Studies of the effect of stress on the immune system provide a way to evaluate the coordination of the immune system with other systems in the maintenance of homeostasis. The objectives of the present study were to characterize the immunomodulatory effect of 2-DG, a metabolic stressor, on both primary and secondary immune organs and to examine the possible neuroendocrine mechanism(s) mediating 2-DG-induced immunomodulation using male, Lewis rats;The first study demonstrated that acute and chronic 2-DG administration induced a decrease total leukocyte counts, organ weight, IFN-[gamma] production, and mitogen response of lymphocytes in both spleen and whole blood. The ratio of CD4+/CD8+ in the spleen was decreased due to a significant increase in CD8+ T-cell subpopulation. In contrast, there was a significant increase in nitrite production in cultures of spleen and blood leukocytes from 2-DG-injected rats compared with saline-injected controls. Production of IL-1 and IL-2 by cells from these tissue was significantly reduced in the blood, but not in the spleen. Moreover, the kinetics of 2-DG-induced immunomodulatory effects in the spleen and blood were different. Hence, acute and repeated 2-DG exposure induced alteration of immune function in both spleen and blood;The objectives of the second and third projects were to examine the role of peripheral catecholamines and adrenal hormones in 2-DG-induced immune alteration. Results indicated that the [beta]-adrenergic receptor antagonist nadolol, attenuated 2-DG-induced suppression in the spleen, but not in the blood. Adrenalectomy attenuated 2-DG-induced alteration of immune parameters in the blood, but did not attenuate altered immune function in the spleen. These data suggest that the sympathetic release of catecholamines is responsible for splenic immune alterations, whereas adrenal hormones are responsible for immune alterations observed in blood leukocytes. Results from the second and third projects also indicate that common neuroendocrine pathways exist for several types of stressors which induce immunomodulation;The characterization of 2-DG modulation of thymic parameters was established in the fourth study. Repeated 2-DG administration induced a significant reduction of thymus weight, total thymocytes, mitogen responsiveness of T-lymphocytes, and nitric oxide production by thymic stromal cells. Additionally, the numbers of CD4+ and CD4+CD8+ double positive T-cells decreased in the thymus of rats which received multiple 2-DG injections, but the numbers of CD8+ T-cells increased. Moreover, 2-DG-induced an elevation of adrenal hormones which initiates a long lasting process of increased apoptosis in the thymus. Thus, 2-DG-induced immunomodulation of the thymus may result in the changes of immune function in the spleen and blood.