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Inhibition of Natural Type I IFN-Producing and Dendritic Cell Development by a Small Molecule Receptor Tyrosine Kinase Inhibitor with Flt3 Affinity¹

Roxane Tussiwand^*, Nobuyuki Onai^*, Luca Mazzucchelli and Markus G. Manz^*,

^* Institute for Research in Biomedicine, Bellinzona, Switzerland; Institute of Pathology, Locarno, Switzerland; and Eberhard-Karls-University Medical School, Department of Medicine II, Tuebingen, Germany

In vivo steady-state type I natural IFN-producing and dendritic cell (DC) development is largely dependent on Flt3 signaling. Natural IFN-producing and DC progenitors and their respective downstream cell populations express the flt3 receptor, and Flt3 ligand (Flt3L)^–/– mice have reduced while Flt3L-injected mice develop markedly increased numbers of both cell types. In the present study, we show that SU11657, a small multitargeted receptor tyrosine kinase inhibitor with Flt3 affinity, suppressed in vitro natural IFN-producing and DC development in Flt3L-supplemented mouse whole bone marrow cell cultures in a dose-dependant manner, while DC development in GM-CSF-supplemented cultures was not affected. In vivo SU11657 application led to a significant decrease of both natural IFN-producing and DCs, comparable to the reduction observed in Flt3L^–/– mice. Conversely, Flt3L plasma levels increased massively in inhibitor-treated animals, likely via a regulatory feedback loop, without being able to compensate for pharmacological Flt3 inhibition. No obvious toxicity was observed, and hemopoietic progenitor cell and stem cell function remained intact as assessed by myeloid colony-forming unit activity and in vivo bone marrow repopulation assays. Furthermore, upon treatment discontinuation, IFN-producing and DCs recovered to normal levels, proving that treatment effects were transient. Given the importance of IFN-producing and DCs in regulation of immune responses, these findings might lead to new pharmacological strategies in prevention and treatment of autoimmune diseases and complications of organ or blood cell transplantation.

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				N. Onai, A. Obata-Onai, R. Tussiwand, A. Lanzavecchia, and M. G. Manz Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development J. Exp. Med., January 23, 2006; 203(1): 227 - 238. [Abstract] [Full Text] [PDF]