A Comprehensive Atlas of Immunological Differences Between Humans, Mice, and Non-Human Primates

Abstract

Animal models are an integral part of the drug development and evaluation process. However, they are unsurprisingly imperfect reflections of humans, and the extent and nature of many immunological differences are unknown. With the rise of targeted and biological therapeutics, it is increasingly important that we understand the molecular differences in the immunological behavior of humans and model organisms. However, very few antibodies are raised against non-human primate antigens, and databases of cross-reactivity between species are incomplete. Thus, we screened 332 antibodies in five immune cell populations in blood from humans and four non-human primate species generating a comprehensive cross-reactivity catalog that includes cell type-specificity. We used this catalog to create large mass cytometry universal cross-species phenotyping and signaling panels for humans, along with three of the model organisms most similar to humans: rhesus and cynomolgus macaques and African green monkeys; and one of the mammalian models most widely used in drug development: C57BL/6 mice. As a proof-of-principle, we measured immune cell signaling responses across all five species to an array of 15 stimuli using mass cytometry. We found numerous instances of different cellular phenotypes and immune signaling events occurring within and between species, and detailed three examples (double-positive T cell frequency and signaling; granulocyte response to Bacillus anthracis antigen; and B cell subsets). We also explore the correlation of herpes simian B virus serostatus on the immune profile. Antibody panels and the full dataset generated are available online as a resource to enable future studies comparing immune responses across species during the evaluation of therapeutics.

Variation of Immune Cell Responses in Humans Reveals Sex-Specific Coordinated Signaling Across Cell Types

“…Incorporation of information from other immunological assays would help provide an even richer picture of the immune state. This work, and the accompanying manuscript by Bjornson-Hooper et al ( 12 ), provide the first analyses of the Cross-Species Immune Atlas dataset. We hope this curated resource as well as these initial analyses will enable future human immune monitoring studies as well as more rational pre-clinical studies.…”

“…The methods for reagent development and sample processing are those used for the Cross-Species Immune Atlas project and are redundantly stated here and in Bjornson-Hooper et al ( 12 ).…”

“…Data were gated and analyzed with . To empower future studies, staining and gating were performed in keeping the cross-species universal mass cytometry staining and gating strategy described in Bjornson-Hooper et al ( 12 ).…”

“…We also looked to expand our understanding of immune cell phenotype and signaling responses in humans and animal model species commonly used in drug development to identify which of these features are conserved across species. In the data presented here and in the accompanying paper by Bjornson-Hooper et al ( 12 ), we profiled blood in response to 15 immune stimuli (including cytokines, growth factors, and microbial products) from 86 human subjects, 88 non-human primates (rhesus macaques, cynomolgus macaques, African green monkeys), and 50 mice using a 39-parameter mass cytometry immune profiling panel. Through the standardization of immune stimuli and antibody panels across the five species and the minimization of technical error using automation and single lots of reagents, we produce a publicly available and curated reference with complete documentation for other researchers.…”

In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

“…Leukemic mice models are generated by exposure to carcinogenic chemicals, genomic integration of oncogenes delivered by virus or transposons, implantation of modified embryos and zygotes transplanted with ex vivo manipulated HSC (transgenic models) or injection of primary patient samples or human cell lines into immunocompromised host animals (xenograft models) (Figure 2) (reviewed by [129]). Much of the scientific advancement in biomedical research has been obtained from studies in transgenic mice [130]; however, several components of the mouse genetic background or the immune system do not faithfully translate to human biology [131][132][133]. Some gene functions can be different among species [134] and many drugs and pathogens are species-specific [135].…”