An immune upgrade for organoids

A few years ago, Timothy Recaldin and Marius Francisco Harter watched magic unfold under the microscope. Timothy had mixed together two cell types that usually live together in the human gut: the epithelial cells that make up the organ’s lining, and the memory T cells critical for its immune function. The two cell types had been separately isolated and processed from patient samples, yet when they reunited in the lab, the T cells knew exactly how to integrate back into the epithelial layer of the self-organizing, complex tissue cultures called organoids.

That astonishing discovery ultimately led to work nowTimothy, Marius, their fellow lead authors Linda Steinacher and Bruno Gjeta, and colleagues report a major breakthrough in organoid engineering: intestinal epithelial organoids that incorporate tissue resident immune cells. 

Unlike previous attempts to integrate immune cells in organoids, which relied on blood-derived immune cells, these immuno-organoids contain tissue-resident immune cells, isolated from the same patient as the epithelial cells used to make the organoid. Since blood-derived immune cells behave differently and have different functions than the immune cells that live and work within tissues, integrating tissue-resident immune cells provides a more accurate model of the body’s innate biology.  In their paper, the scientists not only describe how to generate these immuno-organoids, but show how they can be used to recapitulate the immune-mediated toxic effects of certain cancer therapies that were seen in patients, but not in other traditional in vivo model systems.

Behaviorally, the tissue-resident immune cells acted in the intestinal organoid much as they would in the natural intestine. That is, the cells (shown in red) were very mobile (movement tracked in turquoise) , constantly moving around the organoids (dark circles)  and surveying against invading antigens. 

The success of the project hinged on the team’s highly interdisciplinary approach. Timothy, an immunologist, brought expertise in isolating immune cells from intestinal tissue, optimizing a novel protocol that allows these cells to be successfully grown in culture. Linda contributed her knowledge of toxicology and safety, allowing the team to assess how the new models could be used to study the adverse effects of existing or potential therapies. Marius, an imaging specialist, used microscopy techniques he developed to characterize the interactions between the epithelial and immune cells in the organoid, and Bruno, a computational biologist, provided the single-cell level analyses of the organoids that allowed comparison to other models and patients, and pinpointed the mechanisms underlying toxic drug responses.

The researchers see their work as an exciting starting point both for studying the biology of the gut, including the impact of drugs on both epithelium and immune system, as well as their interplay, but also the foundation for a new kind of model.

Such technology could be used to better understand tumor growth, autoimmune and infectious diseases. For example, Linda, in collaboration with Bruno, is pursuing a similar strategy to build lung organoids that incorporate their resident immune cells, to enable the study of a drug’s side effects in the lung. This work adds an additional layer of complexity, as the immune cells in the lung have different characteristics than those in the gut. While most of the gut immuno-organoid immune cells are memory T cells, the lung contains relatively greater numbers of myeloid cells that Linda is building into the model.

Ultimately, the new immuno-organoids represent an important step towards Roche’s goal of reducing, refining, and replacing the use of animal models in pharmaceutical research, Timothy said.

About the image (at top):

An immuno-organoid with tissue-resident immune cells, shown here using multiplex immunofluorescence staining, 24 hours after intestinal organoids were co-cultured with tissue-resident immune cells. Intestinal organoids show epithelium (red and orange) and integrated T cells (green and turquoise). Credit: Recaldin et al. 2024 Nature.