TY - JOUR
T1 - Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease
AU - Whartenby, Katharine A.
AU - Calabresi, Peter A.
AU - McCadden, Erin
AU - Nguyen, Bao
AU - Kardian, David
AU - Wang, Tianhong
AU - Mosse, Claudio
AU - Pardoll, Drew M.
AU - Small, Donald
PY - 2005/11/15
Y1 - 2005/11/15
N2 - 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.
AB - 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.
KW - Autoimmune disease
KW - FLT3 ligand
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UR - http://www.scopus.com/inward/citedby.url?scp=28044445893&partnerID=8YFLogxK
U2 - 10.1073/pnas.0506088102
DO - 10.1073/pnas.0506088102
M3 - Article
C2 - 16272221
AN - SCOPUS:28044445893
SN - 0027-8424
VL - 102
SP - 16741
EP - 16746
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -