sirolimus and Pancytopenia

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder of lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. It is characterized by non-infectious and non-malignant chronic lymphoproliferation and an increased risk of lymphoid malignancy. The diagnosis of this condition usually combines chronic lymphadenopathy and/or splenomegaly exceeding 6 months, autoimmune cytopenias, with an elevated level of CD3+CD4-CD8- Tαβ lymphocytes, known as "double-negative" T cells. Differential diagnosis includes infections, autoimmune diseases or malignancies. Although clinical examination and laboratory tests are highly suggestive, this disease goes widely unrecognized. We here report, for the first time, the case of ALPS, a Moroccan patient, and aged 8 years, with recurrent fever, splenomegaly and adenopathies. Paraclinical examinations revealed chronic pancytopenia, higher than normal TαÎ

Topics: Autoimmune Diseases; Autoimmune Lymphoproliferative Syndrome; Humans; Immunosuppressive Agents; Pancytopenia; Sirolimus; Splenomegaly

Topics: Adaptor Proteins, Signal Transducing; Autoimmune Diseases; Disease Management; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Male; Mutation; Pancytopenia; Sirolimus

Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. 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. In this study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. 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

Topics: Anemia, Aplastic; Animals; Bone Marrow; Bone Marrow Diseases; Bone Marrow Failure Disorders; Disease Models, Animal; Epitopes, T-Lymphocyte; Hemoglobinuria, Paroxysmal; Immunologic Memory; Immunosuppressive Agents; Mice; Pancytopenia; Signal Transduction; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Treatment Outcome

Topics: Anemia, Aplastic; Animals; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Disease Models, Animal; Mice; Mice, Inbred C57BL; Pancytopenia; Sirolimus

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis. Children present with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias. Recent advances show efficacy of treatment with immunosuppressive drugs. Sirolimus, an mammalian target of rapamycin inhibitor, improves autoimmune cytopenias and lymphoproliferation, with a safe profile. We present 2 patients, a 5-year-old girl and 15-year-old boy, diagnosed with ALPS with initial partial response to steroid treatment. Autoimmune cytopenias and lymphoproliferation then became refractory to treatment, with recurrence of symptoms. In both cases, treatment with sirolimus was started, with a rapid response, complete remission of cytopenias, and resolution of lymphoproliferation, with no significant adverse effects.. sirolimus is an effective and safe drug for controlling children with cytopenias and lymphoproliferation linked to ALPS.

Topics: Adolescent; Autoimmune Lymphoproliferative Syndrome; Child, Preschool; Female; Humans; Lymphoproliferative Disorders; Male; Pancytopenia; Sirolimus; Treatment Outcome

Little is known about metabolic regulation in stem cells and how this modulates tissue regeneration or tumour suppression. We studied the Lkb1 tumour suppressor and its substrate AMP-activated protein kinase (AMPK), kinases that coordinate metabolism with cell growth. Deletion of the Lkb1 (also called Stk11) gene in mice caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion and pancytopenia. HSCs depended more acutely on Lkb1 for cell-cycle regulation and survival than many other haematopoietic cells. HSC depletion did not depend on mTOR activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP levels. HSCs deficient for two catalytic α-subunits of AMPK (AMPK-deficient HSCs) showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell-cycle regulation between HSCs and some other haematopoietic progenitors.

Topics: AMP-Activated Protein Kinases; Aneuploidy; Animals; Catalytic Domain; Cell Cycle; Cell Death; Cell Division; Cell Survival; Centrosome; Energy Metabolism; Enzyme Activation; Female; Gene Deletion; Hematopoietic Stem Cells; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mitochondria; Multiprotein Complexes; Pancytopenia; Protein Serine-Threonine Kinases; Proteins; Regeneration; Signal Transduction; Sirolimus; Spindle Apparatus; TOR Serine-Threonine Kinases

The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft.

Topics: Adolescent; Autoimmune Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Organ Transplantation; Pancytopenia; Sirolimus; Tacrolimus