Inhibition of natural type I IFN-producing and dendritic cell development by a small molecule receptor tyrosine kinase inhibitor with Flt3 affinity.
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.
Tussiwand
Roxane
R
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Onai
Nobuyuki
N
Mazzucchelli
Luca
L
Manz
Markus G
MG
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009930:Organic Chemicals / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis / Q000378:metabolism*
D007370:Interferon Type I; D008565:Membrane Proteins; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors; C474557:SU 11657; C084881:flt3 ligand protein; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3