Calorie Restriction as a Novel Therapeutic Tool to Manipulate Immunity and Improve Therapeutic Potential of First Line Drug Treatments During Relapsing Remitting Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disorder characterized by central nervous system (CNS) inflammation, demyelination, and axonal damage. Its pathogenesis consists of an initial T cell priming against myelin antigens in secondary lymphoid organs (induction phase) followed by migration of auto-reactive T cells and other immune system cells through the blood brain barrier into the CNS (effector phase). MS attacks are self-limiting, illustrating the existence of a regulatory network in which regulatory T cells (Treg) play a key role. Treg cells, which comprise 5%-10% of peripheral cluster of differentiation (CD)4+ T cells, inhibit effector T cell responses and can suppress MS. One of the immune abnormalities observed in MS is a reduction in the number and suppressive functions of Tregs. Furthermore, an abnormal Treg proliferation and metabolic profile was described in MS patients characterized by altered interleukin (IL) 2- IL 2 receptor - STAT5 signaling, and activation of the mammilian target of rapamycin (mTOR) metabolic pathway. More recently, the risk of MS has been associated with several environmental factors, including obesity and diet. Current treatments are only partially effective in controlling disease activity in relapsing-remitting (RR)-MS patients and no drugs are available that prevent or slow the progressive forms of MS. There remains an urgent need for new and safe therapies for patients that do not respond optimally to current drug treatments. In recent times, it has become evident that the control of orexigenic and anorexigenic circuits not only affects the regulation of body weight but also dramatically influences other important physiological and dominant functions, including immune homeostasis. In particular, several cytokines, hormones, neuropeptides and transcription factors play relevant roles in both metabolism and immunity.

It has been shown that dietary intervention can alter autoimmune disease progression, indeed dietary indoles suppress delayed-type hypersensitivity by inducing a switch from pro-inflammatory Th17 cells to anti-inflammatory Treg cells. Recent reports have shown that caloric restriction (CR) can significantly increase the survival and reduce clinical progression in EAE. CR induces multiple metabolic and physiologic modifications, including anti-inflammatory, antioxidant, and neuroprotective effects that could be beneficial in MS. A recent report has shown that dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging, by inhibiting the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. Moreover prolonged fasting (PF) or a fasting mimicking diet (FMD) lasting 2 or more days have been shown to increase protection of multiple systems against a wide variety of chemotherapy drugs; PF or FMD reverses the immunosuppression or immunosenescence effects of either chemotherapy or aging by a hematopoietic stem cell-based regenerative process. Chronic CR, a ketogenic diet (KD) and intermittent fasting have been shown to prevent EAE, reducing inflammation, demyelination, and axon injury - without suppressing immune functions, when administered prior to disease induction or signs. CR associates with increased plasma levels of corticosterone and adiponectin, and with reduced concentrations of IL-6 and leptin. The effects of CR in EAE in the monophasic Lewis rat model show that upon calories restriction by 33% or 66%, EAE can be totally inhibited in the latter group, in which a depressed immune function with fewer T cells in lymphoid organs, impaired proliferation and cytokine production are observed. CR could benefit EAE through multiple metabolic and cytokine/adipokine changes that ultimately lead to a reduced inflammatory response. Other possibilities include CR-associated increase in ghrelin, neuropeptide Y (NPY) and endocannabinoids - all of which can dampen EAE and are increased during CR and starvation. Environmental factors are believed to play a role in the pathogenesis of MS, which is more prevalent in the Western world, where increased intake of saturated fats of animal origin is common. Although there has been speculation that diet may alter the course of MS, only a few randomized, controlled studies of dietary alterations in autoimmunity have been published, and none involving CR. Yet, dietary intervention might be attractive in MS, i.e. with CR associated with adequate nutrition, which can be safely accomplished through proper monitoring and could provide additional benefits such as improved insulin sensitivity, lower low-density lipoprotein, cholesterol, blood pressure and, importantly, reduced inflammation.

In conclusion, in spite of the above robust experimental evidence, no specific studies have been performed to dissect at cellular level the mechanism of action of CR in the context of autoimmunity and MS. This study aims at investigating this specific point to pave for a wider utilization of the nutritional approach to alter MS progression and activity to be associated to first line drug treatments.

Rationale and specific aims.

Several disease modifying drugs are approved for RR-MS treatments and have shown to reduce relapse rates by modulating immune responses; however, their impact on long-term disease progression and accrual of irreversible neurological disability remains largely unclear, underlining the need for novel therapeutic strategies.