Maturity-related Variability of the Thymus in Cynomolgus Monkeys (Macaca fascicularis)

Abstract

Terminal body weights (TBWs), thymus weight parameters, and thymus morphology were retrospectively evaluated in 453 cynomolgus monkeys assigned to control groups on nonclinical toxicity studies. Morphology of bone, ovary, and testis/epididymis were used to determine maturity status of individual animals. There was no correlation between TBW and thymus weight (absolute and/or relative to TBW or brain weight). Thymus weight parameters and grades of decreased lymphocytes in the thymus were highly variable in immature animals compared to mature animals. There was also high (up to 11-fold) variability of thymus weight parameters within a given control group on the same study (generally 3 or 4 animals per sex). Several parameters evaluated had more pronounced age-related changes in males when compared to females. Our results demonstrate the inherent variability of thymus weight parameters and morphologic observations for cynomolgus monkeys on toxicology studies. Changes in thymus parameters in cynomolgus monkeys are unreliable indicators of immunomodulation or immunotoxicity in the absence of other relevant findings. Therefore, the thymus parameters commonly evaluated in preclinical safety assessments should not be the primary data set used to determine the presence of a direct test article-related effect on the immune system.

Variability of Spleen and Mesenteric Lymph Node in Control Cynomolgus Monkeys (Macaca fascicularis) from Nonclinical Safety Studies: A Retrospective Assessment

“…Terms used for light microscopic observations in this study were generally descriptive rather than diagnostic, with the exception of the use of terms historically applied to findings resulting from hemoparasitism (reticuloendothelial [RE] hyperplasia and malarial pigment). This companion study expands on the understanding of the variability of the cynomolgus monkey immune system that was previously described for the thymus (Snyder et al 2016). In addition, this study extends and refines previously published observations of incidental background observations in the spleen (Chamanza et al 2010;Ito et al 1992;Okazaki et al 1996;Kaspareit et al 2006;Spoor, Radi, and Dunstan 2008;McInnes 2011) and MLN (Chamanza et al 2010), providing a detailed evaluation of the range of light microscopic observations with comparisons to other study results.…”

“…When the geographic origin of animals could not be determined from study reports, peripheral blood mean cell volume data were used to assign origin, as monkeys from Mauritius have smaller red blood cells than monkeys from China or Southeast Asia (Butterfield 1997). Although the vast majority of the animals included in this study were also included in a previous manuscript assessing thymus parameters (Snyder et al 2016), the final set of monkeys was not identical because inclusion was dependent on availability of spleen with or without MLN sections for this study and the availability of thymus sections and weights for the previous study.…”

“…Because of questionable accuracy of birth dates and/or ages of subjects, light microscopic assessments of bone and reproductive tissues using hematoxylin and eosin-stained slides prepared from formalin-fixed, paraffin-embedded tissues were used to approximate sexual and skeletal maturity and to assign maturity stages. The mechanisms for determining sexual and skeletal maturity in this population were previously published (Snyder et al 2016). Briefly, testis and epididymis were classified as immature, peripubertal, or mature, and ovaries were classified as corpora lutea (CL) present or CL absent.…”

RNA-Seq-Based Gene Expression Pattern and Morphological Alterations in Chick Thymus during Postnatal Development

“…Since the structure and the function are closely related, the microstructure of different aged thymuses was explored by HE staining that showed a downtrend, except for a small increase at the 3 rd week, with significant alterations in ratio of the cortex to medulla. Similar changes in the aging thymus were also previously reported in rats [41–43], African ostrich chicks [44, 45], and cynomolgus macaques [46, 47]. In addition, we also found an accumulation of adipose tissue while aging.…”

PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

“…The blockade was not observed with increasing pembrolizumab dose, suggesting that tracer distribution in the thymus was not PD-1-mediated. This was not unexpected, since there is a progressively decrease in the number of cortical lymphocytes during age-related thymus involution from about 4 or 5 years old in cynomolgus monkeys [24], and the monkeys in this study were over 7 years of age. Additionally, few studies have reported thymic uptake of radiopharmaceuticals assessing receptor expression on immune cells as a result of dramatic thymic function changes [25]; therefore, the 89 Zr-N-sucDf-pembrolizumab retention in the thymus of monkeys over 5 years old is not considered to be a relevant organ to track the distribution of PD-1-positive immune cells.…”