title: Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis.
abstract: BACKGROUND
  Patients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy.
  
  
  METHODS
  We investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1-phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis.
  
  
  RESULTS
  No adverse events reached a level higher than grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed a reduction in cryoglobulinemia in 9 of 10 patients and improvement of vasculitis in 8 of 10. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25(high), forkhead box P3 (FOXP3+) Tregs [E(max) (maximum value)÷baseline value×100=420%] with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators.
  
  
  CONCLUSIONS
  The trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT00574652.).
authors: Université Pierre et Marie Curie Université Paris 06, Paris, France.
authors: David
authors: D
authors: Saadoun
authors: Michelle
authors: M
authors: Rosenzwajg
authors: Florence
authors: F
authors: Joly
authors: Adrien
authors: A
authors: Six
authors: Fabrice
authors: F
authors: Carrat
authors: Vincent
authors: V
authors: Thibault
authors: Damien
authors: D
authors: Sene
authors: Patrice
authors: P
authors: Cacoub
authors: David
authors: D
authors: Klatzmann
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000032:analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014657:Vasculitis / Q000188:drug therapy* / Q000209:etiology
chemical_list: D015415:Biomarkers; D007376:Interleukin-2; D012367:RNA, Viral