Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes is essential in causing bone marrow failure in patients with aplastic anemia

Aplastic anemia (AA) is regarded as an immunological disorder because of the clinical effect of immunosuppressive therapy. Recent studies have reported that cytokines play an important role in the development of AA. In the present study, we measured levels of T-cell derived intracellular cytokine production in peripheral blood and bone marrow (BM) of patients with AA. We demonstrated that BM lymphocytes, particularly CD4(+) and CD8(+) T cells, in patients with AA produced significantly higher amounts of tumor necrosis factor-alpha (TNF-alpha), compared with lymphocytes in normal controls. We have previously reported that expression of TNF receptor (R)1 and TNFR2 in the CD34(+) CD38(-) and CD34(+) CD38(+) fractions of patients with AA is significantly higher than those in normal control. These results indicate that BM stem cells in patients with AA may possess high sensitivity to TNF-alpha. This in turn suggests that TNF-alpha affects hematopoiesis at an earlier stage in AA patients than in normal controls. We strongly support the hypothesis that a simultaneous increase in TNF-alpha production by BM lymphocytes and sensitivity of stem cells to TNF-alpha leads to BM failure in AA.