Chapter 24 - Spleen, Lymph Nodes, and Thymus

Abstract

Histologic changes in lymphoid organs can be produced by xeobiotics (small or large molecules) or their metabolites. These effects can be unexpected or off target, or can be on target, due to the expected or exaggerated pharmacology of the molecule. Off-target effects can be caused by the compounds directly on the hematopoietic cells and tissues, or indirectly by affecting other organs and causing hormonal alterations and stress that indirectly affect the lymphoid organs. Although clinical and functional reflections of immunotoxicity may be associated with obvious morphological alterations in the spleen, lymph node, thymus, or bone marrow, the standard toxicity or carcinogenicity test is not designed to identify or assess the effects of compounds on immune function. More sensitive in vitro assays and animal models, including the rat, are available for determination of effects on immune function. Histopathology provides only a static view of these lymphoid organs, where the bulk of the parenchyma is formed by cells that are frequently entering and leaving the organs via venous and lymphatic circulation. In addition, these organs have unique compartments, with different cell types and functions, which can be individually affected by xenobiotics, by study specific procedures (route and frequency of administration of test compounds, sample collections, etc), by normal physiologic processes (e.g., hormonal variations, aging) or natural events (e.g., exposure to antigens in mucosal sites). For these reasons, the Society of Toxicologic Pathology published a best practices recommendations on the collection, interpretation, and reporting of organ weights, gross, and microscopic observations. With regard to histopathology, the recommendations are to evaluate the separate compartment within each lymphoid organ individually and to use descriptive rather than interpretative terminology to characterize changes within these compartments. These methods of evaluation, which include recommended descriptive terminology for each lymphoid compartment, are aimed at increasing the sensitivity and specificity of compound-related changes in lymphoid organs. These approaches are especially helpful in identifying these effects in acute and subchronic safety studies. In chronic and carcinogenicity study, which are designed to identify long-term effects of compounds in animals, a more general and concise approach to recording findings in lymphoid organs is more appropriate. For this chapter, the author chose to use terms that have been most commonly applied by toxicologic pathologists in chronic toxicity studies in rats, with the understanding that different terms may eventually be recommended as standard practice.