Bone marrow failure syndromes (BFS) including aplastic anemia (AA), myelodysplastic syndromes (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) are considered to harbor immune-mediated marrow injury. Indeed, immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine ameliorates the hematopoiesis in BFS patients, despite its limit: infrequent relapse of marrow failure after IST, resistance of some patients to IST, and untoward effects like infection. To overcome the difficulties, molecular targeted therapy is alternative. However, neither incitement of marrow injury nor target molecules on marrow cells recognized by cytotoxic lymphocytes has been identified. We have currently suggested that NKG2D ligands such as ULBP and MICA/B serve as triggers for immune-mediated marrow injury in PNH (

). ULBP and MICA/B are stress-inducible membrane proteins that appear in infection and transformation. The ligands share NKG2D receptor on lymphocytes such as NK, CD8+ T, and γδ T cells and promote activation of the lymphocytes. Cells expressing the ligands are then deadly injured by NKG2D+ cells (Groh, PNAS USA 1996; Cosman, Immunity 2001). In this background, we attempted to confirm the clinical significance of the expression of NKG2D ligands in BFS. The ligands were detected by flow cytometry on the granulocytes and marrow cells in 47 (53%) of 89 patients with BFS: 28 (56%) of 50 patients with AA; 11 (65%) of 17 patients with PNH; 8 (36%) of 22 patients with MDS; and none of 17 healthy individuals. The membrane expression of the ligands was supported by their increase in plasma. It is then conceivable that blood cells were exposed to a certain stress to induce NKG2D ligands in the patients, leading to NKG2D-mediated marrow injury. There was a close association of the expression of NKG2D ligands with both progression of marrow failure and favorable response to IST. Thus, we propose that the NKG2D ligands not only are feasible predictors for both immune-mediated marrow injury and IST effects, but also serve for potential targeted therapy in BFS.

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