There are both natural and drug-induced methods of inducing immunosuppression. TGF-beta is the most potent natural immunosuppressor described to date. Homeostasis of the immune system is maintained by TGF-beta. TGF-beta has been shown to downregulate IL-2-mediated proliferation signals, inhibit differentiation of cytotoxic T lymphocytes (CTL), inhibit proliferation of lymphocytes, inhibit production of IFN-gamma and TNF-alpha by T lymphocytes, downregulate IL-2 receptor expression, and mediate many other immunosuppressive activities.1 Treatment with cyclosporin A can block the immune response by interfering with early activation signals, thus preventing the transcription of genes encoding IL-2 and other cytokines.2 As a result, cyclosporin A is commonly used in organ transplantation and certain autoimmune disease treatments.
|Fig. 1. Statins can modulate the immune response by inhibiting MHC-II expression induced by IFN-gamma Statins inhibit this pathway at the transcriptional level, leading to reduced CIITA and subsequently reduced MHC-II expression. Constitutive expression of MHC-II, however, is not affected by statin treatment. Statin downregulation of MHC-II expression may promote decreased Th1 differentiation and activation and subsequent inhibition of pro-inflammatory cytokine release. [Figure is adapted from Palanski, W. (2000) Nature Med. 6:1312.].
Another class of drugs that demonstrates immunosuppressive activity includes the statins. Statins inhibit 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, are effective lipid lowering agents, and they can also modulate the immune response.3 Statins can repress the induction of Class II Major Histocompatability Complex (MHC-II) expression induced by IFN-gamma. The effect of statins on MHC-II is specific for its inducible expression and does not affect the constitutive expression of MHC-II. Statins act at the transcriptional level by inhibiting the class II transactivator (CIITA) IV promoter (i.e. general promoter for MHC-II). The effect is transcriptional, direct, and does not require de novo protein synthesis [see Figure 1]. Some statins are able to completely abolish this induced expression (Atorvastaine), whereas others only reduce the expression (Lovastatin, Prevastatin). This action of the statins can be reversed in the presence of L-mevalonate (a product of HMG-CoA reductase activity). Statins do not have an effect on MHC-I expression.
The decrease in MHC-II expression affects the activation of CD4+ T lymphocytes. This may lead to a decrease in Th1 differentiation and inhibition of the release of pro-inflammatory cytokines. Statins may thus play a beneficial role as immunosuppressors in organ transplantation. Previous findings have indicated improved outcomes of cardiac transplantation with Pravastatin treatment,4 although this was not attributed to the immunosuppressive effect observed by Kwak et al.3 Other potential applications for treatment with statins include diseases with aberrant MHC-II expression and/or aberrant activation of CD4+ T cells. These include autoimmune diseases such as rheumatoid arthritis and multiple sclerosis as well as chronic inflammatory diseases such as atherosclerosis.
- DeVisser, K.E. et al. (1999) Leukemia 13:1188.
- Ho, S. et al. (1996) Clin. Immunol. Immunopath. 80:S40.
- Kwak, B. et al. (2000) Nature Med. 6:1399.
- Kobashigawa, J.A. et al. (1995) New Engl. J. Med. 333:621.