Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.
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PMID:Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). 1675 90

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.
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PMID:Use of Sirolimus (Rapamycin) for Treatment of Cytopenias and Lymphoproliferation Linked to Autoimmune Lymphoproliferative Syndrome (ALPS). Two Case Reports. 2823 35