August 8, 2003
Amit Bar-Or, M.D.
Neurologist and Neuroimmunologist, McGill University and the Montreal Neurological Institute
Recent Viewpoints provided highlights from this yearís annual meeting of the American Academy of Neurology and outlined several areas of promising research. New treatments for multiple sclerosis (MS) that may be both effective and easy to tolerate are especially exciting. In addition to unsaturated fatty acids such as PUFA (discussed in my last Viewpoint), vitamin D represents another dietary supplement that may be an important immune modulator with potential therapeutic properties in MS.
Over the years, vitamin D has been implicated in multiple sclerosis in several interesting ways. From an epidemiological standpoint, it has been suggested that a relative deficiency in vitamin D may explain some of the intriguing geographic trends and uneven distribution of MS seen across populations. The human body does not make itís own vitamin D, and adequate supply of this vitamin depends on dietary intakeóthatís why milk is fortified with vitamin Dóas well as exposure of the skin to sunlight, which helps convert dietary vitamin D from its inactive to its active form.
In the 1970ís, studies by Goldberg (1) described that populations eating foods rich in vitamin D and also exposed to many days of sunlight per year (such as might occur around the equator) had a lower prevalence of MS than more Nordic populations such as Scandinavians, who had on the average significantly less sun exposure. While such trends seemed to hold true in similar studies of North American, Australian and European populations, exceptions were also described.
Several laboratory observations support the hypothesis that vitamin D may influence the MS disease process. Initial experiments using light irradiation reported that vitamin D can modulate immune responses, but only when it has been adequately converted to its active form (also called the 1,25(OH)2D3 form of vitamin D). This may be important since some studies suggest that even when dietary intake of vitamin D appears to be quite reasonable, the actual levels of the active forms of the vitamin may still be relatively low due to a lack of sufficient sun exposure (2). It is premature to recommend increased sun exposure as a way of improving the available levels of active Vitamin D since the potential health benefits of sun exposure must be balanced with the known risks of excessive sunlight, such as skin cancer.
However, it was discovered that the active form of vitamin D could be administered such that further conversion by sunlight is not required. For example, in a commonly used animal model of MS, experimental autoimmune encephalomyelitis (EAE), administration of the active 1,25(OH)2D3 form of the vitamin could prevent the development of disease (3). Follow-up studies aimed at understanding how vitamin D protected against animal MS confirmed that cells of the immune system, including monocytes and T cells, can recognize the active form of vitamin D, and trigger an anti-inflammatory response profile. In addition to its immune modulating effects, vitamin D can also enter directly into the brain, and may mediate its benefits within the central nervous system by acting directly on neural cells. In support of this idea are reports that the receptors for active vitamin D are present on neural cells such as astrocytes, microglia, oligodendrocytes and neurons (4).
Such observations have led to the development of vitamin D analogues, drugs designed to be well tolerated and to trigger the vitamin D receptor without the need for further activation. Early application of these agents to animal models of autoimmune diseases, including models of diabetes and multiple sclerosis, has shown promise. These vitamin D analogues should be quite safe in normal doses. Whether these doses can trigger the immune regulatory effects of vitamin D in humans will determine their potential in the treatment of human autoimmune diseases. Early phase trials in MS should be underway in the near future.
Copyright © 2003, Veritas Medicine