A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Thomas, T.; Rich-Griffin, C.; Pohin, M.; Friedrich, M.; Aschenbrenner, D.; Pakpoor, J.; Jainarayanan, A.; Voda, A.-I.; Sanches Peres, R.; Nee, E.; Sathananthan, D.; Kotliar, D.; Turner, J.; Nayar, S.; Zhang, F.; Jonsson, A.; Brenner, M.; Raychaudhuri, S.; Kulicke, R.; Ramsdell, D.; Stransky, N.; Pagliarini, R.; Belecki, P.; Spies, N.; Wagner, A.; Walsh, A.; Coles, M.; Jostins-Dean, L.; Powrie, F.; Filer, A.; Travis, S.; Uhlig, H.; Dendrou, C.; Buckley, C.

doi:10.1101/2023.05.05.539635

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bioRxiv · 10.1101/2023.05.05.539635

A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

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Abstract

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires an understanding of how cellular networks change following therapy. We describe a therapeutic atlas for Crohns disease (CD) and ulcerative colitis (UC) following anti-tumour necrosis factor (TNF) therapy. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies from 38 patients and three controls, revealing disease- and therapy-specific differences. A systems-biology analysis identified distinct spatially-resolved cellular microenvironments: granuloma signatures in CD and interferon (IFN)-response signatures localising to T-cell aggregates and epithelial damage in CD and UC. Longitudinal comparisons demonstrated that disease progression in non-responders associated with myeloid and stromal cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas informs drug positioning across IMIDs, and suggests a rationale for the use of janus kinase (JAK) inhibition following anti-TNF resistance.

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Thomas, T., Rich-Griffin, C., Pohin, M., Friedrich, M., Aschenbrenner, D., Pakpoor, J., Jainarayanan, A., Voda, A.-I., Sanches Peres, R., Nee, E., Sathananthan, D., Kotliar, D., Turner, J., Nayar, S., Zhang, F., Jonsson, A., Brenner, M., Raychaudhuri, S., Kulicke, R., Ramsdell, D., Stransky, N., Pagliarini, R., Belecki, P., Spies, N., Wagner, A., Walsh, A., Coles, M., Jostins-Dean, L., Powrie, F., Filer, A., Travis, S., Uhlig, H., Dendrou, C., Buckley, C.. 2023-05-06. A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. https://doi.org/10.1101/2023.05.05.539635

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