ANTI-LFA-1 BLOCKING ANTIBODIES PREVENT MOBILIZATION OF HEMATOPOIETIC PROGENITOR CELLS INDUCED BY INTERLEUKIN-8

Previously, we have shown that interleukin (IL)-8 induces the rapid (1 5 to 30 minutes) mobilization of hematopoietic progenitor cells (HPC) in mice, Because integrins are essential for adhesion and transendothe lial migration of HPC, we studied the involvement of the beta(2)-integ rin leukocyte function-associated antigen-1 (LFA-1) in IL-8-induced mo bilization. After a single injection df blocking anti-LFA-1 antibodies , no mobilization of colony-forming cells was observed. In addition, w hen mice were pretreated with anti-LFA-1 or saline and subsequently in jected with 30 mu g of IL-8, mobilization of HPC was completely blocke d. We showed that this was not due to anti-LFA-1 antibodies affecting colony formation, as addition of anti-LFA-1 antibodies to colony cultu res in semisolid medium had no inhibitory activity. Also, anti-interce llular adhesion molecule (ICAM)-1 antibodies, directed to the main lig and of LFA-1 significantly inhibited the IL-8-induced mobilization. Fu rthermore, IL-1-induced mobilization was significantly inhibited by an ti-LFA-1 antibodies. Because LFA-1 is reported to be expressed on more differentiated HPC, it was considered that the IL-8-induced mobilizat ion of more primitive HPC would not be blocked by anti-LFA-1 antibodie s. Transplantation of blood-derived mononuclear cells (MNC) from IL-8- mobilized animals pretreated with anti-LFA-1 antibodies protected only 25% of lethally irradiated recipient mice, whereas the radioprotectio n rate of control mice transplanted with MNC derived from IL-8-mobiliz ed animals was 86% (P < .01). Anti-LFA-1 antibodies did not interfere with stem cell homing, as transplantation of IL-8-mobilized blood MNC, incubated in vitro with these antibodies resulted in 100% radioprotec tion. We conclude that anti-LFA-1 antibodies completely prevent the ra pid mobilization of colony-forming cells and of cells with radioprotec tive capacity induced by IL-8. These results indicate a major role for the beta(2)-integrin LFA-1 in the IL-8-induced mobilization of hemato poietic stem cells. (C) 1998 by The American Society of Hematology.