Impairment of the Immune System

Beta Switch Program

Beta Switch Program by Sue Heintze

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Immunodepression is a key feature of patients with CACS. The severity of immunodepression is related to stage of disease and severity of cachexia. Several of our studies demonstrated that the immune system of cancer patients shows an impaired blastic response to mitogens. The reduced proliferative response to mitogens (such as PHA, anti-CD3 antibody and recombinant IL-2) of peripheral blood mononuclear cells (PBMCs) isolated from cancer patients has to be considered as an index of more complex functional alterations. In normal circumstances (PBMCs isolated from healthy individuals) the above-cited mitogens induce cell cascade events similar to those occurring after antigen activation: production and release of cytokines, synthesis and release of IL-2 from CD4+ cells and surface expression of IL-2 receptor by lymphocytes. Thus, the blastic response depends on the amount of cytokines, IL-2 receptor expression and interaction between IL-2 and its receptor [55]. Patients with advanced cancer often exhibit a poorly functioning immune system manifested by anergy to skin-test antigens, decreased T-cell proliferation, alterations in signal transducing molecules, and reduced production of IL-2.

These defective functions correlate with the severity of disease and poor survival [56] and are actually considered a consequence of the oxidative stress, which in turn is an effect of the cell's impaired glucose metabolism. In advanced cancer patients, the altered energy metabolism and particularly the defective glucose utilisation are responsible for the reduced synthesis of reducing compounds by the pentose-phosphate pathway. However, the correct immune cell functioning requires adequate concentrations of intracellular reducing compounds and particularly GSH. In fact, several studies have widely demonstrated that GSH is essential for the progression of activated lymphocytes into the cell cycle from G1 to S phase; the supplementation of GSH to the medium of cultured T cells increases the IL-2 receptor expression as well as its internalisation and degradation and ameliorates the blastic response of lymphocytes to PHA, anti-CD3 and recombinant IL-2.

Moreover, in addition to reduced antioxidant defences, increased levels of ROS sustained by the cancer-related chronic inflammation directly induce T-cell hyporesponsiveness and alter the expression levels of key T-cell-signalling molecules such as TCR-Z and the TCR-dependent activation [57].

These hypotheses have been confirmed by several of our in vitro experiments, which demonstrated that, by adding the antioxidants N-acetyl cysteine, alpha lipoic acid and amifostine to the medium of cultured PBMCs isolated from advanced cancer patients, we were able to reverse in vitro the most significant functional defects of immune cells, such as response to mitogen (PHA) and antigens (anti CD3), the expression of surface activation markers (CD25 and CD95) and cell cycle progression (from G1 to S phase) [55,58].

These findings confirm that impairment of energy metabolism, by inducing oxidative stress, is responsible for defective immune functions shown in advanced cancer patients and that correction of oxidative stress by appropriate antioxi-dants may reverse immunological deficits.

Leptin is a marker consistent with energy reserves and may be the signal that connects energy stores with the immune system. Moreover, several studies showed that leptin plays a role in immunosuppression: the decrease in leptin plasma concentrations during food deprivation leads to impaired immune function, whereas the restoration of leptin to normal levels by feeding after starvation is sufficient to ameliorate the immune response and is followed by a significant increase in Th1 activity, further supporting the role of leptin as a nutritional sensor for the immune functions [59,60].

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