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,§,§
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*
Thomas E. Starzl Transplantation Institute and Departments of Surgery,
Molecular Genetics and Biochemistry, and
Pathology, and
§
University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213
The generation and activity of NK cells appear to be regulated by a
particular set of cytokines. We examined the in vivo effects of
recombinant human Flt3 ligand (Flt3-L), a recently cloned potent
hemopoietic cytokine, on NK cell development in mice. Daily i.p.
administration of Flt3-L consistently induced striking increases in
both the absolute number and the total cytotoxic activity of mature
nonactivated NK cells within various tissues. Dose- and time-dependent
increases were observed in the bone marrow (
2- and 11-fold,
respectively), thymus (2.8- and 2.0-fold), blood (11- and
15-fold), spleen (10- and 9-fold), and liver (15- and
39-fold). In addition, IL-2 induced a rapid increase in NK activity,
NK cell proliferative responses, generation of lymphokine-activated
killer activity, and development of activated adherent NK cells,
which were all significantly increased by Flt3-L treatment.
Thus, in addition to its recently reported capacity to stimulate
dendritic cell production, Flt3-L has a prominent 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 results also indicate that either
alone or in combination with a potent activator of NK cells, such as
IL-2, Flt3-L could be used to markedly augment the number and activity
of NK cells, especially in the liver. Flt3-L appears to have
considerable potential for therapy of both cancer and viral
infection.
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