A Virus-Like Particle-Based Vaccine Selectively Targeting Soluble Tnf- Protects from Arthritis without Inducing Reactivation of Latent Tuberculosis

Spohn, G.; Guler, R.; Johansen, P.; Keller, I.; Jacobs, M.; Beck, M.; Rohner, F.; Bauer, M.; Dietmeier, K.; Kundig, T.M.; Jennings, G.T.; Brombacher, F.; Bachmann, M.F.

The Journal of Immunology 178(11): 7450-7457

2007


DOI: 10.4049/jimmunol.178.11.7450
Accession: 068490476

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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.