Regulatory immunotoxicology: does the published evidence support mandatory nonclinical immune function screening in drug development?

Snodin, David J.

doi:10.1016/j.yrtph.2004.08.007

Cited by 25 publications

(13 citation statements)

References 102 publications

(125 reference statements)

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“…Cancer, for example virus-induced, may occur due to decreased tumour resistance. (ii) Enhancement of immune responses can induce hypersensitivity and exaggerate autoimmune diseases, leading to chronic inflammation as observed for example in allergic asthma, which will be presented in detail in the next section (Snodin 2004; Descotes 2006). These alterations of normal immune functions have to be detected by testing for adverse immunotoxic effects of xenobiotics.…”

Section: Immunotoxicity Testing – a Tendency To Include In Vitro Assamentioning

confidence: 99%

Assessment of immunotoxicity using precision-cut tissue slices

Sewald

Braun

2012

Xenobiotica

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1. When the immune system encounters incoming infectious agents, this generally leads to immunity. The evoked immune response is usually robust, but can be severely perturbed by potentially harmful environmental agents such as chemicals, pharmaceuticals and allergens.2. Immunosuppression, hypersensitivity and autoimmunity may occur due to changed immune activity. Evaluation of the immunotoxic potency of agents as part of risk assessment is currently established in vivo with animal models and in vitro with cell lines or primary cells.3. Although in vivo testing is usually the most relevant situation for many agents, more and more in vitro models are being developed for assessment of immunotoxicity. In this context, hypersensitivity and immunosuppression are considered to be a primary focus for developing in vitro methods. Three-dimensional organotypic tissue models are also part of current research in immunotoxicology.4. In recent years, there has been a revival of interest in organotypic tissue models. In the context of immunotoxicity testing, precision-cut lung slices in particular have been intensively studied. Therefore, this review is very much focused on pulmonary immunotoxicology. Respiratory hypersensitivity and inflammation are further highlighted aspects of this review. Immunotoxicity assessment currently is of limited use in other tissue models, which are therefore described only briefly within this review.

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Section: Immunotoxicity Testing – a Tendency To Include In Vitro Assamentioning

confidence: 99%

Assessment of immunotoxicity using precision-cut tissue slices

Sewald

Braun

2012

Xenobiotica

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“…With respect to pharmaceuticals in particular, assays for evaluating immune system activity in experimental models must also be modified (or complemented) to improve upon their predictive values of the potential immunotoxicities of not only drugs under development but those already on the market as well (Snodin, 2004;Descotes, 2005). We believe the critical finding of the studies here -that selection of only one host strain should be avoided as this could unintentionally lead to "selecting in" or "out" for potential effects -should be considered during the development of any ex vivo screening method for the analyses of potential immunotoxicities of pharmacological products.…”

Section: Discussionmentioning

confidence: 99%

“…Assays for evaluating immune system activity in experimental models must also be modified or complemented to lead to improved predictive immunomodulatory values, not just for drugs being developed but also for those already being sold (Snodin, 2004;Descotes, 2005). The tools used in this study could become a method of ex vivo screening proving useful for analysis of potential immunotoxicity of pharmacological products.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the Effect of Pentamidine Isethionate on the Immune System Using Mouse Splenocytes as an Experimental Model

Plaza

Marino

Delgado

2007

Journal of Immunotoxicology

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Evaluating immunomodulating effects is currently a fundamental parameter when designing pharmaceutical products. Rather than wait for the appearance of immunotoxic effects in patients, pre-clinical assays that characterize these potential events in experimental models not only can facilitate the understanding of how these phenomena arise, but sometimes reveal findings that can lead to modifications in currently-accepted methodologies used for estimating the pre-clinical assay predictive risk values. Pentamidine isethionate, a drug used as a second option in treating leishmaniasis, has been repeatedly shown in animals and humans to exert a toxicity at the renal, cardiac and hepatic level; however, its immunotoxic effect have not been as fully evaluated. The potential immunomodulatory effects of pentamidine on splenocytes from two species of mice (BALB/c and ICR) were evaluated ex vivo in this study. The results here indicated that there were significant differences in subpopulation profiles between the strains even before treatment with the drug, with the variances most apparent regarding the relative percentages of CD8 + and CD19 + cells in splenocyte preparations. The data also showed that the drug preferentially induced toxicity in BALB/c mice CD8+ and CD19 + cells more so than in their ICR Received 21 May 2007; Accepted 28 August 2007. We would like to thank the Pharmacy Department from the Universidad Nacional de Colombia and the Instituto Nacional de Salud (INS) for donating the mice used in the study. We would also like to thank Jason Garry for translating the manuscript. This research was performed with support from the Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología "Francisco José de Caldas" "Colciencias" Contract #060/2006. We would also like to thank Becton Dickinson Colombia and Equimed Ltda. for supplying some of the materials and reagents needed for carrying out the project. The authors have no conflicts of interest that are directly relevant to the content of this study. Authors Plaza and Marino are also affiliated with the Biology Department, Universidad Nacional de Colombia, Bogota, Columbia; Authors Marino and Delgado have dual affiliation with Pharmacy Department, Universidad Nacional de Columbia, Bogota, and Author Plaza is also affiliated with the Fundacion Instituto de Immunologia de Colombia, Bogota.Abbreviations:7AAD, 7-amino-actinomycin D; ISI, inverse stimulation indices; MFI, mean fluorescence intensity.Address correspondence to Dr. Gabriela Delgado, Carrera 50 No. 45-03, Edificio 450, Departamento de Farmacia, Oficina 206, Ciudad Universitaria, Bogota D.C., Colombia; e-mail: lgdelgadom@ unal.edu.co counterparts. Conversely, the ICR cells seemed to be more susceptible to drug-induced spontaneous blastogenesis than the cells from BALB/c hosts. The differential results seen here confirm that: any potential immunomodulatory effect of a drug should be studied in at least two different mouse strains during an evaluation of overall toxicologic potential; and, there shou...

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“…Despite rare claims that any systemic evaluation of the immunotoxic, in particularly the immunosuppressive potential of drug candidates is not warranted (Snodin, 2004), there is a large body of evidence showing that data obtained in animal studies are fairly well correlated with clinical findings in humans. In fact, when unexpected adverse immunemediated clinical findings are reported in humans, they are more likely due to inadequate or insufficient immunotoxicity assessment during preclinical studies as suggests the author's experience along more than thirty years of post-marketing drug surveillance and pre-clinical safety activities.…”

Section: Role Of Pharmacology Studies In the Evaluation Of The Immunomentioning

confidence: 99%

Safety immunopharmacology: Evaluation of the adverse potential of pharmaceuticals on the immune system

Descotes

2012

Journal of Pharmacological and Toxicological Methods

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The ICH S6R1 and S8 guidelines define a general framework for the immunotoxicity evaluation of biotechnology-derived pharmaceuticals and human pharmaceuticals, respectively. As severe and unpredicted adverse events dramatically showed in the recent years that the immune system is a critical aspect of drug safety, this framework needs to be revisited to enhance the prediction of nonclinical immune safety evaluation. Safety immunopharmacology is deemed to contribute to this awaited improvement by enabling early screening of the potential for drug candidates to induce unexpected immunosuppressive and immunostimulatory effects as well as nonimmune-mediated hypersensitivity reactions. Dedicated safety immunopharmacology can also generate mechanistic data to determine which relevant additional immunotoxicity studies should be conducted. Immunological assays and models that can be considered for use in the context of safety pharmacology studies are presented as well as perspectives for their timely development.

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Regulatory immunotoxicology: does the published evidence support mandatory nonclinical immune function screening in drug development?

Cited by 25 publications

References 102 publications

Assessment of immunotoxicity using precision-cut tissue slices

Assessment of immunotoxicity using precision-cut tissue slices

Characterizing the Effect of Pentamidine Isethionate on the Immune System Using Mouse Splenocytes as an Experimental Model

Safety immunopharmacology: Evaluation of the adverse potential of pharmaceuticals on the immune system

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