title: Delivery with polycations extends the immunostimulant Ribomunyl into a potent antiviral Toll-like receptor 7/8 agonist.
abstract: BACKGROUND
  Upper respiratory tract infection is a frequent cause of morbidity worldwide. Although the course of infection is usually mild, it is responsible for enormous social and economic costs. Immunostimulation with bacterial extracts consisting of ribosomal RNA and proteoglycans, such as Ribomunyl, was introduced into the clinic in the 1980s as a new treatment concept, but did not achieve widespread application. Ribomunyl has been proposed to activate innate immunity, but the contribution of its RNA content as well as its antiviral potential has not been studied.
  
  
  METHODS
  Peripheral blood mononuclear cells from healthy donors and immune cells from adenoids were incubated with Ribomunyl either by itself or formulated in a complex with cationic polypeptides such as poly-l-arginine or protamine, and induction of cytokines was quantified by ELISA.
  
  
  RESULTS
  Ribomunyl in complex with either poly-l-arginine or protamine, but not on its own, was able to strongly induce interferon-α (P<0.01) and interleukin-12 (P<0.01) in peripheral blood mononuclear cells, whereas induced tumour necrosis factor-α and interleukin-6 levels were independent of the formulation. Comparable results were obtained in immune cells from adenoids, suggesting efficacy also in virus-affected tissue. Cell sorting, RNase digests and selective receptor expression show that the RNA in Ribomunyl acts as an agonist of Toll-like receptor (TLR)7 and TLR8.
  
  
  CONCLUSIONS
  Ribomunyl is, in principle, able to potently induce antiviral interferon-α and interleukin-12 via TLR7 and TLR8, respectively, but only when formulated in a complex with cationic polypeptides.
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herberhold
authors.forename: Christoph
authors.initials: C
authors.lastname: Coch
authors.forename: Thomas
authors.initials: T
authors.lastname: Zillinger
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hommertgen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Busch
authors.forename: Christine
authors.initials: C
authors.lastname: Schuberth
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hartmann
authors.forename: Vera
authors.initials: V
authors.lastname: Wimmenauer
authors.forename: Cristina Amparo
authors.initials: CA
authors.lastname: Hagmann
authors.forename: Bastian
authors.initials: B
authors.lastname: Lüdenbach
authors.forename: Martin
authors.initials: M
authors.lastname: Schlee
authors.forename: Friedrich
authors.initials: F
authors.lastname: Bootz
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
mesh_terms: D000234:Adenoids / Q000187:drug effects; D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D016207:Cytokines / Q000032:analysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D057809:HEK293 Cells; D006801:Humans; D007114:Immunization / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D058990:Molecular Targeted Therapy; D011073:Polyamines / Q000737:chemistry* / Q000378:metabolism; D000071228:Polyelectrolytes; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D000998:Antiviral Agents; D001120:Arginine; D016207:Cytokines; D011073:Polyamines; D000071228:Polyelectrolytes; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C034206:Ribomunyl