In the search for an alternative and/or supplementary treatment for AA and BM failure, we turned our attention to rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) pathway that has been used in a variety of animal models of human diseases, such as murine experimental allergic encephalomyelitis, nephritis, lupus erythematosus, and inflammatory bowel disease. These models have been used to test the plausibility of immune mechanisms suggested by the study of patients and patient cells. 5, 6 Like human AA, treatment of murine BM failure in these models with CsA and other immunosuppressive agents ameliorates disease. Human AA has been modeled in mice by adaptation of historic “runt disease” in which infusion of lymph node (LN) cells into recipients mismatched at MHC or minor histocompatibility (minor-H) antigen loci produced BM failure with severe pancytopenia and marrow hypoplasia that mimics human AA. In the clinic, therapeutic strategies to achieve tolerance are highly desirable in order to avoid complications of recurrent pancytopenia that may require re-initiation of transfusions, hospitalizations for neutropenic fever, and control of chronic toxicity due to repeated interventions. 4 However, oligoclones are often not eliminated, and relapse is likely due to their reactivation and renewed destruction of HSPCs and precursors. 3 ATG and CsA appear to partially eliminate and functionally suppress activation of expanded CD8 + effector T-cell clones. 2 The overall and complete response rates to immunosuppressive therapy have increased to almost 100% with the addition of the thrombopoietin mimetic eltrombopag, but relapse on discontinuation of CsA may be especially problematic in these patients. However, patients who have responded to IST often relapse after CsA withdrawal or are dependent on continued CsA administration in order to maintain blood counts. 1 Standard immunosuppressive therapy (IST) with horse anti-thymocyte globulin (ATG) and cyclosporine A (CsA) is effective in 60–70% of AA patients, resulting in hematologic recovery. In most patients, this is due to immune attack of hematopoietic stem and progenitor cells (HSPCs) by auto-reactive T cells. Its specific expansion of regulatory T cells and elimination of clonogenic CD8 + effectors support its potential clinical utility in the treatment of aplastic anemia.Īplastic anemia (AA) is a disease of bone marrow (BM) failure characterized by pancytopenia and marrow hypocellularity. In summary, rapamycin was an effective therapy in mouse models of immune-mediated bone marrow failure, acting through different mechanisms to cyclosporine. Cyclosporine increased cytoplasmic nuclear factor of activated T-cells-1 following T-cell receptor stimulation, whereas rapamycin suppressed phosphorylation of two key signaling molecules in the mammalian target of rapamycin pathway, S6 kinase and protein kinase B. Rapamycin, but not cyclosporine, reduced the proportion of memory and effector T cells and maintained a pool of naïve T cells. Rapamycin effectively reduced Th1 inflammatory cytokines interferon-γ and tumor necrosis factor-α, increased the Th2 cytokine interleukin-10, stimulated expansion of functional regulatory T cells, eliminated effector CD8 + T cells (notably T cells specific to target cells bearing minor histocompatibility antigen H60), and preserved hematopoietic stem and progenitor cells. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. In this study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Most aplastic anemia patients respond to immunosuppressive therapy, usually with anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term administration of cyclosporine to maintain blood counts. Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia.
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