Anti IL-17A therapy inhibits bone loss in TNF-[alpha]-mediated murine arthritis by modulation of the T-cell balance

• Published in: European journal of immunology Vol. 42; no. 2; pp. 413 - 423
• Main Authors: Zwerina, Karin, Koenders, Marije, Hueber, Axel, Marijnissen, Renoud J, Baum, Wolfgang, Heiland, Gisela Ruiz, Zaiss, Mario, Mclnnes, Iain, Joosten, Leo, van den Berg, Wim, Zwerina, Jochen, Schett, Georg
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 01.02.2012
• Subjects: Drug therapy; Medical research; T cell receptors
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201141871

Tumour necrosis factor alpha (TNF-[alpha]) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-[alpha]-mediated inflammation and bone resorption. Human TNF-[alpha] transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1-/- mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-[alpha]-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1-/- mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-[alpha]-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses. [PUBLICATION ABSTRACT]