Enhanced immunoprotective effects by anti-IL17 antibody translates to improved skeletal parameters under estrogen deficiency compared to anti- RANKL and anti-TNFα antibodies

Abstract

Activated T cell has a key role in the interaction between bone and immune system. T cells produce pro-inflammatory cytokines including, RANKL, TNF-α and IL-17, all of which augment osteoclastogenesis. RANKL and TNF- are targeted by inhibitors like denosumab, a human monoclonal RANKL anti¬body and infliximab, which neutralizes TNF-α. IL-17 is also an important mediator of bone loss and an antibody against IL-17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, however the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti-TNF, anti-RANKL or anti-IL17 antibody administration to estrogen deficient mice on CD4+T cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti-RANKL/-TNF/-IL17 subcutaneously, twice a week, post-ovariectomy (Ovx) for four weeks. Animals were then autopsied; bone marrow cells collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that while anti-RANKL and anti-TNF therapies had no effect on Ovx-induced CD4+T cell proliferation and B lymphopoesis; anti-IL17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti-IL17 antibody reduced pro-inflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however cortical bone parameters, bone biomechanical properties and histomorphometry were best preserved by anti-IL17 antibody likely due to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti-IL17 which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL-17 for treatment of post-menopausal osteoporosis.