Expansion of functional NK cells in multiple tissue compartments of mice treated with Flt3-ligand: implications for anti-cancer and anti-viral therapy.
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 (approximately 2- and approximately 11-fold, respectively), thymus (approximately 2.8- and approximately 2.0-fold), blood (approximately 11- and approximately 15-fold), spleen (approximately 10- and approximately 9-fold), and liver (approximately 15- and approximately 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.
Shaw
S G
SG
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, PA 15213, USA.
Maung
A A
AA
Steptoe
R J
RJ
Thomson
A W
AW
Vujanovic
N L
NL
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology; D004306:Dose-Response Relationship, Immunologic; D006410:Hematopoiesis / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count / Q000187:drug effects; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000276:immunology; D010455:Peptides / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007376:Interleukin-2; D008024:Ligands; D008565:Membrane Proteins; D010455:Peptides; C084881:flt3 ligand protein; C041640:poly(lysyl-(leucyl-poly-alanine))