CHRONIC EXPRESSION OF MURINE FLT3 LIGAND IN MICE RESULTS IN INCREASEDCIRCULATING WHITE BLOOD-CELL LEVELS AND ABNORMAL CELLULAR INFILTRATESASSOCIATED WITH SPLENIC FIBROSIS

The effect of chronic expression of flt3 ligand (FL) on in vivo hemato poiesis was studied. Retroviral vector-mediated gene transfer was used in a mouse model of bone marrow transplantation to enforce expression of mouse FL cDNA in hematopoietic tissues, As early as 2 weeks posttr ansplantation, peripheral blood white blood cell counts in FL-overexpr essing recipients were significantly elevated compared with controls. With the exception of eosinophils, all nucleated cell lineages studied were similarly affected in these animals. Experimental animals also e xhibited severe anemia and progressive loss of marrow-derived erythrop oiesis. All of the FL-overexpressing animals, but none of the controls , died between 10 and 13 weeks posttransplantation. Upon histological examination, severe splenomegaly was noted, with progressive fibrosis and infiltration by abnormal lymphoreticular cells. Abnormal cell infi ltration also occurred in other organ systems, including bone marrow a nd liver. In situ immunocytochemistry on liver sections showed that th e cellular infiltrate was CD3(+)/NLDC145(+)/CD11c(+), but B220(-) and F4/80(-), suggestive of a mixed infiltrate of dendritic cells and acti vated T lymphocytes, Infiltration of splenic blood vessel perivascular spaces resulted in vascular compression and eventual occlusion, leadi ng to splenic necrosis consistent with infarction. These results show that FL can affect both myeloid and lymphoid cell lineages in vivo and further demonstrate the potential toxicity of in vivo treatment with FL. (C) 1997 by The American Society of Hematology.