Discovery of novel immunostimulants by dendritic-cell-based functional screening.
Immunostimulants represent an emerging class of drugs for the treatment of infectious disorders and cancer. CpG oligonucleotides and imiquimod, prototypic drugs in this category, are now known to activate dendritic cells (DCs). Here we report the development of a highly sensitive, unbiased functional screen to detect DC-stimulatory signals. Because interleukin-1beta (IL-1beta) mRNA expression is closely associated with DC activation, we engineered DCs to stably express a fluorescent marker gene under the control of IL-1beta promoter. By screening about 3000 compounds with the resulting DC biosensor clone, we identified DC-stimulatory potentials of topoisomerase I inhibitors (camptothecin derivatives) and microtubule depolymerizing drugs (colchicine and podophyllotoxin). In response to treatment with each agent, bone marrow-derived DC preparations exhibited characteristic phenotypic and/or functional changes associated with DC activation. All of these agents also triggered nuclear factor-kappaB (NFkappaB) activation in DCs, suggesting a common pharmacologic mechanism of action. Furthermore, locally administered colchicine induced in situ maturation and migration of DCs and augmented both humoral and cellular immune responses. These results support the practical utility of the DC-based biosensor system to discover novel DC-targeted immunostimulants and unveil previously unrecognized (and totally unexpected) pharmacologic activities of several drugs that are commonly used for the treatment of various disorders.
Mizumoto
Norikatsu
N
Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
Gao
Jimin
J
Matsushima
Hironori
H
Ogawa
Yasushi
Y
Tanaka
Hiroaki
H
Takashima
Akira
A
D000276:Adjuvants, Immunologic / Q000032:analysis*; D000818:Animals; D015374:Biosensing Techniques / Q000379:methods*; D002454:Cell Differentiation; D002460:Cell Line; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
D000276:Adjuvants, Immunologic; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I