immunotoxicologists have long focused on immunosuppression, the nonclinical Immunotoxicity safety assessment of unexpected immunosuppression is based on a number of relatively well standardised and validated animal models and assays. However, there is no general consensus regarding the minimal requirement for this assessment. Many different assays can be used to extend the assessment case by case. Few animal models and assays have been validated for use in the nonclinical safety assessment of unexpected immunostimulation. The situation is worse regarding the prediction of hypersensitivity and autoimmune reactions. Our limited understanding of the molecular and cellular mechanisms of Immunotoxicity accounts, at least partly, for this situation. Recent guidelines for the Immunotoxicity safety assessment of drugs, even though conflicting on several points, will serve as an impetus not only to refine current animal models and assays, but also to search for better alternatives. The new data generated will have to be interpreted and extended to animal species other than just rodents. Likewise, animal results will have to be compared with findings in humans. The search for immunological endpoints that can be used in several animal species and in humans will therefore become essential. Specific endpoints and clinical criteria that can be included in clinical trials to further investigate the potential for Immunotoxicity of new drugs will have to be defined. Because Immunotoxicity plays a key role in drug-induced adverse effects, the role of immunotoxicology in drug safety assessment is indisputable and the systematic nonclinical as well as clinical Immunotoxicity assessment of every new drug is deemed essential.
Henk Van Loveren - One of the best experts on this subject based on the ideXlab platform.
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Nonclinical regulatory Immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls.
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, 2020Co-Authors: Christina Giannakou, Margriet V. D. Z. Park, Wim H. De Jong, Henk Van Loveren, Jan Willem Van Der Laan, Irene E. M. Bosselaers, Rob J. VandebrielAbstract:Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory Immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the Immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory Immunotoxicity assessment strategy, which considers the Immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant Immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the Immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
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A comparison of immunotoxic effects of nanomedicinal products with regulatory Immunotoxicity testing requirements.
International journal of nanomedicine, 2016Co-Authors: Christina Giannakou, Margriet V. D. Z. Park, Wim H. De Jong, Henk Van Loveren, Rob J. VandebrielAbstract:Nanomaterials (NMs) are attractive for biomedical and pharmaceutical applications because of their unique physicochemical and biological properties. A major application area of NMs is drug delivery. Many nanomedicinal products (NMPs) currently on the market or in clinical trials are most often based on liposomal products or polymer conjugates. NMPs can be designed to target specific tissues, eg, tumors. In virtually all cases, NMPs will eventually reach the immune system. It has been shown that most NMs end up in organs of the mononuclear phagocytic system, notably liver and spleen. Adverse immune effects, including allergy, hypersensitivity, and immunosuppression, have been reported after NMP administration. Interactions of NMPs with the immune system may therefore constitute important side effects. Currently, no regulatory documents are specifically dedicated to evaluate the Immunotoxicity of NMs or NMPs. Their Immunotoxicity assessment is performed based on existing guidelines for conventional substances or medicinal products. Due to the unique properties of NMPs when compared with conventional medicinal products, it is uncertain whether the currently prescribed set of tests provides sufficient information for an adequate evaluation of potential Immunotoxicity of NMPs. The aim of this study was therefore, to compare the current regulatory Immunotoxicity testing requirements with the accumulating knowledge on immunotoxic effects of NMPs in order to identify potential gaps in the safety assessment. This comparison showed that immunotoxic effects, such as complement activation-related pseudoallergy, myelosuppression, inflammasome activation, and hypersensitivity, are not readily detected by using current testing guidelines. Immunotoxicity of NMPs would be more accurately evaluated by an expanded testing strategy that is equipped to stratify applicable testing for the various types of NMPs.
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Developmental Immunotoxicity testing of 4-methyl anisole.
Regulatory toxicology and pharmacology : RTP, 2015Co-Authors: Elisa C.m. Tonk, Henk Van Loveren, Aart Verhoef, Eric R. Gremmer, Aldert H. PiersmaAbstract:Abstract The developmental Immunotoxicity of 4-methyl anisole (4MA) was investigated in the rat. Four study designs were used, with either premating or post-weaning onset of exposure, continued to postnatal day 50, and with or without additional oral gavage of pups from postnatal day 10 onward. Reduced litter size (benchmark dose lower confidence limit (BMDL) 80 mg/kg bw/day) was the most sensitive developmental parameter, with pup relative organ weight effects observed at similar BMDLs, in the absence of maternal toxicity. Eosinophil numbers were reduced at lower doses (BMDL 16 mg/kg bw/day). KLH challenge resulted in increased IL-13 and TNF-α responses, and variably reduced IgG production (BMDL 27 mg/kg bw/day). T4 levels were reduced by 11% at maximum with a BMDL of 73 mg/kg bw/day. Differences between exposure cohorts were limited and were considered to be without biological significance. This study shows that 4MA induces developmental Immunotoxicity at doses below those inducing developmental and general toxicity. These observations being independent of the study designs applied suggest that the post-weaning period, included in all designs, is the most relevant sensitive period for inducing 4MA mediated developmental Immunotoxicity. Moreover, this study stresses the importance of including developmental Immunotoxicity testing by default in regulatory toxicology.
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Screening of xenobiotics for direct Immunotoxicity in an animal study.
Methods (San Diego Calif.), 2007Co-Authors: Wim H. De Jong, Henk Van LoverenAbstract:It has now been recognised that the immune system as a whole can be the target for xenobiotic induced toxicity. The discipline of immuntoxicology encompasses non specific direct Immunotoxicity and immunostimulation, and specific responses like hypersensitivity and autoimmunity. Direct Immunotoxicity can be determined in tiered studies, TIER 1 being a general toxicity study with emphasis on evaluation of organs belonging to the immune system, TIER 2 investigating the effects of xenobiotics on immune functionality in immunological challenge experiments. In the TIER 1 study, organ weights and histopathological evaluation of immune organs like spleen, thymus, lymph nodes, blood and bone marrow may detect the occurrence of direct Immunotoxicity. The follow up studies in the TIER 2 phase can then determine the extent of the immunosuppression and identify which specific parts or cellular components of the immune system are involved. In view of the complexity of the immune system and the multitude of interactions within the immune system in vivo animal experiments are needed to investigate xenobiotics for their potential Immunotoxicity. In vitro assays with in vivo exposed cells of the immune system may present additional information on the mechanisms involved in the observed direct Immunotoxicity.
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Toxicogenomics in the assessment of Immunotoxicity
Methods (San Diego Calif.), 2007Co-Authors: Kirsten A. Baken, Rob J. Vandebriel, Jeroen L. A. Pennings, Jos C. S. Kleinjans, Henk Van LoverenAbstract:Microarray analysis is used for simultaneous measurement of expression of thousands of genes in a given sample and as such extends and deepens our understanding of biological processes. Application of the technique in toxicology is referred to as toxicogenomics. The examples of assessment of Immunotoxicity by gene expression profiling presented and discussed here, show that microarray analysis is able to detect known and novel effects of a wide range of immunomodulating agents. Besides the elucidation of mechanisms of action, toxicogenomics is also applied to predict consequences of exposing biological systems to toxic agents. Successful attempts to classify compounds using signature gene expression profiles have been reported. These did, however, not specifically focus on Immunotoxicity. Databases containing expression profiles can facilitate the applications of toxicogenomics. Platforms and methodologies for gene expression profiling may vary, however, hampering data compiling across different laboratories. Therefore, attention is paid to standardization of the generation, reporting, and management of microarray data. Obtained gene expression profiles should be anchored to pathological and functional endpoints for correct interpretation of results. These issues are also important when using toxicogenomics in risk assessment. The application of toxicogenomics in evaluation of Immunotoxicity is thus not yet without challenges. It already contributes to the understanding of immunotoxic processes and the development of in vitro screening assays, though, and is therefore expected to be of value for mechanistic insight into Immunotoxicity and hazard identification of existing and novel compounds.
Rob J. Vandebriel - One of the best experts on this subject based on the ideXlab platform.
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Nonclinical regulatory Immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls.
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, 2020Co-Authors: Christina Giannakou, Margriet V. D. Z. Park, Wim H. De Jong, Henk Van Loveren, Jan Willem Van Der Laan, Irene E. M. Bosselaers, Rob J. VandebrielAbstract:Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory Immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the Immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory Immunotoxicity assessment strategy, which considers the Immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant Immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the Immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
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A comparison of immunotoxic effects of nanomedicinal products with regulatory Immunotoxicity testing requirements.
International journal of nanomedicine, 2016Co-Authors: Christina Giannakou, Margriet V. D. Z. Park, Wim H. De Jong, Henk Van Loveren, Rob J. VandebrielAbstract:Nanomaterials (NMs) are attractive for biomedical and pharmaceutical applications because of their unique physicochemical and biological properties. A major application area of NMs is drug delivery. Many nanomedicinal products (NMPs) currently on the market or in clinical trials are most often based on liposomal products or polymer conjugates. NMPs can be designed to target specific tissues, eg, tumors. In virtually all cases, NMPs will eventually reach the immune system. It has been shown that most NMs end up in organs of the mononuclear phagocytic system, notably liver and spleen. Adverse immune effects, including allergy, hypersensitivity, and immunosuppression, have been reported after NMP administration. Interactions of NMPs with the immune system may therefore constitute important side effects. Currently, no regulatory documents are specifically dedicated to evaluate the Immunotoxicity of NMs or NMPs. Their Immunotoxicity assessment is performed based on existing guidelines for conventional substances or medicinal products. Due to the unique properties of NMPs when compared with conventional medicinal products, it is uncertain whether the currently prescribed set of tests provides sufficient information for an adequate evaluation of potential Immunotoxicity of NMPs. The aim of this study was therefore, to compare the current regulatory Immunotoxicity testing requirements with the accumulating knowledge on immunotoxic effects of NMPs in order to identify potential gaps in the safety assessment. This comparison showed that immunotoxic effects, such as complement activation-related pseudoallergy, myelosuppression, inflammasome activation, and hypersensitivity, are not readily detected by using current testing guidelines. Immunotoxicity of NMPs would be more accurately evaluated by an expanded testing strategy that is equipped to stratify applicable testing for the various types of NMPs.
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In Vitro Testing for Direct Immunotoxicity: State of the Art
Methods in molecular biology (Clifton N.J.), 2009Co-Authors: Danielle P.k. Lankveld, Kirsten A. Baken, H. Van Loveren, Rob J. VandebrielAbstract:Immunotoxicity is defined as the toxicological effects of xenobiotics including pharmaceuticals on the functioning of the immune system and can be induced in either direct or indirect ways. Direct Immunotoxicity is caused by the effects of chemicals on the immune system, leading to immunosuppression and subsequently to reduced resistance to infectious diseases or certain forms of nongenotoxic carcinogenicity.In vitro testing has several advantages over in vivo testing, such as detailed mechanistic understanding, species extrapolation (parallelogram approach), and reduction, refinement, and replacement of animal experiments. In vitro testing for direct Immunotoxicity can be done in a two-tiered approach, the first tier measuring myelotoxicity. If this type of toxicity is apparent, the compound can be designated immunotoxic. If not, the compound is tested for lymphotoxicity (second tier). Several in vitro assays for lymphotoxicity exist, each comprising specific functions of the immune system (cytokine production, cell proliferation, cytotoxic T-cell activity, natural killer cell activity, antibody production, and dendritic cell maturation). A brief description of each assay is provided. Only one assay, the human whole blood cytokine release assay, has undergone formal prevalidation, while another one, the lymphocyte proliferation assay, is progressing towards that phase.Progress in in vitro testing for direct Immunotoxicity includes prevalidation of existing assays and selection of the assay (or combination of assays) that performs best. To avoid inter-species extrapolation, assays should preferably use human cells. Furthermore, the use of whole blood has the advantage of comprising multiple cell types in their natural proportion and environment. The so-called "omics" techniques provide additional mechanistic understanding and hold promise for the characterization of classes of compounds and prediction of specific toxic effects. Technical innovations such as high-content screening and high-throughput analysis will greatly expand the opportunities for in vitro testing.
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Toxicogenomics in the assessment of Immunotoxicity
Methods (San Diego Calif.), 2007Co-Authors: Kirsten A. Baken, Rob J. Vandebriel, Jeroen L. A. Pennings, Jos C. S. Kleinjans, Henk Van LoverenAbstract:Microarray analysis is used for simultaneous measurement of expression of thousands of genes in a given sample and as such extends and deepens our understanding of biological processes. Application of the technique in toxicology is referred to as toxicogenomics. The examples of assessment of Immunotoxicity by gene expression profiling presented and discussed here, show that microarray analysis is able to detect known and novel effects of a wide range of immunomodulating agents. Besides the elucidation of mechanisms of action, toxicogenomics is also applied to predict consequences of exposing biological systems to toxic agents. Successful attempts to classify compounds using signature gene expression profiles have been reported. These did, however, not specifically focus on Immunotoxicity. Databases containing expression profiles can facilitate the applications of toxicogenomics. Platforms and methodologies for gene expression profiling may vary, however, hampering data compiling across different laboratories. Therefore, attention is paid to standardization of the generation, reporting, and management of microarray data. Obtained gene expression profiles should be anchored to pathological and functional endpoints for correct interpretation of results. These issues are also important when using toxicogenomics in risk assessment. The application of toxicogenomics in evaluation of Immunotoxicity is thus not yet without challenges. It already contributes to the understanding of immunotoxic processes and the development of in vitro screening assays, though, and is therefore expected to be of value for mechanistic insight into Immunotoxicity and hazard identification of existing and novel compounds.
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In vitro approaches to the assessment of Immunotoxicity
'Elsevier BV', 2007Co-Authors: E. Corsini, Rob J. Vandebriel, M. Carfì, L. Gribaldo, M. Pallardy, R. Pieters, H.w. Vohr, H. Van LoverenAbstract:At present, hypersensitivity and immunosuppression are considered the primary focus for developing in vitro methods in immunotoxicology. Nevertheless, in vitro assays to detect immunostimulation and autoimmunity are also needed. Although developmental Immunotoxicity is an emerging concern, there are no in vitro test models available at this time. The purpose of this presentation is to reviewthe stateof- the-art in the field of in vitro Immunotoxicity and, in particular, to present data obtained within an ECVAM sponsored project aimed at the optimization of in vitro tests to assess the immunosuppressive potential of chemicals
Thomas T. Kawabata - One of the best experts on this subject based on the ideXlab platform.
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Development of Immunotoxicity Testing Strategies for Immunomodulatory Drugs
Toxicologic pathology, 2012Co-Authors: Thomas T. Kawabata, Ellen W. EvansAbstract:The ICH S8 Immunotoxicity testing guideline for human pharmaceuticals was published in 2006 and was intended to provide guidance for assessing the Immunotoxicity potential of low-molecular-weight drugs that are not intended to alter the immune system. For drugs intended to modulate the immune system, Immunotoxicity testing strategies are generally developed on a case-by-case approach since the targets, intended patient population, and mechanisms of action of the test compound will determine the type of testing needed. Some of the general principles of ICH S8, however, may be applied to Immunotoxicity testing strategies for immunomodulatory drugs. A weight-of-evidence approach using factors discussed in ICH S8 in concert with an assessment of the potential value of additional Immunotoxicity testing should be considered. For most situations, Immunotoxicity studies with immunomodulatory compounds evaluate off-target effects on the immune system and exaggerated pharmacology. The potential use of data from these studies and considerations such as translatability to humans are discussed.
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Chapter 17:Immunotoxicity Testing
Drug Discovery, 2011Co-Authors: Thomas T. Kawabata, Sandra Casinghino, Mark Collinge, Cris Kamperschroer, Jessica WhritenourAbstract:The field of immunotoxicology has been growing rapidly and a wide variety of Immunotoxicity testing methods is now available. This chapter first discusses approaches to developing Immunotoxicity testing strategies and provides a general overview of the types of assays currently available and how they are used. These assays are classified either according to the type of immune response being measured, the experimental design, or the number of immune cell types involved. The chapter then focuses on in vitro and ex vivo assays used during drug development that have been developed more recently, rather than on the more established Immunotoxicity assays (e.g., in vivo T-dependent antibody response). These assays address concerns regarding hypersensitivity reactions, immunoenhancement and immunosuppression. Assays for hypersensitivity include measuring human mast-cell function and activation of the complement cascade, while those for immunoenhancement include the cytokine release assay. Immunosuppression can be measured using assays that use co-cultures of different types of immune cells, such as the human lymphocyte activation assay, three-dimensional culture systems, and by assays that measure T-cell function. Several of the assays presented are in vitro assays that use human immune cells to enhance the translatability to human risk. In addition, assays that can be added to standard toxicology studies are discussed.
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Summary of a workshop on nonclinical and clinical Immunotoxicity assessment of immunomodulatory drugs.
Journal of immunotoxicology, 2009Co-Authors: Joseph R. Piccotti, Herve Lebrec, Ellen W. Evans, Danuta J. Herzyk, Kenneth L. Hastings, Leigh Ann Burns-naas, Ian S. Gourley, Daniel Wierda, Thomas T. KawabataAbstract:The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both regulatory agencies and industry on how best to assess decreased host resistance to infections or adverse immunostimulation caused by immunomodulatory agents such as anti-cytokine antibodies (e.g., the tumor necrosis factor-alpha inhibitors), anti-adhesion molecule antibodies (e.g., anti-alpha-4 integrin inhibitors) and immunostimulatory molecules (e.g., anti-CD28 antibodies). Although several methods have been developed for nonclinical assessment of Immunotoxicity, highly publicized adverse events have brought to light significant gaps in the application of nonclinical Immunotoxicity testing in assessing potential risk in humans. Confounding this problem is inconsistent application of immunotoxicology methods for risk assessment within the scientific community, limited understanding of appropriate Immunotoxicity testing strategy for immunomodulators and inconsistent testing requests by regulatory agencies. To address these concerns, The Immunotoxicology Technical Committee (ITC) of the International Life Science Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized a workshop on Immunomodulators and Clinical Immunotoxicology in May 2007. The Workshop was convened to identify key gaps in nonclinical and clinical Immunotoxicity testing of anti-inflammatory and immunomodulatory agents and to begin to develop consistent approaches for Immunotoxicity testing and risk assessment. This paper summarizes the outcome of the HESI ITC Immunomodulators and Clinical Immunotoxicology Workshop. Topics not discussed at the Workshop were outside the scope of this report. Although more work is needed to develop consistent approaches for Immunotoxicity assessment of immunomodulators, this Workshop provided the foundation for future discussion.
Kenneth L. Hastings - One of the best experts on this subject based on the ideXlab platform.
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Summary of a workshop on nonclinical and clinical Immunotoxicity assessment of immunomodulatory drugs.
Journal of immunotoxicology, 2009Co-Authors: Joseph R. Piccotti, Herve Lebrec, Ellen W. Evans, Danuta J. Herzyk, Kenneth L. Hastings, Leigh Ann Burns-naas, Ian S. Gourley, Daniel Wierda, Thomas T. KawabataAbstract:The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both regulatory agencies and industry on how best to assess decreased host resistance to infections or adverse immunostimulation caused by immunomodulatory agents such as anti-cytokine antibodies (e.g., the tumor necrosis factor-alpha inhibitors), anti-adhesion molecule antibodies (e.g., anti-alpha-4 integrin inhibitors) and immunostimulatory molecules (e.g., anti-CD28 antibodies). Although several methods have been developed for nonclinical assessment of Immunotoxicity, highly publicized adverse events have brought to light significant gaps in the application of nonclinical Immunotoxicity testing in assessing potential risk in humans. Confounding this problem is inconsistent application of immunotoxicology methods for risk assessment within the scientific community, limited understanding of appropriate Immunotoxicity testing strategy for immunomodulators and inconsistent testing requests by regulatory agencies. To address these concerns, The Immunotoxicology Technical Committee (ITC) of the International Life Science Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized a workshop on Immunomodulators and Clinical Immunotoxicology in May 2007. The Workshop was convened to identify key gaps in nonclinical and clinical Immunotoxicity testing of anti-inflammatory and immunomodulatory agents and to begin to develop consistent approaches for Immunotoxicity testing and risk assessment. This paper summarizes the outcome of the HESI ITC Immunomodulators and Clinical Immunotoxicology Workshop. Topics not discussed at the Workshop were outside the scope of this report. Although more work is needed to develop consistent approaches for Immunotoxicity assessment of immunomodulators, this Workshop provided the foundation for future discussion.
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Prospects for developmental Immunotoxicity guidance and an update on ICH S8.
Journal of immunotoxicology, 2005Co-Authors: Kenneth L. HastingsAbstract:Potential adverse effects of drug exposure on the developing immune system had been a relatively neglected area of toxicology until fairly recently. However, with the recent regulatory emphasis on evaluation of drugs for use in pediatric patients, juvenile animal studies have been considered in much more detail than in the past in order to enable clinical trials. Assessment of Immunotoxicity potential in these juvenile animal studies has been a natural consequence of drug development for pediatric patients. Unfortunately, the efforts to evaluate developmental Immunotoxicity studies have not kept pace with the writing of an immunotoxicology guidance for the International Conference on Harmonisation of Technical Requirements for Registration of Human Pharmaceuticals (ICH). This document has recently reached Step 4 in the approval process: it is thus likely that juvenile animal studies for Immunotoxicity would be recommended based on considerations enumerated in the ICH Safety Number 8 (S8) guidance. Sufficient flexibility exists in this document to cover the issue of developmental Immunotoxicity. ICH S8 advocates a weight-of-evidence approach, which should be interpreted to indicate that Immunotoxicity testing would be conducted based on identified cause(s) for concern rather than as a routine screening method. The presentation reflecting these issues, as presented to attendees of the Pharmaceutical Education Associates workshop on Innovative Methods and Applications for Risk Assessment in Pharmaceutical Development is summarized herein.
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Assessment of the Immunotoxic Potential of Human Pharmaceuticals: A Workshop Report
Drug Information Journal, 2002Co-Authors: Esther Putman, Henk Van Loveren, Kenneth L. Hastings, Jack H. Dean, Gerd Bode, Kazuichi Nakamura, François Verdier, Jan Willem Van Der LaanAbstract:The assessment of the immunotoxic potential of human pharmaceuticals has drawn considerable attention worldwide in the past few years. In Europe, the Committee for Proprietary Medicinal Products released its Immunotoxicity guidance documents. The Food and Drug Administration's Center for Drug Evaluation and Research in the United States and the Japanese Ministry of Health, Labor, and Welfare are in the process of finalizing similar guidance documents. This report summarizes the discussions on drug Immunotoxicity assessment held at a November 2001 DIA workshop held in Noordwijk, The Netherlands. This workshop revealed that an important issue for company attendees was the timing of the Immunotoxicity studies during the drug development process. The Committee for Proprietary Medicinal Products requires that Immunotoxicity endpoints be monitored for all new compounds. Industry has interpreted this requirement, and the expectation that these endpoints be studied in a 28-day repeated dose study in rats, as obligatory Immunotoxicity testing for all new compounds, regardless of the stage of development. The Committee for Propietary Medicinal Products requirements, however, are applicable only at the stage of the marketing application. Workshop participants agreed that Immunotoxicity screening should preferably be carried out prior or parallel to Phase 2 development. This will substantially reduce the number of compounds that require enhanced tesitng for Immunotoxicity (approximately 80% of the compounds are dropped from development after Phase 1) and reduce the use of animals. Presentations and discussions at the worshop also demonstrated that there is a strong scientific basis for European requirements as included in the Revised Note for Guidance on Repeated Dose Toxicity Testing. For example, not evaluating the response to a T-cell-dependent antigen would have missed the immunotoxicological effects of several compounds. This is probably due to the dynamic nature of the immune system whereby immune effects are best demonstrated using an immune function assay, as opposed to reliance on an essentially static analysis such as histopathology.
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Immunotoxicity of Pharmaceuticals: Current Knowledge, Testing Strategies, Risk Evaluation & Consequences for Human Health:
Drug Information Journal, 1997Co-Authors: Jan Willem Van Der Laan, Henk Van Loveren, Jeff G. Vos, Jack H. Dean, Kenneth L. HastingsAbstract:This paper provides an overview of the DIA workshop on Immunotoxicity of pharmaceuti-cals held on October 2–4, 1996, in Montreux, Switzerland. The importance of Immunotoxicity testing, and its current status, are discussed. The workshop’s agenda: current animal tests and clinical efforts for which preclinical Immunotoxicity assays need to be developed, are highlighted. Conclusions from the meeting are provided.