Cyclosporin A modulation of the acute inflammatory response: an explanation for the effect of CsA on host defences in infection.
Previous studies have shown that the administration of cyclosporin A (CsA) to animals with experimentally induced pyelonephritis resulted in considerable exacerbation of infection. T-lymphocytes are not involved in the host response to pyelonephritis but neutrophils are known to be a key component in the pathogenesis of this infection, so the effect of CsA on this inflammatory component was investigated. CsA administration did not affect the metabolic activity of neutrophils in vitro nor their ability to phagocytose and kill microorganisms. However, the ability of neutrophils to mobilize to a sterile inflammatory focus in vivo was significantly impaired. Further experiments, using models of pyelonephritis and subcutaneous infection, demonstrated that the CsA-induced suppression of neutrophil mobilization was directly related to the observed increase in bacterial numbers and exacerbation of tissue damage. Additionally, the actual effect of CsA on host defences and the outcome of infection was found to be dependent on the level of the initial infectious challenge. The results of this study provide an explanation for the current pattern of infectious disease in patients treated with CsA, in whom infection with extracellular pathogens is still common. It is also clear that the effect of CsA on inflammatory mechanisms may explain the efficacy of the agent in inflammatory diseases such as rheumatoid arthritis. This suggests a wider therapeutic role for CsA than is currently recognized.
Ormrod
D J
DJ
Department of Medicine, Auckland Hospital, New Zealand.
Cawley
S
S
Miller
T E
TE
D000210:Acute-Phase Reaction / Q000276:immunology*; D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D004927:Escherichia coli Infections / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology*; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011704:Pyelonephritis / Q000276:immunology; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins