The foregoing results indicate that, in contrast to rats receiving a normal diet or a 33% calorie-restricted diet, rats subjected to severe (66%) calorie restriction do not exhibit clinical signs of EAE. The major immune findings in severely calorie-restricted rats were: (i) impaired splenic and lymph node mitogenic response to Con A and a higher splenic response to LPS; (ii) less splenic, lymph node and thymic CD4+, B and T-B cells, and splenic T cells; (iii) increased numbers of splenic and lymph node CD8+ and CD4+- CD8+ cells; (iv) impaired IFN-γ production in the three examined tissues.
Malnutrition produced by low or absent proteins in diet is linked to increased susceptibility to infection, often associated with severe marasmus or kwashiorkor. In contrast, calorie restriction of adult rodents by a diet enriched in proteins and low in fat and carbohydrates significantly increases immune responses [17-19]. Calorie restriction inhibits age-related dysregulation of cytokines and prevents, by enhancement of T cell apoptosis, accumulation of non-replicative, non-functional, senescent T cells [20]. The effect of calorie restriction is also demonstrable in young animals. For example, in young mice with experimental colitis, caloric restriction to 60 % of daily requirement augmented natural killer (NK) cell number and cytotoxicity and decreased IFN-γ release [21]. In a study using peripubertal male Wistar rats submitted to a 66 % calorie restriction diet similar to that employed herein for 4 weeks, we reported that calorie restriction modified 24 h rhythmicity of lymph node mitogenic responses to Con A and LPS, and of T, T-B, CD4+ and CD4+-CD8+ lymph node cell subsets. In addition, mean values of SmLN Con A response and CD4+ cell number increased whereas those of B cell number and IFN-γ release decreased [22]. Collectively, the data are compatible with the view that T-cell responses increase in growing rats fed with a calorie-restricted diet enriched in proteins and low in fat and carbohydrates.
The proinflammatory cytokine IFN-γ, which is secreted by activated T lymphocytes and natural killer cells, stimulates the expression of MHC class I and II molecules on a wide variety of cells and is involved in the activation of macrophages and microglia [23]. Evidence suggests that IFN-γ plays a deleterious role in immune-mediated demyelinating disorders such as MS and EAE [24]. This cytokine, which is not normally present within the CNS, is detectable during the symptomatic phase of these disorders, and much of the pathology observed is consistent with IFN-γ involvement. Moreover, the treatment of MS patients with IFN-γ exacerbates the disease [25] and IFN-γ-secreting T cells can adoptively transfer EAE [26]. Transgenic mice that ectopically express IFN-γ in the CNS display a tremoring phenotype and myelin abnormalities [27] as well as increased susceptibility to EAE [28].
The foregoing results indicate the occurrence of a significant decrease in splenic, lymph node and thymus IFN-γ production in severely calorie-restricted rats, thus agreeing with observations indicating that, in autoimmune-prone mice, calorie restriction lowers mRNA expression of this cytokine [29], and that in young mice with experimental colitis, caloric restriction augments NK cytotoxicity and decreases IFN-γ levels [21].
It must be noted, however, that there is conflicting evidence as to whether IFN-γ provides a disease-reducing role in immune-mediated demyelinating disorders. The administration of antibodies to IFN-γ enhances the severity of EAE, whereas treatment of mice experiencing EAE with IFN-γ results in improved survival [30,31]. It has also been shown that mice with a mutation in either the gene encoding IFN-γ or its receptor are susceptible to EAE and that mouse strains that are normally resistant to EAE become susceptible when incapable of synthesizing or responding to this cytokine [32,33]. Clearly, the role that IFN-γ plays in demyelinating disorders is complex.
Summarizing, the present results are compatible with the view that the acute phase of EAE can be significantly curtailed by severe calorie restriction, presumably through an impaired IFN-γ production. The immunological status of rodents fed a calorie-restricted diet is superior to the immunological status of the non-restricted animals and through this mechanism caloric restriction may retard EAE development. Indeed, experimental calorie restriction (e.g. 25–50 % reduction of caloric intake), without deficiency in essential nutrients, may be a useful manipulation in slowing MS evolution [1].
However, caution should be taken in extrapolating the present experimental results to the clinical situation in view of the fact that monophasic EAE, particularly in the Lewis rat model, is a disease that shares only some aspects of human MS. In addition, EAE is defined in the present study on clinical grounds only and further histopathological and immunological examination of the brain is needed before a clear picture on what is happening in calorie restricted rats during EAE is obtained.
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