It has been shown that in vivo and in vitrotreatment with G-CSF induces the generationof low-density granulocytes (LDGs),which copurify with PBMCs and inhibitIFN- production by humanT cells. Theseresults prompted us to postulate an immunomodulatoryrole for LDGs in acute graftversus-host disease (aGVHD). Here it isshown that in the mouse experimentalmodel, in vivo and in vitroG-CSF treatmentgenerates LDGs capable of inhibiting80% of T-cell IFN- production. Toassess the role of these LDGs in aGVHD,lethally irradiated (C57BL/6 BALB/c) F1hosts were reconstituted with T celldepleted bone marrow cells plus nylonwoolpurified spleencells from G-CSFtreated (G-NWS) or nontreated (NWS)C57BL/6 donors. Recipients of G-NWShad a 75% survival rate in contrast to arate of 25% in the NWS recipients. Theprotective effect was completely abolished,and the mortality rate was 100% ifdonor-cell infusion was treated with anti-Gr1. Moreover, if LDGs were infused withNWS, full protection of aGVHD was observed,and no signs of disease wereevidenced by mortality rate, weight loss,or histopathology of target organs. Theseresults revealed the unexpected immunosuppressivecapacity of G-CSF based onthe generation of LDGs, leading to thepossibility of using these cells as inhibitorsof aGVHD.