Toward a Role for Statins in Immunomodulation
Statins are a group of drugs defined as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (1) and have been described as the principal and the most effective class of drugs to clinically reduce serum cholesterol levels (2) . These clinical benefits, directly attributed to the cholesterol lowering effect of statins, have been extensively demonstrated in patients with atherosclerosis and cardiovascular diseases with or without coronary artery disease symptoms (3, 4) . At present, five statins are available in the US and most other Western countries: atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. It is estimated that about twenty-five million people worldwide are currently being treated with a statin. The number of prescriptions for statins issued in developed countries in 2000 was almost thirtyfold greater than the number written in 1991. World Health Organization statistics indicate that there are about 200 million people worldwide with coronary artery disease, stroke, other occlusive vascular diseases, or diabetes mellitus. Consequently, a proposal has been made that tens of millions of people at increased risk of heart attacks and strokes should begin statin treatment before onset of disease (5) .
In addition to their recognized positive effects in cardiovascular diseases, statins might also have some additional clinical benefits. Although not yet demonstrated systematically and convincingly in human studies, such additional benefits of statins have been the subject of much speculation. The prevailing view is that such additional effects, if real, could result from indirect consequences of cholesterol lowering by statins. Others have argued in favor of pleiotropic effects of statins, through unknown mechanisms unlinked to cholesterol-lowering properties (6) . For instance, the suggestion of beneficial effects of statins in cardiac transplantation was generally thought to result from favorable consequences of stringent and adequate lowering of cholesterol levels (7, 8) . Laufs et al. showed that statins regulate nitric oxide (NO) levels in vitro, contributing to the view that statins might have pleiotropic effects (9) . But despite this interest in the possibility of additional effects of statins, there was until recently no scientific rationale for statins to be considered as a method of treatment outside the field of atherosclerosis and cardiovascular diseases. In particular, they had not been considered or employed as immunomodulators or as drugs relevant to immune-related diseases.
The first direct scientific and mechanistic evidence that statins might have a role in immunomodulation reported that, unexpectedly, statins inhibited the expression of major histocompatibility complex (MHC) class II genes [also referred to as Immune Response (IR) genes] (10, 11) . More specifically, statins inhibited the transcription of CIITA (MHC class II transactivator), a transcription factor essential for the expression of MHC II genes. This specific mechanism, together with the key role of the regulation of MHC class II expression in the control of immune responses in general, provided for the first time a scientific rationale for advocating statins as immunomodulators and immunosuppressive agents, independently of their well-known effects on lowering cholesterol levels. This finding led to the suggestion that statins might become novel therapeutic agents in the area of immunosuppression, anti-inflammation, and immune-related disorders such as auto-immune diseases (12) . Indeed, the demonstrated ability of statins to block expression of MHC class II qualified them for use in novel immunomodulation therapeutic strategies. Recently, certain additional effects of statins, also distinct from cholesterol lowering, have been reported, such as inhibition of expression of CD40 (13, 14) , binding to LFA-1 (15) , inhibition of expression of adhesion molecules (13) , cytokines, and chemokines (16) .
In addition to these findings, several very recent publications identify a therapeutic use for statins in the treatment of multiple sclerosis (17, 18) , and in particular to the mouse model of multiple sclerosis—termed experimental autoimmune encephalomyelitis (EAE)—are particularly interesting and not entirely unexpected. Youssef et al. (17) describe how oral statin treatment prevents or reverses chronic and relapsing paralysis and suppresses clinical and histological EAE. In these experiments, statin treatment reduces CNS infiltration (TH 1 lymphocytes) and MHC class II expression, inhibits the activity of CD40, CD80, and CD86 co-stimulatory molecules, largely inhibits the secretion of numbers of proinflammatory cytokines [for example, tumor necrosis factor–α (TNFα ), interferon-γ (IFN-γ ), interleukin-12 (IL-12)], and even induces the production of anti-inflammatory cytokines [such as tumor growth factor–β (TGFβ ) and IL-10]. In addition, statin treatment of either antigen-presenting cells (APC) or T lymphocytes from EAE-susceptible mice suppressed antigen-specific T-cell activation. These statin-mediated effects are specific for the inhibition of the enzyme HMG-CoA reductase. In their conclusion, the authors suggest that statins may be beneficial for multiple sclerosis and other TH 1 lymphocyte-mediated autoimmune diseases. These findings were largely confirmed in another recent report published by Neuhaus et al. (18) . It is important to bear in mind that one of the current treatments of choice for multiple sclerosis, IFN-β , also inhibits expression of MHC class II, although the exact mechanism is unknown. Investigations on possible synergy between statins and IFN-β treatment on immunomodulation and proinflammatory molecules are currently being explored and may result in novel therapeutic strategies to influence the clinical issue of multiple sclerosis.
In a similar vein, it is tempting to argue that the clinical benefit observed with statins in cardiac transplantation (7, 8) is not the result of the lowering of cholesterol levels, as was suggested, but rather the result of their demonstrated role as inhibitors of expression of the MHC class II regulator CIITA. Indeed, the disruption of the CIITA gene in mice has a very strong, favorable effect on the outcome of cardiac transplantation (19) , confirming that inhibiting CIITA, and thus MHC class II expression, is beneficial in organ transplantation.
The practical implications of new roles for statins as immunomodulators, as deduced from their effect on MHC class II expression (10, 11) and from their effect in preventing an autoimmune disease in mice (17, 18) , are interesting. First, statins will, no doubt soon, be tested in several human autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn’s disease, and psoriasis. Second, the effect of combination therapy with IFN-β and statins in multiple sclerosis should be attempted. And third, direct pharmacological inhibition of expression of MHC class II, acting either on CIITA or on the three other MHC class II-specific transcription factors that form the regulatory factor X (RFX) complex (20) , should be explored. In view of the recently recognized effect of statins—not only on the expression of MHC class II genes, but also on certain key immunoregulators such as CD40, or on the pathway mediated by LFA-1—one can expect to hear about other new examples of clinical benefit from statin treatment in autoimmune or inflammatory diseases. We have recently observed, for instance, remarkable effects of statins in mice models of skin transplantation and of collagen-induced arthritis (21) . Although it is to be hoped that statins may prove to be clinically useful in autoimmune diseases, one should also keep in mind that some degree of immunosuppression over a very long time period might have negative consequences. It is thus relevant to mention that in the recent human clinical trial PROSPER (22) , it was reported that the use of statin in elderly individuals might increase the risk of cancer. Nonetheless, the future seems bright for the statin family in immune regulation.
- © American Society for Pharmacology and Experimental Theraputics 2002
References
François Mach, MD, is Principal Investigator, Head of Clinical and Basic Cardiovascular Research in the Cardiology Division, Department of Medicine at Geneva University Hospital, School of Medicine, Geneva, Switzerland. E-mail Francois.Mach{at}medecine.unige.ch; fax +41 22 382 7245.
