Histological thymus alterations in rats treated with a S1P receptor agonist

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Evaluation of methyl methanesulfonate, 2,6-diaminotoluene and 5-fluorouracil: Part of the Japanese Center for the Validation of Alternative Methods (JaCVAM) international validation study of the in vivo rat alkaline Comet assay

As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline Comet assay, we examined methyl methanesulfonate, 2,6-diaminotoluene, and 5-fluorouracil under coded test conditions. Rats were treated orally with the maximum tolerated dose (MTD) and two additional descending doses of the respective compounds. In the MMS treated groups liver and stomach showed significantly elevated DNA damage at each dose level and a significant dose-response relationship. 2,6-diaminotoluene induced significantly elevated DNA damage in the liver at each dose and a statistically significant dose-response relationship whereas no DNA damage was obtained in the stomach. 5-fluorouracil did not induce DNA damage in either liver or stomach

Spontaneous and Drug-induced Arteritis/Polyarteritis in the Göttingen Minipig—Review

Arteritis/polyarteritis occurs spontaneously in many species used in preclinical toxicology studies. In Göttingen minipigs, arteritis/polyarteritis is an occasionally observed background change. In the minipig, this finding differs in frequency and nature from age-related polyarteritis nodosa in rats or monkeys, and Beagle pain syndrome in dogs. In minipigs, it can be present in a single small- or medium-sized artery of an organ or a few organs and is most commonly recorded in the cardiac and extracardiac blood vessels, vagina, oviduct, rectum, epididymis, spinal cord, pancreas, urinary bladder, kidneys, and stomach. The etiology is unknown although it has been considered in minipigs as well as in rats, dogs, and monkeys to be possibly immune mediated. This background change is important with respect to its nature and distribution in the minipig in order to distinguish it from drug-induced vascular changes, which might occur in similar locations and have similar morphologic features. This review summarizes the morphology, incidence, and predilection sites of arteritis as a spontaneously occurring background change and as a drug-induced vasculopathy in the minipig, and also describes the main aspects to consider when evaluating vascular changes in Göttingen minipig toxicity studies and their human relevance

The effects of PKC (Protein Kinase C) inhibitors on steroid hormones: a 2-week rat oral (gavage) investigative study focusing on pathology and hormone analysis in plasma and tissues

The Protein Kinase C (PKC) family is a family of serine/threonine kinases with various classical and novel isoforms. Some of these isoforms are expressed in T and B cells and have a key role in T-lymphocyte activation, downstream of the T-cell receptor and CD28 co-receptor signaling, therefore being used as immunosuppressive agents. PKC could also have a potential role as a receptor and/or transducer of the non-genomic effects of steroid hormones which regulate a wide variety of cellular responses (regulation of ion transport and cell proliferation/migration/differentiation and death) (Alzamora and Harvey, 2008). The inhibition of PKC could alter steroid hormone actions and regulation leading to disturbances in multiple organ systems, particularly the reproductive system. To investigate the potential effects of PKC inhibitors on steroid hormones and its consequences, a 2-week oral mechanistic study in rats was conducted with a PKC inhibitor at two doses, focusing on pathology and hormone analysis in plasma and tissues. In males, tubuloalveolar pattern (feminization) in the mammary glands was observed microscopically and hormone analysis showed decreased androstenedione and testosterone concentrations in plasma, adrenals and testes. In females, atretic follicles and corpora luteal degeneration in ovaries was present microscopically, accompanied with disturbed estrus cycle, as evident in the vagina histology and vaginal smear cytology. Hormone analysis revealed decreased estrogens and its precursor androstenedione in the ovaries. Progesterone was increased in ovarian and adrenal tissues, whereas it was decreased in plasma. In both sexes, Luteinizing Hormone (LH) was decreased in blood. LH decrease was considered responsible for the reduction of androgens, estrogens and plasma progesterone which in turn led to the observed disturbances in estrous cycle. However, as progesterone levels were elevated in ovaries, it was thought that PKC inhibitor might have an additional direct effect in the corpora lutea which is independent of the LH reduction. In both sexes, aldosterone was elevated in plasma and adrenal glands associated with increased cortical vacuolation microscopically. Lymphoid depletion of various lymphoid organs (thymus, lymph nodes and spleen) seen in both sexes at both doses was consistent with known immunosuppressive effects of PKC inhibitors. Absent/decreased germinal centers of lymph nodes are also supportive of the inhibitory properties on lymphocyte activation and proliferation by PKC inhibitors (Matz et al, 2011). In summary, the results of this study support possible PKC inhibitors induced hormonal imbalances in the rat, likely due to a disturbance of the hypothalamus-pituitary-gonad axis and/or direct effect on the ovaries and adrenals. The results also confirm the expected immunosuppressive effect of PKC inhibitors. References: Alzamora and Harvey (2008). Direct binding and activation of protein kinase C isoforms by steroid hormones. Steroids 73 (9-10), 885-888. Matz et al (2011). Evaluation of the novel protein kinase C inhibitors otrastaurin as immunosuppressive therapy after renal transplantation. Expert Opin Drug Metab Toxicol, 7 (1): 103-113

Reduced activity of sphingosine-1-phosphate lyase Induces podocyte-related glomerular proteinuria, skin Irritation, and platelet activation

Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity of the enzyme in animal models of inflammation. Since S1P lyase deficiency in mice causes a severe, lethal phenotype, it was of interest to investigate any pathological alterations associated with only partially reduced activity of S1P lyase as may be encountered upon pharmacological inhibition. Both genetic reduction of S1P lyase activity in mice and inhibition of S1P lyase with a low-molecular-weight compound in rats consistently resulted in podocyte-based kidney toxicity, which is the most severe finding. In addition, skin irritation and platelet activation were observed in both instances. The similarity of the findings in both the genetic model and the pharmacological study supports the value of analyzing inducible partially target-deficient mice for safety assessment. If the findings described in rodents translate to humans, target-related toxicity, particularly podocyte dysfunction, may limit chronic systemic treatment of autoimmune diseases with S1P lyase inhibitors. Furthermore, partial deficiency or inhibition of S1P lyase appears to provide an in vivo rodent model to enable studies on the mechanism of podocyte dysfunction

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists

Deficiency in MALT1 paracaspase activity promotes multi-organ inflammation

The paracaspase MALT1 plays an important role in signaling pathways leading to NF-kB activation. To investigate the contribution of its proteolytic activity to overall pathway regulation we generated MALT1 protease-deficient mice (Malt1PD/PD) and compared them to MALT1 KO animals (Malt1-/-). Malt1PD/PD mice displayed defects in multiple cell types including Treg, IL10-producing B cells and mature T and B cells. Immune defects were more pronounced in Malt1-/- animals. Both mouse lines showed abrogated B cell responses upon immunization and were protected in a Th17-dependent EAE model. Surprisingly, Malt1PD/PD animals developed a multi-organ inflammation characterized by Th2-type responses and enhanced IgG1 and IgE levels which was prevented by reconstitution with WT Treg. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and its relevance in human health and disease