Modulation of non-specific cellular defence mechanisms by cyclosporin A
The immune response modifier Cyclosporin A (CsA) is widely used in the management of organ graft rejection and in the treatment of inflammatory disorders. CsA is a potent suppressor of T-lymphocyte function and it’s biological effects have been defined almost exclusively in these terms. However, recent studies in which the agent was shown to exacerbate a T-lymphocyte independent, experimentally induced bacterial infection of the kidney (pyelonephritis), indicated that CsA had effects on host defence mechanisms other than T-lymphocytes. The present study, using animal models, was undertaken to identify the host defence component modified by CsA. Neutrophils are a key component in the early response to infection and the administration of CsA resulted in an increase in the number of these cells in the circulation. When the effect of CsA on the in vitro metabolic activity of neutrophils and their ability to kill microorganisms was investigated, no changes were observed, but the in vivo ability of neutrophils to emigrate from the vasculature to a sterile inflammatory foci was markedly impaired. A model of localised subcutaneous infection was used to determine the effect of this CsA-associated suppression of neutrophil emigration on the ability of the host to mount a response to an infectious challenge. In CsA treated animals, neutrophil accumulation in E. coli infected, subcutaneously implanted sponges was initially suppressed, allowing bacterial numbers to increase rapidly. By 48 hours this powerful bacterial stimulus overrode the suppressive effects of CsA and led to a substantial increase in the size of the neutrophilic infiltrate. This finding of an initially reduced inflammatory response, followed by an increase in the influx of inflammatory cells, provided a possible explanation for the earlier observation that CsA promoted infection and tissue damage in experimental pyelonephritis. The relationship between the effect of CsA on neutrophil emigration and the pathogenesis of experimental pyelonephritis was therefore investigated. When CsA was administered to animals prior to inducing pyelonephritis, the neutrophilic infiltrate was markedly suppressed in the early stages. As predicted, this led to a logarithmic increase in bacterial numbers, the infiltration of large numbers of neutrophils and, ultimately, an exacerbation of tissue damage. Further studies, examining the effects of CsA on neutrophil-mediated inflammatory mechanisms, identified impaired neutrophil-to-endothelial cell adhesion as the most likely explanation for the observed defect in host defences. The integrated nature of cellular defence mechanisms in infectious disease is highlighted by these investigations. when microorganisms invade tissue, even though the number and function of circulating leucocytes may be normal their effective participation in the host response to infection depends on the ability to emigrate from the blood vessels to the site of infection. In summary, the discovery of additional properties of CsA provide an explanation for the patterns of infectious disease in patients treated with CsA, in whom infection with extracellular pathogens is common. It also seems likely that the ability of CsA to suppress neutrophil emigration may contribute to the effectiveness of the agent in the management of inflammatory diseases, such as rheumatoid arthritis, uveitis and psoriasis.