Retrospective Analysis of the Effects of Identification Procedures and Cage Changing by Using Data from Automated, Continuous Monitoring.

Many variables can influence animal behavior and physiology, potentially affecting scientific study outcomes. Laboratory and husbandry procedures-including handling, cage cleaning, injections, blood collection, and animal identification-may produce a multitude of effects. Previous studies have examined the effects of such procedures by making behavioral and physiologic measurements at specific time points; this approach can be disruptive and limits the frequency or duration of observations. Because these procedures can have both acute and long-term effects, the behavior and physiology of animals should be monitored continuously. We performed a retrospective data analysis on the effects of 2 routine procedures, animal identification and cage changing, on motion and breathing rates of mice continuously monitored in the home cage. Animal identification, specifically tail tattooing and ear tagging, as well as cage changing, produced distinct and reproducible postprocedural changes in spontaneous motion and breathing rate patterns. Behavioral and physiologic changes lasted approximately 2 d after tattooing or ear tagging and 2 to 4 d for cage changing. Furthermore, cage changes showed strain-, sex-, and time-of-day-dependent responses but not age-dependent differences. Finally, by reviewing data from a rodent model of multiple sclerosis as a retrospective case study, we documented that cage changing inadvertently affected experimental outcomes. In summary, we demonstrate how retrospective analysis of data collected continuously can provide high-throughput, meaningful, and longitudinal insights in to how animals respond to routine procedures.

Farletuzumab, a monoclonal antibody directed against folate receptor alpha, shows no evidence of teratogenicity in cynomolgus monkeys.

Farletuzumab is a humanized monoclonal antibody targeting human folate receptor alpha, which is being developed as an anti-cancer drug. A non-human primate reproductive study was conducted to evaluate whether it could cause any embryonic or fetal abnormalities. Farletuzumab was administered intravenously to pregnant cynomolgus monkeys (n = 16/group) at doses of 0 or 67.5 mg/kg once weekly during gestation day (GD) 20 through 97. C-section was performed on GD100 ±â€¯2, and fetuses were evaluated for morphologic (external, visceral and skeletal) effects. No farletuzumab-related changes were observed in maternal animals or fetuses, which are supported by the fact that farletuzumab has no effects on cellular uptake of folate. These data support the potential use of farletuzumab for oncologic indications during pregnancy.

Opportunistic infections in non-human primates exposed to immunomodulatory biotherapeutics: considerations and case examples.

Immunomodulatory biotherapeutics are most often evaluated for safety preclinically by way of repeat dose toxicity studies in non-human primates. Since immunomodulation is expected with this class of therapeutics, and since non-human primates share many opportunistic or latent infectious agents with humans, non-human primates in these toxicity studies may present with opportunistic or recrudescent infections that would be of concern if they occurred clinically in humans. In such instances, it is suggested that non-clinical safety assessment scientists consider a series of key questions that aim to clarify the relationship of the findings to the biotherapeutic under study and the expected predictivity of the findings to the human clinical setting. In this review, relevant case examples are considered comprising (i) gammaherpesviruses-mediated B-lymphocyte proliferation associated with a T-lymphocyte depleting fusion protein; (ii) increased plasmodial hemoparasite burdens associated with a monoclonal antibody inhibitory to T-lymphocyte trafficking and macrophage function, and (iii) the expected predictivity of non-human primate models for the occurrence of encephalic polyomavirus infections.

Naturally occurring infections in non-human primates (NHP) and immunotoxicity implications: discussion sessions.

Non-human primates (NHP) are used to best understand and address pharmacology and toxicology obligations for human patients with highest and/or unmet need. In order to ensure the most appropriate care and use of NHP, it is important to understand the normal micro flora and fauna of NHP and ensure their utmost health to generate the most valuable and applicable data. There are many infections, including viral, bacterial, parasitic, and fungal that may perturb physiologic endpoints relevant to human health, and are essential to monitor and/or eradicate for NHP health. This publication captures a discussion involving the experience, knowledge and opinion from academic, industry and government experts regarding emerging and normal infections in NHP as they relate to immunotoxicity, and treatment and consequences of known infections.

CD4+ T-cell responses and distribution at the colonic mucosa during Brachyspira hyodysenteriae-induced colitis in pigs.

The spirochaete Brachyspira hyodysenteriae causes swine dysentery, a severe colitis characterized by mucosal enlargement as a result of crypt elongation and epithelial necrosis. Most efforts to understand the pathogenesis of this disease have focused on the aetiological agent and its virulence factors. However, the host immune response has been considered an important factor in disease development. Previous research has shown that B. hyodysenteriae induces systemic CD4(+) and gammadelta T-cell responses after intramuscular immunization. Here, we have evaluated changes in the CD4(+) and gammadelta T-cell composition and distribution the different compartments of the colonic mucosa of pigs challenged with B. hyodysenteriae. We report that, in infected pigs, gammadelta T cells were significantly depleted from the epithelial layer, although their numbers were maintained in the lamina propria. In addition, CD4(+) T cells aggregated in clusters located in the lamina propria and submucosa. Ex vivo analyses of CD4(+) T-cell responses to B. hyodysenteriae antigens correlated with the changes in the mucosal CD4(+) T-cell distribution observed in infected pigs; CD4(+) T cells recovered from peripheral blood and colonic lymph nodes of infected pigs proliferated to B. hyodysenteriae antigens, whereas no differences were found in the gammadelta T-cell responses between challenged and control groups. In addition, colonic lymph node CD4(+) T cells had a predominant memory/activated phenotype. These results indicate that infection with B. hyodysenteriae induces a mucosal CD4(+) T-cell response and points to CD4(+) T cells being important contributors to the immunopathogenesis of swine dysentery.

Nutritional regulation of porcine bacterial-induced colitis by conjugated linoleic acid.

Excessive intake of saturated fatty acids and/or linoleic acid favors the induction of an array of lipid mediators and cytokines enhancing inflammatory responses. Conversely, dietary supplementation with (n-3) fatty acids or vitamin D ameliorates inflammation and autoimmune diseases. Although it was well accepted that conjugated linoleic acid (CLA) prevented diseases with a common inflammatory pathogenesis (i.e., cancer and atherosclerosis), no studies were available on the roles of CLA in mucosal inflammation. The present study was designed to investigate the anti-inflammatory actions and molecular mechanisms underlying the regulation of colonic health by CLA. We hypothesized that colonic inflammation can be ameliorated by dietary CLA supplementation. To test this hypothesis, inflammation of the colonic mucosa was triggered by challenging pigs fed either soybean oil-supplemented or CLA-supplemented diets with an enteric bacterial pathogen (i.e., Brachyspira hyodysenteriae). Immunoregulatory cytokines and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA expression were assayed in colonic lymph nodes and colon of pigs. Colonic mucosal lesions and lymphocyte subset distribution were evaluated by histology and immunohistochemistry. Supplementation of CLA in the diet before the induction of colitis decreased mucosal damage; maintained cytokine profiles (i.e., interferon-gamma and interleukin-10) and lymphocyte subset distributions (i.e., CD4+ and CD8+), resembling those of noninfected pigs; enhanced colonic expression of PPAR-gamma; and attenuated growth failure. Therefore, CLA fed preventively before the onset of enteric disease attenuated inflammatory lesion development and growth failure.