Gary J. Brenner

Sympathetic nervous system modulation of the immune system. III. Alterations in T and B cell proliferation and differentiation in vitro following chemical sympathectomy

Functional changes in lymph node (LN) and spleen lymphocytes were examined following sympathetic denervation of adult mice with 6-hydroxydopamine (6-OHDA). Sympathectomy reduced in vitro proliferation to concanavalin A (ConA) by LN cells and decreased LN Thy-1+ and CD4+ T cells. At the same time, ConA-induced interferon-gamma (IFN-gamma) production was increased, but interleukin-2 (IL-2) production was not altered. After sympathectomy, lipopolysaccharide (LPS)-stimulated proliferation of LN B cells was enhanced, in parallel with an increase in the proportion of sIgM+ cells. LPS-induced polyclonal IgM secretion was decreased, whereas polyclonal IgG secretion was dramatically enhanced. In the spleen, ConA and LPS responsiveness was reduced after sympathectomy, as was IL-2 and IFN-gamma production. The decreased proliferation was not associated with changes in splenic T and B cell populations. The uptake blocker desipramine prevented the 6-OHDA-induced changes in spleen and LN, indicating that these alterations were dependent upon neuronal destruction. These results provide evidence for heterogeneity of sympathetic nervous system regulation of T and B lymphocyte function and for organ-specific influences on immune function.

Stressor-Induced Alterations in Immune Response and Viral Clearance Following Infection with Herpes Simplex Virus-Type 1 in BALB/c and C57Bl/6 Mice

Extending earlier studies of stress-induced modulation of herpes simplex virus (HSV) infection and immunity, we investigated the effects of electric foot shock (0.3 mA) on cytokine production and immune effector function in response to a nonlethal inoculum of HSV-1 in two strains of inbred mice, C57B1/6 and BALB/c. Increased levels of infectious virus at the site of infection were observed in foot-shocked mice of both strains compared to control mice. The specific pattern of changes in interleukin (IL)-2 and interferon-gamma, as well as IL-4 and IL-10, induced by foot-shock stress differed between the two strains. IgM anti-HSV antibody responses were, however, increased in both strains.

The effects of handling on antibody production, mitogen responses, spleen cell number, and lymphocyte subpopulations

The effects of a simple psychosocial manipulation, handling, on immune function in BALB/c.ByJ mice were studied. Handling for two minutes/day prior to immunization was shown to be associated with a decreased primary IgG antibody response to the protein antigen keyhole limpet hemocyanin. Handling was also associated with decreased T cell proliferative responses to Concanavalin A. No reliable changes in spleen cell number or lymphocyte subsets were found. These findings demonstrate that simply picking up an animal results in modulation of the immune response. These data are also of interest for their obvious methodological implications.

Repeated intraperitoneal injections of saline attenuate the antibody response to a subsequent intraperitoneal injection of antigen.

The results of two experiments with male C3H/HeJ mice indicated that repeated intraperitoneal (ip) injections of sterile saline over a 2-week period resulted in an attenuated antibody response to the subsequent ip injection of a soluble protein antigen, keyhole limpet hemocyanin. There were no differences among experimental groups that received a different number of preimmunization injections of saline, and comparable effects were obtained simply by the daily handling of mice. Neither repeated ip injections nor handling altered preimmunization (baseline) corticosterone levels, and only previously unmanipulated mice showed an elevation in corticosterone levels 30 min after ip immunization. These latter results suggest that the depressed IgM and IgG responses were not due to the immunosuppressive effects of endogenously elevated adrenocortical steroids.

INCREASED PULMONARY METASTASES AND NATURAL KILLER CELL ACTIVITY IN MICE FOLLOWING HANDLING

We have demonstrated that holding BALB/c female mice for two minutes per day for two weeks prior to injection of line 1, a BALB/c derived alveolar carcinoma, results in a significant increase in pulmonary metastases compared to unhandled controls. Handling did not affect splenic in vitro or in vivo natural killer (NK) cell activity but, surprisingly, was associated with increased NK cell activity in the lungs of these handled mice. These results demonstrate that a simple psychosocial manipulation may effect the metastatic process. The implications of these findings and potential mechanisms are discussed.

Sympathetic nervous system modulation of tumor metastases and host defense mechanisms

The sympathetic nervous system can signal cells of the immune system through release of norepinephrine (NE), and may thus modulate several aspects of immune reactivity. We have examined the consequences of chemical denervation using 6-hydroxydopamine (6-OHDA) on the response of BALB/c mice to tumor cell challenge. In this study, chemical axotomy prior to the intravenous (i.v.) injection of the alveolar carcinoma line 1 significantly increased the number of pulmonary metastases. In contrast, axotomy performed after i.v. injection of tumor cells had no effect on the number of lung metastases. Line 1 tumor cells have been reported to be susceptible to lysis by natural killer (NK) cells. To examine possible mechanisms through which prior axotomy leads to increased lung metastases, we tested the effects of axotomy on in vitro and in vivo NK cell activity. No differences in NK cell activity were found between 6-OHDA- and vehicle-treated mice. Line 1 tumor cell growth in vitro was unaffected by both 6-OHDA and NE, and the tumor cells do not express beta-adrenergic receptors. Priming mice with lethally irradiated line 1 cells significantly reduced the number of lung metastases following challenge with live tumor cells; axotomy did not alter this decrease in metastases associated with priming. In summary, chemical axotomy of mice prior to injection of alveolar carcinoma cells resulted in an increased number of pulmonary metastases that was not correlated with alterations in either NK cell cytotoxicity or the putative immunological consequences of in vivo priming.

Stress-Induced Modulation of Immune Function in Mice

Publisher Summary Stress, which is the response of an organism to stimulation or change, is characterized by activation of the autonomic nervous system and the hypothalamo-pituitary-adrenal (HPA) axis. The resulting neurochemical changes have been demonstrated to affect immune function directly and indirectly. Direct effects are possible because lymphocytes bear receptors on their surfaces for many neurohormones and transmitters, and lymphocytes are exposed to neurochemicals in lymphoid organs and in peripheral blood. More indirect mechanisms for neural-immune interactions might involve changes in lymphocyte trafficking resulting from changes in sympathetic vascular tone. The elucidation of pathways of communication between the central nervous system and the immune system has advanced, to a large extent, from studies utilizing stressor administration in animal models. Application of stressor in animals results in diverse changes in specific humoral and cell-mediated immune parameters, and in non-specific natural killer (NK) cell number and/or activity.

Neural, Endocrine, and Immune System Interactions

The integration of the central and peripheral nervous systems and the immune system has become a focal point in the understanding of human health and disease. The nervous system communicates with the immune system via the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). The immune system, particularly via proinflammatory cytokines such as IL-1, can, in turn, regulate CNS activity. That the nervous system can modulate immunity has been inferred from several lines of evidence.