Decrease of circulating hematopoietic progenitor cells during interleukin-2 treatment is associated with an increase of vascular cell adhesion molecule-1, a critical molecule for progenitor cell adhesion

Administration of interleukin-2 (IL-2) to cancer patients has been shown to transiently decrease the number of circulating hematopoietic progenitor ce lls, but the mechanism of this phenomenon is unknown. Recently, the interac tion of vascular adhesion molecule-1 (VCAM-1) with leukocyte very late anti gen-4 (VLA-4) has been demonstrated to play a crucial role in the adhesion of progenitor cells to bone marrow stromal elements. Cytokine induced upreg ulation of VCAM-1 leads to increased binding of progenitor cells to stromal cells in vitro, and inhibition of this interaction by monoclonal antibodie s is associated with marked progenitor cell mobilisation in vivo. In the pr esent study we serially determined peripheral blood progenitor cell numbers during IL-2 treatment (10 courses) in 6 cancer patients and determined in parallel levels of soluble VCAM-1 as a surrogate marker for the in vivo act ivation of this molecule. Our data indicate that continuous intravenous adm inistration of IL-2 for 5 days leads to a marked decrease of circulating pr ogenitor cells associated with a substantial increase of circulating VCAM-1 . Circulating myeloid progenitor cells (CFU-GM) dropped from a mean value o f 167 +/- 187 / ml pre IL-2 to 16 +/- 15 / ml on day 3 (p < 0.01). Similari ly, mean erythroid progenitors (BFU-E) decreased from 282 +/- 204 / ml befo re IL-2 administration to 86 +/- 61 / ml on day 3 (p < 0.005). In contrast, soluble VCAM-1 rose from a mean value of 1814 +/- 451 ng/ml before to 4607 +/- 736 ng/ml at the end of IL-2 therapy (p < 0.0001). Sera from IL-2 trea ted patients did not inhibit hematopoietic colony formation from normal bon e marrow, These results suggest redistribution and increased adhesion of pr ogenitor cells to stromal and/or endothelial elements during IL-2 via the V CAM-1/VLA-4 interaction as a possible mechanism for the decrease of circula ting progenitor cells during IL-2 therapy.