title: A virus-like particle-based vaccine selectively targeting soluble TNF-alpha protects from arthritis without inducing reactivation of latent tuberculosis.
abstract: Neutralization of the proinflammatory cytokine TNF-alpha by mAbs or soluble receptors represents an effective treatment for chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, or Crohn's disease. In this study, we describe a novel active immunization approach against TNF-alpha, which results in the induction of high titers of therapeutically active autoantibodies. Immunization of mice with virus-like particles of the bacteriophage Qbeta covalently linked to either the entire soluble TNF-alpha protein (Qbeta-C-TNF(1-156)) or a 20-aa peptide derived from its N terminus (Qbeta-C-TNF(4-23)) yielded specific Abs, which protected from clinical signs of inflammation in a murine model of rheumatoid arthritis. Whereas mice immunized with Qbeta-C-TNF(1-156) showed increased susceptibility to Listeria monocytogenes infection and enhanced reactivation of latent Mycobacterium tuberculosis, mice immunized with Qbeta-C-TNF(4-23) were not immunocompromised with respect to infection with these pathogens. This difference was attributed to recognition of both transmembrane and soluble TNF-alpha by Abs elicited by Qbeta-C-TNF(1-156), and a selective recognition of only soluble TNF-alpha by Abs raised by Qbeta-C-TNF(4-23). Thus, by specifically targeting soluble TNF-alpha, Qbeta-C-TNF(4-23) immunization has the potential to become an effective and safe therapy against inflammatory disorders, which might overcome the risk of opportunistic infections associated with the currently available TNF-alpha antagonists.
authors.affiliation: Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
authors.forename: Gunther
authors.initials: G
authors.lastname: Spohn
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.forename: Pål
authors.initials: P
authors.lastname: Johansen
authors.forename: Iris
authors.initials: I
authors.lastname: Keller
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
authors.forename: Markus
authors.initials: M
authors.lastname: Beck
authors.forename: Franziska
authors.initials: F
authors.lastname: Rohner
authors.forename: Monika
authors.initials: M
authors.lastname: Bauer
authors.forename: Klaus
authors.initials: K
authors.lastname: Dietmeier
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kündig
authors.forename: Gary T
authors.initials: GT
authors.lastname: Jennings
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
mesh_terms: D017908:Allolevivirus / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000517:prevention & control; D005260:Female; D008088:Listeriosis / Q000276:immunology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010316:Particle Size; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D015202:Protein Engineering; D012720:Severity of Illness Index; D012995:Solubility; D014376:Tuberculosis / Q000175:diagnosis / Q000276:immunology* / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D022721:Vaccines, Virosome / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
chemical_list: D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D018074:Vaccines, Conjugate; D022721:Vaccines, Virosome