CpG-C Oligodeoxynucleotides Limit the Deleterious Effects of β-adrenoceptor Stimulation on NK Cytotoxicity and Metastatic Dissemination

Abstract

Suppression of natural killer (NK) cell activity is common following stress, has been reported to predict malignant recurrence in cancer patients, and was shown to underlie metastatic dissemination in animal models. We have previously reported that catecholamines play a major role in NK cell suppression, particularly in the context of physiological stress and surgery. In the current study using F344 rats, we examined the prophylactic use of different regimens of type-C CpG oligodeoxynucleotides (CpG-C ODN) on NK activity and metastatic dissemination in the context of pharmacological stress (using metaproterenol for β-adrenoceptor stimulation). Our results indicated that the beneficial effects of CpG-C ODN were more profound under pharmacological stress than under baseline conditions. A bolus of CpG-C ODN (330μg/kg, i.p.) 24 hrs prior to metaproterenolchallenge was most effective at reducing lung tumor retention of an experimental syngeneic mammary adenocarcinoma (MADB106), while having no observable side effects. Depletion of NK cells revealed their key role in improving baseline levels of resistance to metastatic dissemination following CpG-C ODN administration. When NK cell cytotoxicity was assessed in the circulation and the marginating-pulmonary immune compartments we found that CpG-C ODN protected individual NK cells from metaproterenol-induced suppression in both compartments. Moreover, in the critical marginating-pulmonary compartment, CpG-C ODN also elevated baseline cytotoxicity per NK cell against MADB106 tumor cells, and increased NK cell numbers in non-stressed rats. Overall, prophylactic CpG-C ODN treatment can improve immunocompetence and potentially reduce metastatic dissemination, especially in clinical settings characterized by enhanced sympathetic stress responses.

Resilience of the Immune System in Healthy Young Students to 30-Hour Sleep Deprivation with Psychological Stress

“…The same formula was used for each other leukocyte subset and for the total number of leukocytes. The coefficient of variation for this method was found in our laboratory to be 6% for identical samples [27,39,40]. …”

Plasmids Enriched with CpG Motifs Activate Human Peripheral Blood Mononuclear CellsIn Vitroand Enhance Th-1 Immune Responses to Hepatitis B Surface Antigen in Mice

“…CpG ODNs are recognized by TLR9 molecules expressed by plasmacytoid dendritic cells (pDCs) and B cells, and are essential for proinflammatory cytokine production and other inflammatory responses (8)(9)(10)(11). They also play a role in induction of the Th-1-acquired immune response and in B-cell …”

“…Synthetic oligodeoxynucleotides (ODNs) containing CpG motifs have been shown to act as potent adjuvants that can induce Th-1 immunity by mimicking the effects of bacterial DNA (8)(9)(10)(11). ODNs can improve immune responses to a variety of coadministered antigens, and therefore represent a promising new approach for improving vaccine efficacy (12)(13)(14).…”

Nerve Driven Immunity: Noradrenaline and Adrenaline

“…Interestingly, impairment of NK activity and reduced antitumor resistance following stress and b-AR stimulation seem to be affected by age as well as by gender (Page et al 2008). Recently, the prophylactic use of type-C CpG oligodeoxynucleotides (CpG-C ODN) was shown to improve NK activity and immunocompetence, potentially reducing metastatic dissemination after enhanced sympathetic stress responses (Goldfarb et al 2009) and in association with pharmacological blockade of b-ARs and COX inhibition it was proposed as a potential approach to limit postoperative immunosuppression and metastatic progression (Goldfarb et al 2011).…”