Nonproliferative and Proliferative Lesions of the Rat and Mouse Hematolymphoid System

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) 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 changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

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

Toxicologic Pathology ◽

10.1177/0192623320968181 ◽

2021 ◽

Vol 49 (1) ◽

pp. 5-109

Author(s):

Jochen Woicke ◽

Muthafar M. Al-Haddawi ◽

Jean-Guy Bienvenu ◽

Jessica M. Caverly Rae ◽

Franck J. Chanut ◽

...

Keyword(s):

Great Britain ◽

North America ◽

Diagnostic Criteria ◽

Laboratory Animals ◽

The Internet ◽

Common Language ◽

International Harmonization ◽

Research Organizations ◽

The World ◽

Safety Studies

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.

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

Toxicologic Pathology ◽

10.1177/0192623320975373 ◽

2021 ◽

Vol 49 (1) ◽

pp. 110-228

Author(s):

Mikala Skydsgaard ◽

Zuhal Dincer ◽

Wanda M. Haschek ◽

Kris Helke ◽

Binod Jacob ◽

...

Keyword(s):

Great Britain ◽

North America ◽

Diagnostic Criteria ◽

Laboratory Animals ◽

The Internet ◽

Common Language ◽

International Harmonization ◽

Research Organizations ◽

The World ◽

Safety Studies

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 microscopic lesions observed in most tissues and organs from the minipig 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 as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. 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.

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Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80.

Journal of Experimental Medicine ◽

10.1084/jem.161.3.475 ◽

1985 ◽

Vol 161 (3) ◽

pp. 475-489 ◽

Cited By ~ 254

Author(s):

S H Lee ◽

P M Starkey ◽

S Gordon

Keyword(s):

Bone Marrow ◽

Small Bowel ◽

Lymph Nodes ◽

Large Bowel ◽

Adult Mouse ◽

Specific Antigen ◽

Lymphoid Tissues ◽

Mesenteric Lymph Nodes ◽

Mesenteric Lymph ◽

Mouse Tissues

We have estimated the macrophage content of different tissues of the normal adult mouse using F4/80, a highly specific antigen marker for mature mouse macrophages. An absorption indirect binding assay was used to quantitate F4/80 antigen against a calibration standard made from the J774.2 macrophage-like cell line. The richest sources of tissue F4/80 antigen were found to be bone marrow, spleen, cervical and mesenteric lymph nodes, large bowel, liver, kidneys, and small bowel. The organs that have the highest total F4/80 antigen content are the liver, large bowel, small bowel, bone marrow, spleen, cervical and mesenteric lymph nodes, and kidney. We conclude that the mononuclear phagocyte system is mainly distributed in the gastrointestinal tract and liver, followed by hemopoietic and lymphoid tissues.

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[18F]-Fluorodeoxyglucose Uptake in Lymphoid Tissue Serves as a Predictor of Disease Outcome in the Nonhuman Primate Model of Monkeypox Virus Infection

Journal of Virology ◽

10.1128/jvi.00897-17 ◽

2017 ◽

Vol 91 (21) ◽

Cited By ~ 2

Author(s):

Julie Dyall ◽

Reed F. Johnson ◽

Svetlana Chefer ◽

Christopher Leyson ◽

David Thomasson ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Lymph Nodes ◽

Metabolic Activity ◽

Fdg Pet ◽

Ct Imaging ◽

Lymphoid Tissues ◽

Fdg Uptake ◽

Pet Ct ◽

Fdg Pet Ct

ABSTRACT Real-time bioimaging of infectious disease processes may aid countermeasure development and lead to an improved understanding of pathogenesis. However, few studies have identified biomarkers for monitoring infections using in vivo imaging. Previously, we demonstrated that positron emission tomography/computed tomography (PET/CT) imaging with [18F]-fluorodeoxyglucose (FDG) can monitor monkeypox disease progression in vivo in nonhuman primates (NHPs). In this study, we investigated [18F]-FDG-PET/CT imaging of immune processes in lymphoid tissues to identify patterns of inflammation in the monkepox NHP model and to determine the value of [18F]-FDG-PET/CT as a biomarker for disease and treatment outcomes. Quantitative analysis of [18F]-FDG-PET/CT images revealed differences between moribund and surviving animals at two sites vital to the immune response to viral infections, bone marrow and lymph nodes (LNs). Moribund NHPs demonstrated increased [18F]-FDG uptake in bone marrow 4 days postinfection compared to surviving NHPs. In surviving, treated NHPs, increase in LN volume correlated with [18F]-FDG uptake and peaked 10 days postinfection, while minimal lymphadenopathy and higher glycolytic activity were observed in moribund NHPs early in infection. Imaging data were supported by standard virology, pathology, and immunology findings. Even with the limited number of subjects, imaging was able to differentiate the difference between disease outcomes, warranting additional studies to demonstrate whether [18F]-FDG-PET/CT can identify other, subtler effects. Visualizing altered metabolic activity at sites involved in the immune response by [18F]-FDG-PET/CT imaging is a powerful tool for identifying key disease-specific time points and locations that are most relevant for pathogenesis and treatment. IMPORTANCE Positron emission tomography and computed tomography (PET/CT) imaging is a universal tool in oncology and neuroscience. The application of this technology to infectious diseases is far less developed. We used PET/CT imaging with [18F]-labeled fluorodeoxyglucose ([18F]-FDG) in monkeys after monkeypox virus exposure to monitor the immune response in lymphoid tissues. In lymph nodes of surviving monkeys, changes in [18F]-FDG uptake positively correlated with enlargement of the lymph nodes and peaked on day 10 postinfection. In contrast, the bone marrow and lymph nodes of nonsurvivors showed increased [18F]-FDG uptake by day 4 postinfection with minimal lymph node enlargement, indicating that elevated cell metabolic activity early after infection is predictive of disease outcome. [18F]-FDG-PET/CT imaging can provide real-time snapshots of metabolic activity changes in response to viral infections and identify key time points and locations most relevant for monitoring the development of pathogenesis and for potential treatment to be effective.

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Hemophagocytic Syndrome in a Case of Splenic Large B-Cell Lymphoma

Tumori Journal ◽

10.1177/030089169608200623 ◽

1996 ◽

Vol 82 (6) ◽

pp. 621-624 ◽

Cited By ~ 2

Author(s):

Gualtiero Büchi ◽

Giuseppe Termine ◽

Renzo Orlassino ◽

Mauro Pagliarino ◽

Roberto Boero ◽

...

Keyword(s):

Bone Marrow ◽

Lymph Nodes ◽

B Cell ◽

Diagnostic Criteria ◽

Hemophagocytic Syndrome ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Peripheral Lymph ◽

Large B Cell

A case of splenic large B-cell lymphoma with hemophagocytic syndrome is reported. The difficulties of diagnosis are emphasized especially when peripheral lymph nodes or bone marrow lymphomatous infiltration are not present. Diagnostic criteria for hemophagocytic syndrome and their relationship with the pathogenesis of the disease are also stressed.

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Kidney Tertiary Lymphoid Structures in Lupus Nephritis Develop into Large Interconnected Networks and Resemble Lymph Nodes in Gene Signature

American Journal Of Pathology ◽

10.1016/j.ajpath.2020.07.015 ◽

2020 ◽

Vol 190 (11) ◽

pp. 2203-2225

Author(s):

Seyed Esmaeil Dorraji ◽

Premasany Kanapathippillai ◽

Aud-Malin Karlsson Hovd ◽

Mikael Ryan Stenersrød ◽

Kjersti Daae Horvei ◽

...

Keyword(s):

Lupus Nephritis ◽

Lymph Nodes ◽

Gene Signature ◽

Interconnected Networks ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

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CHANGES IN PLASMA LEVELS OF CALCIUM AND IN BONE MARROW MITOSIS AFTER ANTIGENIC CHALLENGE IN RATS AND MICE

Journal of Endocrinology ◽

10.1677/joe.0.0900445 ◽

1981 ◽

Vol 90 (3) ◽

pp. 445-452 ◽

Cited By ~ 4

Author(s):

D. J. EDWARDS ◽

J. J. RIMMER ◽

M. J. ATKINSON ◽

A. D. PERRIS

Keyword(s):

Bone Marrow ◽

Bovine Serum Albumin ◽

Blood Cells ◽

Proliferative Response ◽

Plasma Calcium ◽

Lymphoid Tissues ◽

Antigenic Challenge ◽

Form Part ◽

Bacterial Lipopolysaccharides ◽

Rats And Mice

When rats or mice were immunized with sheep red blood cells, bacterial lipopolysaccharides or bovine serum albumin, a proliferative response could be detected in the bone marrow and spleen. This response was associated with a hypercalcaemic phase. Parathyroidectomy, which resulted in a protracted hypocalcaemia, prevented the development of an increase in levels of plasma calcium. This operation also prevented the rise in bone marrow proliferation following antigenic challenge, but did not ablate the normal proliferative response to antigen by cells in the spleen. Antibody production and numbers of antibody-forming cells were not significantly reduced by parathyroidectomy. These results suggest that there is a pool of antigen-insensitive cells in the bone marrow which are stimulated after antigenic challenge. It is postulated that these events are mediated by the development of a parathyroid-dependent hypercalcaemia which stimulates the cells non-specifically. These events may form part of a cellular homeostasis, replacing cells in peripheral lymphoid tissues.

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Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

Blood ◽

10.1182/blood-2016-10-695957 ◽

2017 ◽

Vol 129 (6) ◽

pp. 680-692 ◽

Cited By ~ 87

Author(s):

Elisa Rumi ◽

Mario Cazzola

Keyword(s):

Bone Marrow ◽

Diagnostic Criteria ◽

Myeloproliferative Neoplasms ◽

Phenotypic Variability ◽

Vascular Complications ◽

Prognostic Models ◽

Lymphoid Tissues ◽

Driver Genes ◽

Jak2 Mutation ◽

Endogenous Erythropoietin

Abstract Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone.

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Lymphoid reconstitution after transplantation of congenic hematopoietic cells in busulfan-treated mice

Blood ◽

10.1182/blood.v78.12.3312.3312 ◽

1991 ◽

Vol 78 (12) ◽

pp. 3312-3316 ◽

Cited By ~ 27

Author(s):

AM Yeager ◽

C Shinn ◽

DM Pardoll

Keyword(s):

Bone Marrow ◽

Lymph Nodes ◽

Hematopoietic Cell Transplantation ◽

Lymphoid Tissues ◽

High Dose ◽

Flow Cytometric ◽

Donor Cells ◽

Total Body ◽

Therapy Strategies ◽

Dose Dependent

Abstract The effects of pretransplant conditioning with high-dose busulfan, a myeloablative but nonimmunosuppressive alkylating agent, on reconstitution of lymphoid tissues by donor cells after bone marrow transplantation (BMT) has not been extensively examined. We used flow cytometric analyses to study the kinetics and extent of lymphocyte repopulation in C57BL/6 mice (immunophenotype Ly-5.2) given graded doses of busulfan (10 to 100 mg/kg) or total body irradiation (TBI; 900 rad) and hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) from congenic Ly-5.1 donors. Mice transplanted after 10 mg/kg of busulfan had slow and incomplete lymphoid engraftment; only 6% to 11% of lymphocytes in the peripheral blood, lymph nodes, and spleen were positive for Ly-5.1 at 30 days after transplant, slightly increased to 13% to 20% at 60 days, and stabilized at 40% to 46% by 180 days after HCT. Higher doses of busulfan (20 to 100 mg/kg) provided dose-dependent congenic lymphoid reconstitution. Thirty days after HCT, the range of Ly-5.1 cells in blood, lymph nodes, and spleen of Ly-5.2 recipient mice was 43% to 54% after 20 mg/kg of busulfan, 66% to 71% after 50 to 80 mg/kg, and 77% to 85% after 100 mg/kg. Sixty days after transplant, lymphoid chimerism increased to 57% to 68% in 20 mg/kg recipients, 72% to 79% after 35 mg/kg, and 75% to 90% in animals given 50 mg/kg or greater, as seen in radiation chimeras. Despite slower early reconstitution after lower doses of busulfan, donor lymphocytes exceeded 90% to 95% by 90 to 120 days after HCT in all mice given at least 20 mg/kg. Even though busulfan lacks directly immunosuppressive properties, virtually complete sustained lymphoid reconstitution by transplanted congenic donor stem cells occurs after its administration. These observations suggest that pretreatment with busulfan may be effective in gene therapy strategies that involve infusion of autologous marrow cells into which functional genes have been inserted.

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Intracellular localization and properties of phosphate-dependent glutaminase in rat mesenteric lymph nodes

Biochemical Journal ◽

10.1042/bj2170289 ◽

1984 ◽

Vol 217 (1) ◽

pp. 289-296 ◽

Cited By ~ 30

Author(s):

M S M Ardawi ◽

E A Newsholme

Keyword(s):

Bone Marrow ◽

Lymph Nodes ◽

Intracellular Localization ◽

Lymphoid Tissues ◽

Mesenteric Lymph Nodes ◽

Ph Optimum ◽

Mesenteric Lymph ◽

Phosphorylated Compounds ◽

Glutaminase Activity

Phosphate-dependent glutaminase was present at approximately similar activities in lymph nodes from mammals other than rat, and in thymus, spleen, Peyer's patches and bone marrow of the rat. This suggests that glutamine is important in all lymphoid tissues. Phosphate-dependent glutaminase activity was shown to be present primarily in the mitochondria of rat mesenteric lymph nodes, and most of the activity could be released by detergents. The properties of the enzyme in mitochondrial extracts were investigated. The pH optimum was 8.6 and the Km for glutamine was 2.0 mM. The enzyme was activated by phosphate, other phosphorylated compounds including phosphoenolpyruvate, and also leucine: 50% activation occurred at 5, 0.2 and 0.6 mM for phosphate, phosphoenolpyruvate and leucine respectively. The enzyme was inhibited by glutamate, 2-oxoglutarate, citrate and ammonia, and by N-ethylmaleimide and diazo-5-oxo-L-norleucine; 50% inhibition was observed at 0.7 and 0.1 mM for glutamate and 2-oxoglutarate respectively. Some of these properties may be important in the control of the enzyme activity in vivo.

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