The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative among the Societies of Toxicological 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 microscopic lesions observed in the endocrine organs (pituitary gland, pineal gland, thyroid gland, parathyroid glands, adrenal glands and pancreatic islets) of laboratory rats and mice, with color photomicrographs illustrating examples of the lesions. 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 and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for endocrine lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

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Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a doseresponsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An

Asthma is frequently associated with inhalant sensitivities, particularly allergens of indoor environment. The aim of the study is to determine whether an indoor allergen, cockroach (CRa), can induce guinea pig sensitization without adjuvant or special manipulation. Six regimens were used in sensitizing guinea pigs by CRa aerosols: low daily (C-I), low intermittent (C-II), high intermittent (C-III), maximum intermittent (C-IV), high daily (C-V) and high alternate day (C-VI) doses, and results were compared with that of intraperitoneal sensitization (C-VII). Also studied was a role of CRa in the aerosol ovalbumin (OA) sensitization in comparison with placebo and an adjuvant, Al(OH)₃. Reaginic guinea pig antibodies, anti-CRa-IgGla-like (IgGla) and IgE-like (IgE), were measured by passive cutaneous anaphylaxis (PCA). Results show that IgGla was produced only in high-dose aerosol groups, C-V and C-VI, but no IgE in all aerosol groups. The antibody was detected on day 22 (C-V) and day 19 (C-VI) and sustained till day 52 (titers 1:20 to 1:200). The preliminary pulmonary function measurements revealed that the sensitized animals (C-VI) showed a decreased ventilatory function upon CRa challenge. Aerosolized OA sensitization also produced anti-OA-IgGla in high intermittent regimens. In addition, PCA titers (anti-OA-IgGla) in OA-sensitized animals were not influenced by pretreatment with CRa, Al(OH)₃, or placebo. Thus, the study indicates that simple aerosolized CRa contamination in a chamber makes guinea pigs cockroach-sensitive and become asthmatic. Yet, CRa does not enhance other allergen sensitization.

In nonclinical toxicity studies, stage-aware evaluation is often expected to assess drug-induced testicular toxicity. Although stage-aware evaluation does not require identification of specific stages, it is important to understand microscopic features of spermatogenic staging. Staging of the spermatogenic cycle in dogs is a challenging and time-consuming process. In this study, we first defined morphologic features for the eight spermatogenic stages in standard histology sections (H&E slides) of dog testes. For image analysis, we defined the key morphologic features of five stages/pooled stage groups (I-II, III-IV, V, VI-VII, and VIII). These criteria were used to develop a deep learning (DL) algorithm for staging of the spermatogenic cycle of control dog testes using whole slide images. In addition, a DL-based nucleus segmentation model was trained to detect and quantify the number of different germ cells, including spermatogonia, spermatocytes, and spermatids. Identification of spermatogenic stages and quantification of germ cell populations were successfully automated by the DL models. Combining these two algorithms provided color-coding visual spermatogenic staging and quantitative information on germ cell populations at specific stages that would facilitate the stage-aware evaluation and detection of changes in germ cell populations in nonclinical toxicity studies.