Noradrenergic Interactions and Immunity

Rider University, Lawrenceville NJ

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The integration of nervous and immune system function is an important component for understanding human disease. Through innervation of immune organs and shared chemical messengers, our nervous system influences our susceptibility to and progression of infections, autoimmune diseases and cancer. The goal of this application is to better understand the involvement of sympathetic nervous system (SNS)-derived norepinephrine (NE) in coordinating and modulating host immune defenses. In particular, we are interested in studying the role of the SNS in modulating immune responses in subjects who are taking chemotherapeutic agents. Studying these interactions will help us determine if pharmacologically immunomodulated subjects are more susceptible to opportunistic infections in part because of underlying perturbations in neural-immune communication. Consistent with this idea, preliminary data show that splenic NE concentrations are elevated by low doses of the widely used chemotherapeutic drug cyclophosphamide (CY). We also show that the combination of CY and psychological stress increases antibody production to a greater extent than either CY or stress alone. Based on these observations, we propose that low doses of CY can modulate the neurochemical environment and that CY-induced elevations in neurochemical milieu, especially NE, act to exaggerate the neuroimmunomodulatory consequences of SNS activation. We will use this AREA application to develop and evaluate a murine model for studying the effects of CY on noradrenergic activity as well as on humoral and cellular immune effector responses. To achieve these goals, the first part of this proposal further characterizes CY-induced changes in NE concentration in immune and non-immune organs. The second part of this project investigates CY-induced changes in cytokine and antibody responses. The third part of this project examines the interaction of pharmacological (CY-induced) and behavioral (stressor-induced) changes in NE concentrations on measures of humoral and cell-mediated immunity. Our data will be evaluated in the context of a model in which NE promotes humoral immune effector responses and attenuates cell mediated immune effector responses via stimulation of beta-adrenergic receptors on T-helper-1 and B cells.