This article is a summary of a half-day continuing education course jointly sponsored by the Society for Toxicologic Pathology (STP) and the Health and Environmental Sciences Institute (HESI) at the annual meeting of the STP in Baltimore, MD, held June 16-19, 2024. Presenters discussed pathology, toxicology, immunotoxicology, and regulatory implications of findings in the immune system in context of development of immunomodulatory therapeutics. Interpretation of pathology findings requires knowledge of immune system morphology and function including species-specific differences and spontaneous findings in animal model systems. A weight of evidence (WoE) approach is required to integrate pathology findings and immunotoxicology assay results to assess translatability to humans. Communication and collaboration among scientists of various disciplines can be instrumental in optimal generation and interpretation of appropriate data for development of immunomodulatory therapeutics.
Bjornson-HooperZBFragiadakisGKSpitzerMH, et al. A comprehensive atlas of immunological differences between humans, mice, and non-human primates. Front Immunol. 2022;13:867015. doi:10.3389/fimmu.2022.867015.
2.
BussiereJLMartinPHornerM, et al. Alternative strategies for toxicity testing of species-specific biopharmaceuticals. Int J Toxicol. 2009;28(3):230-253. doi:10.1177/1091581809337262.
3.
ChamanzaR. Chapter 1. Non-human primates: cynomolgus (Macaca fascicularis) and rhesus (Macaca mulatta) macaques and the common marmoset (Callithrix jacchus). In: McInnesEFMannP, ed. Background Lesions in Laboratory Animals: A Color Atlas. Amsterdam, Netherlands: Saunders/Elsevier; 2012:1-15.
4.
ChamanzaRMarxfeldHABlancoAINaylorSWBradleyAE. Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol Pathol. 2010;38(4):642-657. doi:10.1177/0192623310368981.
5.
ColmanKAndrewsRNAtkinsH, et al. International harmonization of nomenclature and diagnostic criteria (INHAND): non-proliferative and proliferative lesions of the non-human primate (M. fascicularis). J Toxicol Pathol. 2021;34(3 suppl):1s-182s. doi:10.1293/tox.34.1S.
6.
De SmedtMHoebekeIReynvoetKLeclercqGPlumJ. Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment. Blood. 2005;106(10):3498-3506. doi:10.1182/blood-2005-02-0496.
7.
ElmoreSA. Enhanced histopathology of the immune system: a review and update. Toxicol Pathol. 2012;40(2):148-156. doi:10.1177/0192623311427571.
8.
European Medicines Agency. ICH Guideline M3(R2) on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals (EMA/CPMP/ICH/286/1995). Amsterdam, Netherlands: European Medicines Agency; 2009.
9.
European Medicines Agency. ICH Guideline S6 (R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (EMA/CHMP/ICH/731268/1998). Amsterdam, Netherlands: European Medicines Agency; 2011.
10.
European Medicines Agency. ICH S9: Non-Clinical Evaluation for Anticancer Pharmaceuticals (EMA/CHMP/ICH/646107/2008). Amsterdam, Netherlands: European Medicines Agency; 2010.
11.
European Medicines Agency. ICH Topic S 8: Immunotoxicity Studies for Human Pharmaceuticals (CHMP/167235/2004). Amsterdam, Netherlands: European Medicines Agency; 2006.
12.
EverdsNESnyderPWBaileyKL, et al. Interpreting stress responses during routine toxicity studies: a review of the biology, impact, and assessment. Toxicol Pathol. 2013;41(4):560-614. doi:10.1177/0192623312466452.
13.
HaleyPJ. The lymphoid system: a review of species differences. Toxicol Pathol. 2017;30(2):111-123. doi:10.1293/tox.2016-0075.
14.
HamiltonSEBadovinacVPBeuraLK, et al. New insights into the immune system using dirty mice. J Immunol. 2020;205(1):3-11. doi:10.4049/jimmunol.2000171.
15.
HuYHuQLiY, et al. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther. 2023;8(1):434. doi:10.1038/s41392-023-01653-8.
16.
KaplanBLFSulenticCEWHaggertyHGHolsappleMPKaminskiNE. Toxic responses of the immune system. In: KlaassenCD, ed. Casarett & Amp; Doull’s Toxicology: The Basic Science of Poisons. 9th ed.New York: McGraw-Hill Education; 2019.
17.
KumarABockenstedtMLaastVSharmaA. Historical control background incidence of spontaneous neoplastic lesions of Sprague-Dawley rats in 104-week toxicity studies. Toxicol Pathol. 2023;51(6):329-356. doi:10.1177/01926233231224466.
18.
KuperCFRuehl-FehlertCElmoreSAParkerGA. Chapter 49—Immune system. In: HaschekWMRousseauxCGWalligMA, eds. Haschek and Rousseaux’s Handbook of Toxicologic Pathology (Third Edition). San Diego, CA: Academic Press; 2013:1795-1862.
19.
McInnesEF. Chapter 2. Wistar and Sprague-Dawley rats. In: McInnesEFMannP, ed. Background Lesions in Laboratory Animals: A Color Atlas. Amsterdam, Netherlands: Saunders/Elsevier; 2012:17-36.
20.
MestasJHughesCCW. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172(5):2731-2738. doi:10.4049/jimmunol.172.5.2731.
21.
NamdariRJonesKChuangSS, et al. Species selection for nonclinical safety assessment of drug candidates: examples of current industry practice. Regul Toxicol Pharmacol. 2021;126:105029. doi:10.1016/j.yrtph.2021.105029.
22.
PriorHHaworthRLabramBRobertsRWolfreysASewellF. Justification for species selection for pharmaceutical toxicity studies. Toxicol Res (Camb). 2020;9(6):758-770. doi:10.1093/toxres/tfaa081.
23.
SatoJDoiTKannoTWakoYTsuchitaniMNaramaI. Histopathology of incidental findings in cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. J Toxicol Pathol. 2012;25(1):63-101. doi:10.1293/tox.25.63.
24.
SatoJDoiTWakoY, et al. Histopathology of incidental findings in beagles used in toxicity studies. J Toxicol Pathol. 2012;25(1):103-134. doi:10.1293/tox.25.103.
25.
ScudamoreC. Chapter 3. Beagle dog. In: McInnesEFMannP, ed. Background Lesions in Laboratory Animals: A Color AtlasAmsterdam, Netherlands: Saunders/Elsevier; 2012:37-44.
26.
ShultzLDBrehmMAGarcia-MartinezJVGreinerDL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12(11):786-798. doi:10.1038/nri3311.
27.
TaoLReeseTA. Making mouse models that reflect human immune responses. Trends Immunol. 2017;38(3):181-193. doi:10.1016/j.it.2016.12.007.
28.
TaylorI. Chapter 4. Mouse. In: McInnesEFMannP, ed. Background Lesions in Laboratory Animals: A Color AtlasAmsterdam, Netherlands: Saunders/Elsevier; 2012:45-72.
29.
U.S. Food and Drug Administration. Guidance for Industry: Nonclinical Evaluation of the Immunotoxic Potential of Pharmaceuticals (FDA-2019-D-5607). Silver Spring, MD: U.S. Food and Drug Administration; 2023.
30.
U.S. Food and Drug Administration. Guidance for Industry: S8 Immunotoxicity Studies for Human Pharmaceuticals (FDA-2005-D-0398). Silver Spring, MD: U.S. Food and Drug Administration; 2006.
31.
Willard-MackCLElmoreSAHallWC, et al. Nonproliferative and proliferative lesions of the rat and mouse hematolymphoid system. Toxicol Pathol. 2019;47(6):665-783. doi:10.1177/0192623319867053.
32.
WoickeJAl-HaddawiMMBienvenuJG, et al. International harmonization of nomenclature and diagnostic criteria (INHAND): nonproliferative and proliferative lesions of the dog. Toxicol Pathol. 2021;49:5-109.
