Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

Abstract

Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by inoculation with myelin basic protein (MBP) and adjuvants. Rats were treated with second daily injections of saline or cyclosporin A (CsA) from the day of inoculation. Saline-treated rats had an acute episode of disease followed by clinical recovery. Rats treated with CsA 16 or 32 mg/kg had minimal signs of EAE at the usual time after inoculation, but developed signs of disease after treatment was ceased. Rats treated with CsA 8 mg/kg had a delayed first episode of disease and then developed a relapsing or a chronic persistent course of disease. CsA 4 mg/kg delayed the onset of disease. To study the effects of CsA on the inflammatory infiltrate, cells were extracted from the spinal cords of rats with EAE, 16 h after a single injection of CsA or saline. Extracted cells were labelled with antibodies to T cells, CD11b/c (macrophages/microglia), CD95 (Fas) and Fas ligand. CsA 4 mg/kg did not alter the composition of the inflammatory infiltrate. Treatment with higher single doses of CsA caused a dose-dependent decline in the percentage of T cell receptor (TCR) + cells in the inflammatory infiltrate. All doses of CsA caused a significant increase in the number and percentage of cells that were apoptotic. CsA treatment caused an increase in the percentages of CD5 + and TCR + cells that were apoptotic. There was a decline in the percentage of apoptotic T cells that were V 8.2 + , compared to the percentage of nonapoptotic T cells that were V 8.2 + , in CsA treated rats compared to saline-treated controls. This suggests that, while CsA treatment caused a non-specific increase in the overall level of T cell apoptosis in the spinal cord, it abrogated the selective apoptosis of V 8.2 + encephalitogenic T cells that normally occurs during spontaneous recovery from acute EAE.

Cyclosporine A Regulates Pro-Inflammatory Cytokine Production in Ulcerative Colitis

“…The induction of apoptosis is believed to play a central role in the molecular mechanism of action of clinically efficacious therapies in IBD ( Van den Brande et al 2007). The finding that CsA treatment can induce apoptosis of T cells was also shown in a model for experimental autoimmune encephalomyelitis (EAE) (McCombe et al 1999). In this study, CsA treated Lewis rats suffering from EAE prevented the development of disease during treatment, but after ceasing CsA treatment the rats developed delayed signs of disease.…”

Cyclosporin A treatment modulates cytokine mRNA expression by inflammatory cells extracted from the spinal cord of rats with experimental autoimmune encephalomyelitis induced by inoculation with myelin basic protein

“…However, the results do not necessarily represent direct effects of CsA on cytokine expression in the CNS, as the alteration in the expression of cytokine mRNA may have occurred before the cells entered the CNS. We have previously shown that CsA treatment of MBP-EAE causes a decline in the proportion of T cells in the spinal cord inflammatory infiltrate 19 . Such a decline could also contribute to a decrease in the expression of T cell cytokine mRNA in the inflammatory infiltrate.…”

“…These effects could occur in the CNS or in the periphery and lead to downregulation of disease in the CNS. We have shown that a single treatment with high dose CsA causes a significant reduction in the number of T cells in the spinal cord of rats with EAE, and an increase in the number of apoptotic lymphocytes in the spinal cord 19 . CsA also inhibits the disruption of the bloodbrain barrier that occurs in EAE 26 .…”

“…We have previously shown that therapy with high dose CsA suppresses MBP-EAE, although rats have an episode of disease after therapy is ceased, and that low dose CsA causes chronic relapsing EAE 19 . We have also demonstrated that a single dose of CsA leads to a reduction in the number and percentage of T cells, as well as increased T cell apoptosis, and an increase in the percentage of macrophages/microglia in the inflammatory infiltrate in the spinal cord in rats with EAE 19 . The present study confirmed that a single dose of CsA causes a reduction in the number of inflammatory cells obtained from the spinal cord.…”

“…It can be seen that a single dose of CsA caused a dose-dependent reduction in the number of inflammatory cells/g of spinal cord, with significant declines at doses of 16 and 64 mg/kg. Using this technique, we have previously shown that these cells extracted from the spinal cord of rats with MBP-EAE are predominantly T lymphocytes and macrophages/microglia 33 and that CsA causes a decline in the number of T cells in the spinal cord 19 . …”