Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the ben-
IntroductionMore than 25 years have passed since our first, highly speculative review of aplastic anemia; in that fortunately obscure publication, pathophysiology was addressed tentatively and immunosuppressive therapies hardly at all. The article did reflect both the dismal prospects for patients with the severe form of marrow failure and the formidable practical difficulties of experimentation in a rare disorder in which the cells of interest had disappeared. Aplastic anemia was considered heterogenous in origin and virtually impossible to study systematically. At the bedside, the clinical emphasis was the identification of a putative causal factorexposure to benzene or a culpable pharmaceutical-to allow classification in an otherwise doomed patient. As progenitor assays were developed, diverse factors could be held theoretically responsible for failure to form colonies in tissue culture, ranging from quantitative and qualitative defects in stem cells and blocks in differentiation to a lack of stroma support or inadequate cytokine production, or the effects of a chemical poison.In the intervening decades, our understanding of aplastic anemia has cohered around a unified immune mechanism of hematopoietic-cell destruction, which was inferred from but also has informed effective immunosuppressive therapies for the disease (Figure 1). Technical advances in cell biology, flow cytometry, molecular biology, and immunology have provided methods to measure numbers and function of very limited numbers of cells. As a result, we have a more unified and rational view of aplastic anemia's pathophysiology; the disease is understood in its relation to other related marrow failure syndromes; and in many important respects an unusual blood syndrome can model more common autoimmune diseases of other organ systems (Figure 2). Particularly satisfying is that aplastic anemia is now amenable to cure or amelioration in most patients, based both on high-quality clinical trials and mechanistic insights from the experiment...
