Immune mechanism of aplastic anemia

Immune-mediated suppression of hematopoiesis has been considered the most important mechanism in the development of idiopathic aplastic anemia (AA), mainly based on high rates of response to immunosuppressive therapy in patients with AA. However, the lack of an experimental animal model and the heterogeneity of the disease has hindered elucidation of immune mechanisms underlying AA. Recent studies on a subset of AA patients characterized by repetitive response to cyclosporine (CyA) therapy revealed a strong association of HLA-DRB1*1501 with susceptibility to such immune-mediated AA. Other studies of the T-cell clonotype in the bone marrow (BM) of the patients using the polymerase chain reaction (PCR)-single strand conformation polymorphism analysis and sequencing of T-cell receptor V beta cDNA showed dominant proliferation of a limited number of T-cells, indicating the presence of certain antigenic stimuli in the BM. More recently, we isolated a CD4+ T-cell clone that proliferated most dominantly among V beta 21+ T-cells in the BM of a CyA-dependent AA patient and was capable of killing autologous hematopoietic cells. Lysis of allogeneic hematopoietic cells by this T-cell clone required the presence of HLA-DR4 on the target cells. Further studies on such T-cell clones will help identify key molecules on hematopoietic cells that induce the development of AA.