Immunomodulation of Murine Leishmaniasis with Cyclosporin A

Abstract

The fungal metabolite, cyclosporin A (CsA), is an undecapeptide with novel immunosuppressive effects as well as anti-parasitic and antiinflammatory properties (1,2). CsA is particularly effective in preventing activation of T helper and T cytotoxic cells at the induction phase of T cell responses both in vitro and in vivo (3). Although the mode of action of CsA is not yet entirely clear, it has been shown to inhibit the production of IL-2 and may have effects on other lymphoid communication signals and responsiveness (2–4). Cyclosporin A has been shown to have unexpected beneficial effects on certain parasitic infections in animal models of human disease. In murine malaria, cyclosporin A exhibited potent activity against P. yoelii and P. berghei when administered to mice either prophylactically or therapeutically (5,6). Furthermore, CsA also markedly inhibited the growth of Plasmodium falciparum in cultured human erythrocytes (6). In this work, both the therapeutic and prophylactic effects of the drug were thought to be due to the direct effect of the CsA on the Plasmodium parasites. Surprisingly, CsA also had protective effects in mice infected with the helminth Schistosoma mansoni. Animals were protected both from primary infections and secondary challenges (7,8). In these studies, however, no direct effect of the drug on the parasite was observed, and it was concluded that the drug evoked a stimulation of host mechanisms directed against the parasite (8). In contrast to these studies, CsA treatment of Trypanosoma cruzi infected mice was found to exacerbate the disease (9).