Antibiotics with Interleukin-15 inhibition reduces joint inflammation and bone erosions but not cartilage destruction in Staphylococcus aureus-induced arthritis

Background: Staphylococcus aureus-induced arthritis causes rapid joint destruction, often leading to disabling joint damage despite antibiotics. We have previously shown that IL-15 inhibition without antibiotics is beneficial in S. aureus-induced arthritis. We therefore hypothesized that inhibition of IL-15, in combination with antibiotics, might represent a useful therapy that would both reduce inflammation and joint destruction, but preserve the host's ability to clear the infection. Methods: Female wildtype C57BL/6 mice were intravenously inoculated with the TSST-1-producing LS-1 strain of S. aureus with 0.8x108 S. aureus LS-1/mouse. Three days later the treatment was started consisting of cloxacillin followed by flucloxacillin, together with either anti-IL-15 antibodies (aIL-15ab) or control antibodies. Outcomes included survival, weight change, bacterial clearance, and joint damage. Results: The addition of aIL-15ab to antibiotics in S. aureus-induced arthritis reduced synovitis and bone erosions compared to controls. The number of bone-resorbing osteoclasts in the joints was reduced, whereas cartilage destruction was not significantly altered. Importantly, the combination therapy did not adversely affect the clinical outcome of S. aureus-induced arthritis, such as survival, weight change or compromise the host's ability to clear the infection. Conclusions: As the clinical outcome of S. aureus-induced arthritis was not affected, the addition of aIL-15ab to antibiotics ought to be safe. Taken together, the combination of aIL-15ab and antibiotics is a beneficial, but not optimal, treatment of S. aureus-induced arthritis as it reduces synovitis and bone erosions but has a limited effect on cartilage destruction

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive VH81X from both pool

Immune modulation in Staphylococcus aureus-induced arthritis by a combination of antibiotics and inhibition of Interleukin-15

ABSTRACT Background: 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. Method: 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. Results: 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. Discussion: 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

Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice

International audienceBACKGROUND:Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.METHODS:C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.RESULTS:Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection.CONCLUSIONS:Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model