A screening platform for human plasma cells (PCs) reveals a selective response to SYK inhibition
| Autor: | Michelle Campbell, Sophie J Stephenson, Kevin Whale, Stephen Rapecki, Helene Finney, Gina M Doody, Reuben M Tooze |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 202:123.23-123.23 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Therapeutic targeting of PC populations has potential value in various auto-immune, allergic and neoplastic cell states, but at present few options exist for selective targeting. However, the unique physiology and niche dependence of PCs suggests that such targeting may be achievable. To this end we have developed a sensitive screening platform capable of detecting changes in PC biology. Starting from our published methods for in vitro PC generation we optimised conditions to allow maintenance of PCs in polarised niche environments reflective of homeostatic and inflammatory conditions in microtitre plates. Using this assay format we probed PC biology via small molecule inhibitors (SMIs) targeting BCL2 family members, proteasome, and kinase signalling pathways. We were able to identify SMIs with broad and selective toxicity, as well as SMIs with no effect on PCs. Under all conditions analysed we found consistent divergence in the impact of targeting aspects of B cell receptor (BCR)-associated signalling pathways. Targeting SYK via two distinct SMIs consistently resulted in selective killing of subsets of PCs. By contrast BTK inhibition had no significant effect on PC viability. Whilst the importance of SYK signalling has been well documented at the B cell stage its importance to PCs has to our knowledge not been extensively documented. Retention of functional BCRs has been recently described in BM IgA+ and IgM+ PCs, and examination of expression data indicates selective retention of components of the BCR signalling complex in our assay system. The data presented here demonstrate the potential utility of an in vitro screening platform to evaluate the selective dependency of subsets of PCs on therapeutically targetable pathways. |
| Databáze: | OpenAIRE |
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