Dendritic cells (DC) and Langerhans cells (LC) are distinguished by their potent antigen presenting cell (APC) capacity for activating T- cells, particularly in 1/0 immune responses. Application of gene- targeted techniques to investigate the biology of these cells has been hampered by a lack of well-defined DC/LC-specific regulatory gene elements. We have identified a 5'-flanking region (5FR) of the DC/LC- specific dectin-2 gene that can induce mRNA synthesis in a DC/LC- specific manner. The goal of this pilot and feasibility study is to develop a novel mouse model in which dectin-2 5FR-driven gene expression can be conditionally manipulated so as to permit depletion of DC/LC locally or systemically. To define logistics and optimal requirements we will first establish transient DC/LC-targeted systems in vitro and in mouse skin using dectin-2 5FR, the luciferase gene, and the Tet-On system, in which exogenously administered doxycycline can induce gene expression. Subsequently, we will generate transgenic mice bearing DC/LC-targeted luciferase expression also conditioned by doxycycline. Finally, we will develop dectin-2 5FR-driven, doxycycline responsive transgenic mice that carry the Herpes simplex thymidine kinase gene, in which DC/LC can be depleted by treatment with ganciclovir locally or systemically. These DC/LC-targeted conditional gene expression model systems will be valuable tools for amplifying our understanding of DC/LC biology. Establishment of these model systems will open the door to several other genes that can be targeted for DC/LC-specific expression. Ultimately, our depletion studies may prove applicable to the management of patients with histiocytosis X, a potentially fatal disease of unrestrained LC proliferation for which no satisfactory treatment currently exists.
Showing the most recent 10 out of 56 publications
