title: Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations.
abstract: Autoimmune lymphoproliferative syndrome (ALPS) is a paediatric disease characterized by lymphoproliferation and autoimmunity. Most patients are known to carry heterozygous mutations of the TNFRSF6 gene leading to diminished Fas-mediated apoptosis and failure of activated lymphocytes to undergo apoptosis. A subgroup of patients without the TNFRSF6 gene mutation has similar defective apoptosis and clinical features. No effective treatment has been reported so far. Glucocorticoids, intravenous immunoglobulin and/or immunosuppressive drugs have usually led to only transient clinical improvement. Seven ALPS patients (two type Ia and five type III) were treated with the antimalarial drug Fansidar. No toxicity was observed. An objective response was seen in six of them and, in two, the treatment was stopped without reappearance of the symptoms. Moreover, a marked decrease in interleukin-10 levels was observed in two patients during the treatment. We found that the drug induced apoptosis in activated lymphocytes through activation of the mitochondrial apoptotic pathway.
authors.affiliation: Department of Physiology, Children's Hospital, Dutch-speaking Free University of Brussels, Brussels, Belgium. jutte.vanderwerff@chello.be
authors.forename: Jutte
authors.initials: J
authors.lastname: van der Werff Ten Bosch
authors.forename: Peter
authors.initials: P
authors.lastname: Schotte
authors.forename: Alice
authors.initials: A
authors.lastname: Ferster
authors.forename: Nadira
authors.initials: N
authors.lastname: Azzi
authors.forename: Thomas
authors.initials: T
authors.lastname: Boehler
authors.forename: Geneviève
authors.initials: G
authors.lastname: Laurey
authors.forename: Mikko
authors.initials: M
authors.lastname: Arola
authors.forename: Christian
authors.initials: C
authors.lastname: Demanet
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Jacques
authors.initials: J
authors.lastname: Otten
mesh_terms: D000293:Adolescent; D000962:Antimalarials / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000188:drug therapy*; D016022:Case-Control Studies; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D015331:Cohort Studies; D003574:Cytochrome c Group / Q000378:metabolism; D004252:DNA Mutational Analysis; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000188:drug therapy*; D008297:Male; D011739:Pyrimethamine / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013413:Sulfadoxine / Q000627:therapeutic use; D013577:Syndrome
chemical_list: D000962:Antimalarials; D003574:Cytochrome c Group; D004338:Drug Combinations; D018124:Receptors, Tumor Necrosis Factor; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D011739:Pyrimethamine