EXPANSION OF FUNCTIONAL NK CELLS IN MULTIPLE TISSUE COMPARTMENTS OF MICE TREATED WITH FLT3-LIGAND - IMPLICATIONS FOR ANTICANCER AND ANTIVIRAL THERAPY

The generation and activity of NK cells appear to be regulated by a pa rticular set of cytokines, We examined the in vivo effects of recombin ant human Flt3 ligand (Flt3-L), a recently cloned potent hemopoietic c ytokine, on NK cell development in mice, Daily i,p. administration of Flt3-L consistently induced striking increases in both the absolute nu mber and the total cytotoxic activity of mature nonactivated MZ cells within various tissues. Dose- and time-dependent increases were observ ed in the bone marrow (similar to 2- and similar to 11-fold, respectiv ely), thymus (similar to 2.8- and similar to 2.0-fold), blood (similar to 11- and similar to 15-fold), spleen (similar to 10- and similar to 9-fold), and liver (similar to 15- and similar to 39-fold). In additi on, IL-2 induced a rapid increase in Mt activity, NK cell proliferativ e responses, generation of lymphokine-activated killer activity, and d evelopment-of activated adherent NK cells, which were all significantl y increased by Flt3-L treatment. Thus, in addition to its recently rep orted capacity to stimulate dendritic cell production, Flt3-L has a pr ominent biologic role in NK cell generation in vivo. This is probably a result of selectively induced expansion of NK cell progenitors (pro- NK cells), because Flt3-L stimulates in vitro proliferation of pro-NK cells without affecting the cytotoxicity of mature NK cells. The resul ts also indicate that either alone or in combination with a potent act ivator of NK cells, such as IL-2, FIt3-L could be used to markedly aug ment the number and activity of NK cells, especially in the liver. Flt 3-L appears to have considerable potential for therapy of both cancer and viral infection.