The effectiveness of immunosuppressive therapy implies that in many patients with acquired aplastic anemia, bone marrow failure results from an immunologically mediated, tissue-specific, organ-destructive mechanism. The fact that 50% of identical twins with severe aplastic anemia will not engraft with no conditioning after the infusion of syngeneic stem cells supports this notion in at least half the cases. A reasonable theory suggests that exposure to an inciting antigen, cells, and cytokines of the immune system destroys stem cells in the marrow, resulting in pancytopenia. Treatment with immunosuppressive modalities leads to marrow recovery.
Clinical and laboratory studies have suggested that interferon y (IFN-y) plays a central role in the pathophysiology of aplastic anemia. In vitro studies show that the T cells from aplastic anemia patients secrete IFN-y and tumor necrosis factor (TNF). Long-term bone marrow cultures (LTBMCs) have shown that IFN-y and TNF are potent inhibitors of both early and late hematopoietic progenitor cells. Both of these cytokines suppress hematopoiesis by their effects on the mitotic cycle and, more importantly, by the mechanism of cell killing. The mechanism of cell killing involves the pathway of apoptosis (i.e., IFN-y and TNF unregulate each other's cellular receptors, as well as the Fas receptors in hematopoietic stem cells). Cytotoxic T cells also secrete interleukin-2 (IL-2), which causes polyclonal expansion of the T cells. Activation of the Fas receptor on the hematopoietic stem cell by the Fas ligand present on the lymphocytes leads to apoptosis of the targeted hematopoietic progenitor cells. Additionally, IFN-y mediates its hematopoietic suppressive activity through interferon regulatory factor 1 (IRF-1), which inhibits the transcription of cellular genes and their entry into the cell cycle. IFN-y also induces the production of the toxic gas nitric oxide, diffusion of which causes additional toxic effects on the hematopoietic progenitor cells. Direct cell-cell interactions between effective lymphocytes and targeted hematopoietic cells probably also occur.
In vivo observation in aplastic anemia patients supports the following in vitro findings:
1. IFN-y messenger RNA, which is undetectable in normal marrow, is detectable in most patients with aplastic anemia.
2. Hematopoietic cells of patients with aplastic anemia express Fas receptors and, as a result, their marrow contains an increased number of apoptotic cells.
3. An increased number of activated cytotoxic lymphocytes are present in the blood and bone marrow of these patients.
4. Successful treatment with antithymocyte globulin and cyclosporine results in a decrease in the number of these cytotoxic cells.
5. The importance of immunosuppressive therapy was recognized when (a) an unexpected improvement in pancytopenia was observed in aplastic anemia patients following failure of engraftment in allogeneic bone marrow transplantation and (b) the need for immunosuppressive preparative therapy was realized for successful engraftment in about half of hematopoietic stem cells in identical twin bone marrow transplantation performed for aplastic anemia.
Table 6-16 shows an etiologic classification of aplastic anemia, and Table 6-17 lists the various causes of acquired aplastic anemia.
Table 6-16. An Etiologic Classification of Aplastic Anemia
Direct toxicity Radiation" Chemotherapy Benzene"
Intermediate metabolites of some common drugs Immune-mediated causes Iatrogenic causesa
Transfusion-associated graft versus host diseasea Eosinophilic fasciitis" Hepatitis-associated disease" Pregnancy
Intermediate metabolites of some common drugs Idiopathic aplastic anemia
"Indicates relatively well-established mechanism.
From Young NS, Macijewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med 1997;336:1365-72, with permission.
Table 6-17. Causes of Acquired Aplastic Anemia"
I. Idiopathic (70% or more of cases)
1. Predictable, dose dependent, rapidly reversible (affects rapidly dividing maturing hematopoietic cells rather than pluripotent stem cells)
a. 6-Mercaptopurine b. Methotrexate c. Cyclophosphamide d. Busulfan e. Chloramphenicol
2. Unpredictable, normal doses (defect or damage to pluripotent stem cells)
a. Antibiotics: chloramphenicol, sulfonamides b. Anticonvulsants: mephenytoin (Mesantoin), hydantoin c. Antirheumatics: phenylbutazone, gold d. Antidiabetics: tolbutamide, chlorpropamide e. Antimalarial: quinacrine
B. Chemicals: insecticides (e.g., DDT, Parathion, Chlordane)
C. Toxins (e.g., benzene, carbon tetrachloride, glue, toluene)
1. Viral hepatitis (hepatitis A, B, and C and non-A, non-B, non-C, and non-G hepatitis)
2. HIV infection (AIDS)
3. Infectious mononucleosis (Epstein-Barr virus)
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