title: Inhibition of the mTORC pathway in the antiphospholipid syndrome.
abstract: BACKGROUND
  Although thrombosis is considered the cardinal feature of the antiphospholipid syndrome, chronic vascular lesions are common, particularly in patients with life-threatening complications. In patients who require transplantation, vascular lesions often recur. The molecular pathways involved in the vasculopathy of the antiphospholipid syndrome are unknown, and adequate therapies are lacking.
  
  
  METHODS
  We used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. We also evaluated autopsy specimens from persons who had catastrophic antiphospholipid syndrome. The molecular pathways through which antiphospholipid antibodies modulate the mTORC pathway were evaluated in vitro, and potential pharmacologic inhibitors were also tested in vitro. Finally, we studied the effect of sirolimus in kidney-transplant recipients with the antiphospholipid syndrome.
  
  
  RESULTS
  The vascular endothelium of proliferating intrarenal vessels from patients with antiphospholipid syndrome nephropathy showed indications of activation of the mTORC pathway. In cultured vascular endothelial cells, IgG antibodies from patients with the antiphospholipid syndrome stimulated mTORC through the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Patients with antiphospholipid syndrome nephropathy who required transplantation and were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy as compared with patients with antiphospholipid antibodies who were not receiving sirolimus. Among 10 patients treated with sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation versus 3 of 27 untreated patients (11%). Activation of mTORC was also found in the vessels of autopsy specimens from patients with catastrophic antiphospholipid syndrome.
  
  
  CONCLUSIONS
  Our results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome. (Funded by INSERM and others.).
authors: From INSERM Unité 1151, Institut Necker-Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité (G.C., F.B., F.T., G.F., L.H.-M., C.L., F.T.), Service de Néphrologie Transplantation Adultes (G.C., R.S., C.L.), Service de Physiologie-Explorations Fonctionnelles (F.B., G.F.), Service d'Anatomie et Cytologie Pathologiques (L.-H.N.), Hôpital Necker-Enfants Malades, Service d'Immunologie Biologique (M.-A.D.-D.), Hôpital Européen Georges Pompidou, and Laboratoire de Neuropathologie, Hôpital Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris (G.B., D.S.) - all in Paris.
authors: Guillaume
authors: G
authors: Canaud
authors: Frank
authors: F
authors: Bienaimé
authors: Fanny
authors: F
authors: Tabarin
authors: Guillaume
authors: G
authors: Bataillon
authors: Danielle
authors: D
authors: Seilhean
authors: Laure-Hélène
authors: LH
authors: Noël
authors: Marie-Agnès
authors: MA
authors: Dragon-Durey
authors: Renaud
authors: R
authors: Snanoudj
authors: Gérard
authors: G
authors: Friedlander
authors: Lise
authors: L
authors: Halbwachs-Mecarelli
authors: Christophe
authors: C
authors: Legendre
authors: Fabiola
authors: F
authors: Terzi
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D017152:Antibodies, Antiphospholipid / Q000378:metabolism*; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D001344:Autopsy; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008875:Middle Aged; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017152:Antibodies, Antiphospholipid; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus