ANTIBODIES TO VLA4 INTEGRIN MOBILIZE LONG-TERM REPOPULATING CELLS ANDAUGMENT CYTOKINE-INDUCED MOBILIZATION IN PRIMATES AND MICE

Although the use of cytokine-mobilized peripheral blood stem cells has gained a significant momentum in clinical transplantation, the mobili zation schemes practiced are guided by a great deal of empiricism. The mechanism(s) by which cytokines or chemokines, alone or in combinatio n, bring about redistribution of stem/progenitor cells from bone marro w to peripheral blood are poorly understood. Likewise the fate of mobi lized stem/progenitor cells and their biological properties are incomp letely defined. One of the leading hypotheses to explain the mechanism of cytokine-induced mobilization encompasses the view that cytokines disrupt, directly or indirectly, cytoadhesive interactions of stem/pro genitor cells with their bone marrow stroma. Compatible with this view are changes in the expression and/or function of several cytoadhesion molecules, especially integrins, postmobilization, and extensive in v itro experimentation supporting the concept of cytokine[integrin inter actions. To provide a further insight on the cytokine/integrin interpl ay in vivo, we have combined cytokine treatments with anti-integrin tr eatments for mobilization in primates and mice. We found that anti-VLA 4 treatment combined with either granulocyte colony-stimulating factor (G-CSF) treatment or kit ligand treatment leads to significant enhanc ement of mobilization efficiency (fivefold to eight-fold) well above t he levels produced by either cytokine alone or anit-VLA4 treatment alo ne. Similar enhancement was seen when combinations of cytokines, ie, G -CSF plus kit ligand or G-CSF plus Flt3-ligand were used with anti-VLA 4 in primates and mice. Furthermore, when anti-VLA4 was given in 5-Flu orouracil-treated primates, significant numbers of progenitor cells we re circulating for several days during the recovery period only in the anti-VLA4 treated animals. These data suggest that (1) the effect of anti-VLA4 on mobilization, when used alone, is unlikely to be mediated by secondary cytokine elaboration in vivo; (2) three different cytoki nes and their combinations do not appear to influence the in vivo resp onsiveness to anti-VLA4 in coadministration schemes; 13) even if cytok ine treatments on their own exert downmodulation of VLA4 function, the target progenitor cells influenced by anti-VLA4 or by cytokines may n ot necessarily overlap; and (4) augmentation of mobilization in cytoki ne/anti-VLA4 treatments is most likely caused by an amplification of t he pool of target cells on which anti-VLA4 exerts its effects. Because cytokines or anti-VLA4 are each capable of mobilizing long-term repop ulating cells and because we show with the present studies that anti-V LA4 in an autologous bone marrow cell transplantation setting does not cause any delay ih engraftment, the combination of cytokine/anti-inte grin treatment enhancing mobilization may have a clinical use. (C) 199 7 by The American Society of Hematology.