Reproductive/developmental toxicity and immunotoxicity assessment in the nonhuman primate model

Buse, Eberhard; Habermann, Gunnar; Osterburg, Ingrid; Korte, Rainhart; Weinbauer, Gerhard F.

doi:10.1016/s0300-483x(02)00614-5

Cited by 66 publications

(35 citation statements)

References 9 publications

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“…, Junko FUJISHIMA 1) , Tomohiro FURUKAWA 1) , Tsuyoshi YOSHIKAWA 1) , Rinya KODAMA 1) , Yuji SASAKI 1) , Takaharu NAGAOKA 1) , Yasuhiro KAMIMURA 1) , Hiroshi MAEDA 1) , Takuya HIRAI 2,3) and Ryoji YAMAGUCHI 2) Immune system toxicity encompasses a variety of adverse effects including the suppression or enhancement of immune response. Suppression of immune response can lead to decreased host resistance to pathogens or tumor cells.…”

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confidence: 99%

“…The importance of nonhuman primates is widely recognized in biomedical research, and their use for preclinical toxicologic and safety evaluations is increasing because of their phylogenetic similarity to humans [1][2][3]. Among these, the cynomolgus monkey (Macaca fascicularis) is the most frequently used in toxicity studies [2]. It is clear that species-specific characteristics of immune organs must be considered during pathological evaluations of immunotoxicity [5].…”

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confidence: 99%

“…This position paper focused on rodents, but stated that when a nonrodent species such as the monkey or dog is used, attention must be paid to variability in organ weights and gross and microscopic observations. The importance of nonhuman primates is widely recognized in biomedical research, and their use for preclinical toxicologic and safety evaluations is increasing because of their phylogenetic similarity to humans [1][2][3]. Among these, the cynomolgus monkey (Macaca fascicularis) is the most frequently used in toxicity studies [2].…”

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confidence: 99%

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Quantitative Analyses of Lymphoid Tissue in the Spleen, Lymph Nodes and Peyer's Patches in Cynomolgus Monkeys

Moriyama

Fujishima

Furukawa

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. To clarify the morphological characteristics of the cynomolgus monkey immune system, we analyzed quantitative data on their lymphoid organs. Spleens, major lymph nodes and Peyer's patches were sampled from cynomolgus monkeys, and the lymphoid follicle and germinal center areas and percentages of CD3-and CD20-positive areas were calculated. All the organs analyzed showed large interindividual variations in the sizes of lymphoid follicles and germinal centers. Lymphoid follicle in the spleen, submandibular lymph nodes and Peyer's patches showed no marked difference in size. Germinal center size in the mesenteric lymph nodes and Peyer's patches were significantly smaller than those in the spleen. Areas containing T cells were largest in the lymph nodes, while those containing B cells were largest in the spleen and Peyer's patches. The mean size of the splenic lymphoid follicle in cynomolgus monkeys is larger than that in rats and similar to that in humans. Based on the large individual variation and the characteristics of lymphoid organs, it is important to use cynomolgus monkeys in standard toxicity studies. Taking advantage of the characteristics of each species enables reliable evaluation of the immunologic system in standard toxicity studies.

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Quantitative Analyses of Lymphoid Tissue in the Spleen, Lymph Nodes and Peyer's Patches in Cynomolgus Monkeys

Moriyama

Fujishima

Furukawa

et al. 2011

The Journal of Veterinary Medical Science

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“…However, when selecting the NHP as a species of choice for DART testing, there are a number of factors that need to be considered, including: the ethical use of these animals versus lower-order species, the number of facilities experienced at conducting the studies, the limited group sizes compared to rodent studies, the expense and duration of the studies, as well as the usefulness of the endpoints for evaluating human risk. One advantage of using macaques is that they are very similar to humans in terms of endocrine and reproductive physiology (Weinbauer 2002;Buse et al, 2003).…”

Section: Use Of Non-traditional Animal Speciesmentioning

confidence: 99%

Considerations in assessing the developmental and reproductive toxicity potential of biopharmaceuticals

Martin¹,

Breslin

Rocca

et al. 2009

Birth Defects Research Pt B

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This report discusses the principles of developmental and reproductive toxicity (DART) testing for biopharmaceuticals. Biopharmaceuticals are large‐molecular‐weight proteins or peptides produced by modern biotechnology techniques incorporating genetic engineering and hybridoma technologies. The principles of DART testing for biopharmaceuticals are similar to those for small‐molecule pharmaceuticals and in general follow the regulatory guidance outlined in International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) document S5(R2). However, because many biopharmaceuticals are species‐specific, alternate approaches may be needed to evaluate DART potential as outlined in ICH S6. For molecules that show species‐specific cross‐reactivity restricted to non‐human primates (NHP), some aspects of DART may require NHP testing. For biopharmaceuticals that are uniquely specific and only active on intended human targets or human and chimpanzee targets, surrogate molecules that cross‐react with the more traditional rodent species may need to be developed and used for DART testing. Alternatively, genetically modified transgenic animals may also need to be considered. Surrogate molecules and transgenic animals may also be considered for DART testing even if the biopharmaceutical is active in NHPs in order to reduce the use of NHPs. Because of the unique properties of biopharmaceuticals, a case‐by‐case approach is needed for DART and general toxicity evaluation, which requires consideration of specific product attributes including biochemical and biophysical characteristics, pharmacological activity, and intended clinical indication. Birth Defects Res (Part B), 33:176–203, 2009. © 2009 Wiley‐Liss, Inc.

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“…Establishing the similarity of immunosuppressive mechanisms of nonhuman primates and humans is beneficial for the reliable evaluation of changes affecting the immune system [9,17]. Considering the importance of cynomolgus monkeys in toxicity studies in recent years [5,6], we reported quantitative data on the spleen, lymph nodes, and Peyer's patches in naive cynomolgus monkeys in 2011 [14]. In this report, we suggest that in addition to microscopic observations, the evaluation of the changes affecting the immune system using multiple parameters is important due to the large individual variations in cynomolgus monkeys.…”

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Pathological Effects in Lymphoid Tissues of the Spleen, Lymph Nodes, and Peyer’s Patches in Cyclosporin-Treated Cynomolgus Monkeys

Moriyama

Maeda

Hirai

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. Germinal center/lymphoid follicle area ratio and CD3/CD20-positive area ratio were calculated for the spleen, submandibular and mesenteric lymph nodes, and Peyer's patches in cynomolgus monkeys treated orally with cyclosporin A (CsA), an immunosuppressant which blocks Ca 2+ /NFAT signaling. A difference in hypocellularity between lymphoid organs was observed after CsA administration in a dose-dependent manner. Regarding drug efficacy, the highest susceptibility to CsA tended to be shown in the Peyer's patches, and susceptibility then descended in the order of the spleen, mesenteric lymph nodes, and submandibular lymph nodes. It was shown in the present study that decreases in germinal center area and CD3-positive area were sensitive indicators of the efficacy of CsA for lymphoid organs and tissue in cynomolgus monkeys.

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Reproductive/developmental toxicity and immunotoxicity assessment in the nonhuman primate model

Cited by 66 publications

References 9 publications

Quantitative Analyses of Lymphoid Tissue in the Spleen, Lymph Nodes and Peyer's Patches in Cynomolgus Monkeys

Quantitative Analyses of Lymphoid Tissue in the Spleen, Lymph Nodes and Peyer's Patches in Cynomolgus Monkeys

Considerations in assessing the developmental and reproductive toxicity potential of biopharmaceuticals

Pathological Effects in Lymphoid Tissues of the Spleen, Lymph Nodes, and Peyer’s Patches in Cyclosporin-Treated Cynomolgus Monkeys

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