INCREASED EXPRESSION OF FAS ANTIGEN ON BONE-MARROW CD34(+) CELLS OF PATIENTS WITH APLASTIC-ANEMIA

Fas antigen, a receptor molecule that mediates signals for programmed cell death, is involved in T-cell-mediated killing of malignant, virus-infected or allogeneic target cells, Interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), potent inhibitors of haemopoiesis, enhance Fas receptor expression on bone marrow (BM) CD34(+) cells, and both cytokines render haemopoietic progenitor cells susceptible to Fas-mediated inhibition of colony formation due to the induction of apoptosis, Haemopoietic suppression in aplastic anaemia (AA) has been associated with aberrant IFN-gamma, increased TNF-beta expression, and elevated numbers of activated cytotoxic T-cells in marrow, We have now examined Fas antigen expression in fresh AA BM samples, In normal individuals few CD34(+) cells expressed Fas antigen and normal marrow cells had low sensitivity to Pas-mediated inhibition of colony formation. In contrast, in early AA, BM CD34(+) cells showed markedly increased percentages of Pas receptor-expressing CD34(+) cells, which correlated with increased sensitivity of AA marrow cells to anti-Fas antibody-mediated inhibition of colony formation. The proportion of Fas antigen-bearing cells was lower in recovered patients' BM. Fas antigen was also detected in the marrow of some patients with myelodysplasia, especially the hypocellular variant, These results are consistent with the hypothesis that AA CD34(+) cells, probably including haemopoietic progenitor cells, express high levels of Fas receptor due to in vivo exposure to IFN-gamma and/or TNF-alpha and are suitable targets for T-cell-mediated killing. Our results suggest that the Pas receptor/Fas ligand system are involved in the pathophysiology of BM failure.