Psychoneuroendocrine interventions aimed at attenuating immunosenescence: a review.

There is evidence suggesting that immunosenescence can be accelerated by external factors such as chronic stress. Here we review potential psychoneuroendocrine determinants of premature aging of the immune system and discuss available interventions aimed at attenuating immunosenescence. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis. The immunological impact of such neuroendocrine dysregulation may be further amplified by a dramatic decline in dehydroepiandrosterone (DHEA) levels, acting in part as an endogenous glucocorticoid antagonist. Stress-buffering strategies show beneficial effects on various biomarkers in elderly populations. Likewise, supplementation of DHEA, melatonin or growth hormone has yielded significant beneficial effects in a number of studies, including: increased well-being, memory performance, bone mineral density and improved immunocompetence as evidenced by results of in vitro (T cell proliferation, cytotoxicity, cytokine production), and in vivo immune challenges. However, the side-effects of hormonal supplementation are also discussed. Finally, moderate exercise via the promotion of cortisol/DHEA balance or epigenetic modifications, is associated with lower serum pro-inflammatory cytokines, greater lymphoproliferative responses and lower counts of senescent T cells. Taken together, these data suggest that immune system is plastic and immunosenescence can be attenuated psychoneuroendocrine interventions.

Peripheral glucocorticoid sensitivity in children with controlled persistent asthma.

BACKGROUND: Persistent asthma in children is a chronic inflammatory disease and glucocorticoids (GCs) are currently recognized as the mainstay of therapy. Clinical and in vitro steroid resistance has been demonstrated in severe asthma. However, GC insensitivity has not been studied in children with controlled persistent asthma. OBJECTIVES: To analyze peripheral blood mononuclear cell (PBMC) sensitivity to GC in children (6-15 years) with persistent asthma and healthy controls. METHODS: Children with persistent asthma were selected and lung function and skin-prick tests were performed in all studied asthmatic children. PBMCs were isolated and cultured in vitro to assess mitogen-induced proliferation and cellular sensitivity to dexamethasone. RESULTS: Fifty-seven children with persistent and controlled asthma (mean age 10 years) were recruited and divided into 3 groups (severe, moderate and mild), and compared to healthy children (n = 18). Children with asthma, regardless of the severity of disease, presented similar sensitivity to GCs when compared to healthy children. Patients with mild asthma showed significantly less sensitivity to dexamethasone and children with severe asthma had similar sensitivity to dexamethasone when compared to controls. CONCLUSIONS: In vitro insensitivity to GCs was not demonstrated in children with controlled persistent asthma, even in those with severe disease. Our findings suggest that resistance to GCs in older patients with severe asthma might be an acquired process. However, future longitudinal studies are necessary to confirm this hypothesis.

Changes in T cell phenotype and activated MAPKs are correlated to impaired cellular responses to antigens and glucocorticoids during HTLV-I infection.

Lymphocytes of human T-lymphotropic virus type-I (HTLV-I) infected patients were previously found tolerant to mitogenic stimuli as well as glucocorticoid treatment. These data suggest that common signaling events are impaired during this infection. The underlying mechanisms of these phenomena may include changes in cellular composition, cytokine milieu and the differential activation of mitogen-activated protein kinases (MAPKs). We investigated the role of (i) p38 and ERK MAPKs, (ii) lymphocyte subpopulations, (iii) and cytokines implicated in antigen or glucocorticoid-induced immunomodulation. Twenty-one asymptomatic carriers (AC), 19 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 21 healthy subjects took part in this study. Lymphocytes were isolated and cultured in vitro to assess lymphocyte proliferation and sensitivity to dexamethasone. The expression of phospho-MAPKs, lymphocyte subsets and cytokines were assessed by flow cytometry. Patients with HAM/TSP had a higher p38/ERK ratio (p<0.05) associated with a reduced response to mitogens (phytohaemagglutinin or PMA+ionomycin) (p<0.001) and higher sensitivity to dexamethasone (p<0.05). HAM/TSP patients presented increased frequency of activated T cells and CD8(+)CD28(-) regulatory T cells, being negatively related to the mitogenic response. These data suggest that multiple underlying mechanisms could be involved with HTLV-related changes in cellular response to mitogens and glucocorticoids.