A virus-like particle-based vaccine selectively targeting soluble TNF-α protects from arthritis without inducing reactivation of latent tuberculosis

Neutralization of the proinflammatory cytokine TNF-α 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-α, which results in the induction of high titers of therapeutically active autoantibodies. Immunization of mice with virus-like particles of the bacteriophage Qβ covalently linked to either the entire soluble TNF-α protein (Qβ-C-TNF1-156) or a 20-aa peptide derived from its N terminus (Qβ-C-TNF4-23) yielded specific Abs, which protected from clinical signs of iniammation in a murine model of rheumatoid arthritis. Whereas mice immunized with Qβ-C-TNF-1-156 showed increased susceptibility to Listeria monocytogenes infection and enhanced reactivation of latent Mycobacterium tuberculosis, mice immunized with Qβ-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-α by Abs elicited by Qβ-C-TNF-1-156, and a selective recognition of only soluble TNF-α by Abs raised by Qβ-C-TNF4-23. Thus, by specifically targeting soluble TNF-α, Qβ-C-TNF4-23 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-α antagonists. Copyright © 2007 by The American Association of Immunologists, Inc.