In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice

Bouffi, Carine; Wikenheiser-Brokamp, Kathryn A.; Chaturvedi, Praneet; Sundaram, Nambirajan; Goddard, Gillian R.; Wunderlich, Mark; Brown, Nicole; Staab, Janet F.; Latanich, Rachel; Zachos, Nicholas C.; Holloway, Emily M.; Mahé, Maxime M.; Poling, Holly M.; Vales, Simon; Fisher, Garrett W; Spence, Jason R.; Mulloy, James C.; Zorn, Aaron M.; Wells, James M.; Helmrath, Michael A.

doi:10.1038/s41587-022-01558-x

Cited by 51 publications

(28 citation statements)

References 40 publications

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“…T cells engrafted with iPSC‐derived thymus organoids generated both cellular and humoral responses, including induction of proinflammatory responses and inhibition of allogeneic tumor graft growth (Zeleniak et al., 2022). Human intestinal organoids (HIOs) derived from pluripotent stem cells that were subsequently engrafted under the kidney capsule of humanized mice created a microenvironment resembling human intestinal lymphoid follicles containing T and B cells and GALT‐like structures (Bouffi et al., 2023). Intestine‐immune crosstalk was detected in these mice and microbial exposure activated immune cells.…”

Section: Future Perspectivesmentioning

confidence: 99%

Humanized Mouse Models for Immuno‐oncology Drug Discovery

Kumari¹,

Feuer²,

Bourré³

2023

Current Protocols

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Breakthroughs in cancer treatment with immunotherapeutics have provided long‐term patient benefits for many different types of cancer. However, complete response is not achieved in many patients and tumor types, and the mechanisms underlying this lack of response are poorly understood. Despite this, numerous new targets, therapeutics, and drug combinations are being developed and tested in clinical trials. Preclinical models that recapitulate the complex human tumor microenvironment and the interplay between tumor and immune cells within the cancer‐immunity cycle are needed to improve our understanding and screen new therapeutics for efficacy and safety/toxicity. Humanized mice, encompassing human tumors and human immune cells engrafted on immunodeficient mice, have been widely used for many years in immuno‐oncology, with developments to improve both the humanization and the translational value central to the next generation of models. In this overview, we discuss recent advances in humanized models relevant to immuno‐oncology drug discovery, the advantages and limitations of such models, the application of humanized models for efficacy and safety assessments of immunotherapeutics, and the potential opportunities. © 2023 Crown Bioscience. Current Protocols published by Wiley Periodicals LLC.

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Section: Future Perspectivesmentioning

confidence: 99%

Humanized Mouse Models for Immuno‐oncology Drug Discovery

Kumari¹,

Feuer²,

Bourré³

2023

Current Protocols

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“…However, the incorporation of a mucosal lymphocyte compartment has proven elusive. A recent study described the generation of gut-associated lymphoid tissue in iPSC-derived human intestinal organoids upon transplantation in humanized mice (26). Although an important advance, the in vivo formation of immune tissue removes some of the advantages of organoids as controllable in vitro systems.…”

Section: Main Textmentioning

confidence: 99%

Human intestinal organoids with an autologous tissue-resident immune compartment

Recaldin,

Gjeta,

Steinacher

et al. 2023

Preprint

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The intimate relationship between the epithelium and the immune system is crucial for maintaining tissue homeostasis, with perturbations in epithelial-immune interactions linked to autoimmune disease and cancer. Whereas stem cell-derived organoids are powerful models of tissue-specific epithelial function, these structures lack tissue-resident immune cells that are essential for capturing organ-level processes. We describe human intestinal immuno-organoids (IIOs), formed through self-organization of epithelial organoids and autologous tissue-resident lymphocytes (TRMs), a portion of which integrate within the IIO epithelium and survey the barrier. IIO formation was driven by TRM migration and interaction with epithelial cells, as orchestrated by TRM-enriched transcriptomic programs governing cell motility and epithelial inspection. We combined IIOs and single-cell transcriptomics to investigate intestinal inflammation triggered by cancer-targeting biologics in patients, and found that the system recapitulates clinical outcomes and the underlying cellular mechanisms. Inflammation was associated with the emergence of an activated population of CD8+ T cells, which progressively acquired intraepithelial and cytotoxic features. The appearance of this effector population was preceded and likely mediated by a Th1-like CD4+ population, which initially displayed a cytokine-producing character and subsequently became cytotoxic itself. A system amenable to direct perturbation and interrogation, IIOs allowed us to identify the Rho pathway as a novel target for mitigating immunotherapy-associated intestinal inflammation. Given that they recapitulate both the phenotypic outcomes and the underlying inter-lineage immune interactions, IIOs can be used to broadly study tissue-resident immune responses in the context of tumorigenesis, infectious and autoimmune diseases.

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“…A new human intestinal organoid with immune cells has shown activation of immune response and IgA antibody secretion upon microbial exposure, providing a model for studying infectious or allergen-driven intestinal diseases. 96 The direct integration of liver organoids with liquid chromatography-MS (LC-MS) allows for selective automatic tracking of drug metabolism. The liver organoids are equipped with liquid chromatography column housings, which can monitor and analyze drug phase 1 metabolism by coupling the 'organ-in-a-column' unit with LC-MS online.…”

Section: Macroscopic Systematic Processmentioning

confidence: 99%

“…Current gut‐like organoids still lack full representation of human intestinal biology and immune components in vivo. A new human intestinal organoid with immune cells has shown activation of immune response and IgA antibody secretion upon microbial exposure, providing a model for studying infectious or allergen‐driven intestinal diseases 96 …”

Section: Introductionmentioning

confidence: 99%

Organoid assessment technologies

Gu,

Zhang,

et al. 2023

Clinical & Translational Med

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Despite enormous advances in the generation of organoids, robust and stable protocols of organoids are still a major challenge to researchers. Research for assessing structures of organoids and the evaluations of their functions on in vitro or in vivo is often limited by precision strategies. A growing interest in assessing organoids has arisen, aimed at standardizing the process of obtaining organoids to accurately resemble human‐derived tissue. The complex microenvironment of organoids, intricate cellular crosstalk, organ‐specific architectures and further complicate functions urgently quest for high‐through schemes. By utilizing multi‐omics analysis and single‐cell analysis, cell‐cell interaction mechanisms can be deciphered, and their structures can be investigated in a detailed view by histological analysis. In this review, we will conclude the novel approaches to study the molecular mechanism and cell heterogeneity of organoids and discuss the histological and morphological similarity of organoids in comparison to the human body. Future perspectives on functional analysis will be developed and the organoids will become mature models.

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In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice

Cited by 51 publications

References 40 publications

Humanized Mouse Models for Immuno‐oncology Drug Discovery

Humanized Mouse Models for Immuno‐oncology Drug Discovery

Human intestinal organoids with an autologous tissue-resident immune compartment

Organoid assessment technologies

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