Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease.
Autoimmune diseases often result from inappropriate or unregulated activation of autoreactive T cells. Traditional approaches to treatment of autoimmune diseases through immunosuppression have focused on direct inhibition of T cells. In the present study, we examined the targeted inhibition of antigen-presenting cells as a means to downregulate immune responses and treat autoimmune disease. Dendritic cells (DCs) are the central antigen-presenting cells for the initiation of T cell responses, including autoreactive ones. A large portion of DCs are derived from hematopoietic progenitors that express FLT3 receptor (CD135), and stimulation of the receptor via FLT3 ligand either in vivo or in vitro is known to drive expansion and differentiation of these progenitors toward a DC phenotype. We hypothesized that inhibition of FLT3 signaling would thus produce an inhibition of DC-induced stimulation of T cells, thereby inhibiting autoimmune responses. To this end, we used small-molecule tyrosine kinase inhibitors targeted against FLT3 and examined the effects on DCs and their role in the promulgation of autoimmune disease. Results of our studies show that inhibition of FLT3 signaling induces apoptosis in both mouse and human DCs, and thus is a potential target for immune suppression. Furthermore, targeted inhibition of FLT3 significantly improved the course of established disease in a model for multiple sclerosis, experimental autoimmune encephalomyelitis, suggesting a potential avenue for treating autoimmune disease.
Whartenby
Katharine A
KA
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. whartka@jhmi.edu
Calabresi
Peter A
PA
McCadden
Erin
E
Nguyen
Bao
B
Kardian
David
D
Wang
Tianhong
T
Mosse
Claudio
C
Pardoll
Drew M
DM
Small
Donald
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000276:immunology*; D002227:Carbazoles / Q000494:pharmacology; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005663:Furans; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002227:Carbazoles; D004791:Enzyme Inhibitors; D005663:Furans; D007211:Indoles; C119379:lestaurtinib; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3