title: Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).
abstract: 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.
authors.affiliation: Divisions of Oncology and Hematology, Children's Hospital of Philadelphia, ARC 902, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA. teacheyd@email.chop.edu
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.forename: Dana A
authors.initials: DA
authors.lastname: Obzut
authors.forename: Kelly
authors.initials: K
authors.lastname: Axsom
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Goldsmith
authors.forename: Junior
authors.initials: J
authors.lastname: Hall
authors.forename: Jessica
authors.initials: J
authors.lastname: Hulitt
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Manno
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rhodin
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
authors.forename: Valerie I
authors.initials: VI
authors.lastname: Brown
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology; D058570:TOR Serine-Threonine Kinases
chemical_list: D000974:Antibodies, Antinuclear; D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid; D020123:Sirolimus