Please use this identifier to cite or link to this item: http://hdl.handle.net/1946/13283
Immune modulation in Staphylococcus aureus-induced arthritis by a combination of antibiotics and inhibition of Interleukin-15
Staphylococcus aureus arthritis is characterized by a severe and rapid joint destruction where many of the affected patients develop permanent joint damage despite adequate antibiotic treatment. The permanent nature of the damage and the inadequacy of antibiotic treatment spur a need for new therapeutic procedures. Interleukin-15 (IL-15) is a pluripotent, antiapoptotic, and pro-inflammatory cytokine, which has been previously implicated in osteoclastogenesis. We have recently shown that inhibition of IL-15 alone leads to a less destructive S. aureus induced arthritis without affecting morbidity and the host's ability to clear the bacteria. In this study we investigate the potential benefits of a combination of antibiotic and inhibition of IL-15, using anti-IL-15 (aIL-15), as a treatment in S. aureus- induced arthritis.
Toxic shock syndrome toxin-1-producing S. aureus was intravenously inoculated in C57BL/6 wildtype mice. Treatment was started three days later with antibiotics and aIL-15ab or isotype control antibodies.
Treatment with aIL-15ab combined with antibiotics reduced synovitis without significantly affecting bone and cartilage erosivity. Moreover, the treatment did not have a negative impact on mortality, morbidity nor bacterial clearance. Assessment of bone mineral density revealed that the treatment did not have an impact on general bone loss. We did not observe that expression of OPG, RANK or RANKL was influenced by the treatment, except for significantly lower serum levels of OPG in the treated mice at day 12 after bacterial inoculation. Preliminary in vitro data showed a trend towards decreased osteoclastogenesis in cultures with the aIL-15ab compared with cultures with the isotype control antibody.
The combination of antibiotics and aIL-15 antibodies decreases the severity of synovitis in S. aureus-induced arthritis, but does not affect cartilage/bone destruction or general bone loss. Further, it does not have a negative impact on general infection. We conclude that, firstly, adding aIL-15ab to antibiotic treatment has limited additional benefits with respect to joint damage; and secondly, the effect of IL-15 on osteoclastogenesis is probably mediated via an indirect pathway.
Key words: IL-15; S. aureus; arthritis; osteoclasts; mice.