Chronic overexpression of membrane-bound flt3 ligand by T lymphocytes in severe aplastic anaemia

Aplastic anaemia (AA) is an immune-mediated bone marrow failure associated with high serum levels of flt3 ligand (FL). We examined expression of the m embrane-bound isoform of FL in peripheral blood and bone marrow cells from AA patients at diagnosis (n = 16) and after immunosuppressive (IS) treatmen t (n = 36). Flow cytometry demonstrated strongly increased FL levels on the cell surface of T lymphocytes in AA relative to normal controls (P < 0.000 1). T-cell-specific expression of membrane-bound FL was confirmed by confoc al microscopy. FL mRNA and total cellular FL protein levels were increased about threefold. Overexpression of FL in AA was observed for up to 20 years after IS treatment. FL levels correlated inversely with CD34(+) cell numbe rs and the colony-forming ability of AA bone marrow (R = -0.68 and -0.85 re spectively). Histological examination of spleen specimens and bone marrow b iopsies gave no evidence of degeneration or fibrosis due to prolonged expos ure to high FL. Levels of membrane-bound FL were not increased in autoimmun e diseases (n = 23), including rheumatoid arthritis and lupus erythematosus , nor in graft-versus-host disease (n = 8). Chronic overexpression of FL on the surface of T lymphocytes in AA, but not in other T-cell-mediated disor ders, suggests that membrane-bound FL plays a role in cell-cell interaction s in bone marrow failure and may be important for long-term haemopoietic re covery.