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IL-17 Stimulates Granulopoiesis in Mice: Use of an Alternate, Novel Gene Therapy-Derived Method for In Vivo Evaluation of Cytokines¹

Paul Schwarzenberger^2,*,, Vincent La Russa^||, Allan Miller^||, Peng Ye^*,, Weitao Huang^*,, Arthur Zieske^§, Steve Nelson^*,, Gregory J. Bagby^¶, David Stoltz^*,¶, Randall L. Mynatt^#, Melanie Spriggs^** and Jay K. Kolls^*,,

^* Gene Therapy Program, Department of Medicine, Department of Pediatrics, ^§ Department of Pathology, and ^¶ Department of Physiology, Louisiana State University Medical Center, New Orleans, LA 70112; ^|| Bone Marrow Transplant Program, Tulane University, New Orleans, LA; ^# Pennington Research Center, Baton Rouge, LA; and ^** Immunex Corporation, Seattle, WA 98101

IL-17 is a novel cytokine secreted principally by CD4⁺ T cells. It has been shown to support the growth of hemopoietic progenitors in vitro; however, its in vivo effects are presently unknown. Adenovirus-mediated gene transfer of the murine IL-17 cDNA targeted to the liver (5 x 10⁹ plaque-forming units (PFU) intravenous) resulted in a transiently transgenic phenotype, with dramatic effects on in vivo granulopoiesis. Initially, there was a significant increase (fivefold) in the peripheral white blood count (WBC), including a 10-fold rise in the absolute neutrophil count. This was associated with a doubling in the spleen size over 7–14 days after gene transfer, which returned to near baseline by day 21, although the white blood cell count remained elevated. There was a profound stimulation of splenic hemopoiesis as demonstrated by an increase in total cellularity by 50% 7 days after gene transfer and an increase in hemopoietic colony formation. A maximal increase in frequency of high proliferative potential colonies (HPPC) (11-fold) and CFU-granulocyte-macrophage (GM) and CFU-granulocyte-erythrocyte-megakaryocyte-monocyte (GEMM) (CFU) (6-fold) was seen on day 3 after IL-17 gene transfer. Both CFU and HPPC remained significantly elevated in the spleen throughout day 21, but at reduced levels compared with day 3. Bone marrow CFU and HPPC were elevated on day 3 only by 75% and 25%, respectively, without changes in total cellularity. Thus, murine IL-17 is a cytokine that can stimulate granulopoiesis in vivo. Since IL-17 is principally produced by CD4⁺ T cells, this cytokine could have therapeutic implications in AIDS-related bone marrow failure and opportunistic infections.