Sympathetic nervous system and macrophage function.
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Biomedical subjects
Publications and source records attributed to E Chelmicka-Schorr.
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Adoptively transferred experimental allergic encephalomyelitis (EAE) was significantly augmented in Lewis rats with ablated sympathetic nervous system. Sympathectomy was obtained by treatment of newborn rats with 6-hydroxydopamine. Sham-injected rats were used as a control. EAE was elicited in 7-8-week-old donor Lewis rats by immunization with a suspension of guinea pig (GP) brain and spinal cord in complete Freund's adjuvant. Successful transfer of EAE was accomplished with 50 x 10(6) lymph node cells (LNC)/rat, incubated for 72 h with GP myelin basic protein. LNC were obtained from draining lymph nodes, 9 days after immunization for EAE. The severity of passively transferred EAE was significantly augmented when donor LNC obtained from normal Lewis rats immunized for EAE were injected into sympathectomized rats as compared to sham-injected rats. When LNC were obtained from sympathectomized or sham-injected donors, the disease was significantly more severe in recipients of cells from sympathectomized animals. The severity of histological lesions in the brain and spinal cord was greater in rats with passively transferred EAE which received LNC from sympathectomized donors.
We have reported previously that sympathectomy augments immune responses in mice and rats. In the present study, we show that ablation of the sympathetic nervous system augments macrophage function as measured by increased TNF secretion. We also show that a factor present in the sympathetic ganglia of newborn rats, suppresses secretion of TNF by LPS-stimulated macrophages as does the beta-adrenergic agonist isoproterenol.
We have reported previously that ablation of the sympathetic nervous system augments immune responses in mice and rats. In the present study we show that a factor present in the sympathetic cervical ganglia of newborn rats suppresses Con A-induced stimulation of splenic T lymphocytes significantly whether added prior to, throughout, or following exposure to Con A. We also show that rat PC 12 pheochromocytoma cells secrete a factor which has the same inhibitory effect on T cell proliferation as the sympathetic ganglia-derived factor.
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Treatment with the beta-adrenergic agonist isoproterenol suppresses clinical and histological experimental allergic encephalomyelitis in Lewis rats. The effect of isoproterenol treatment is greater when the drug is given from the time of immunization through the acute phase of the illness or from 8 to 14 days post-immunization than when given for the first 7 days after immunization.
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A trophic factor secreted by PC12 rat pheochromocytoma augments growth of C1300 neuroblastoma clonal lines S20, N18 and C46, but does not affect growth of the NIE 115 line. A trophic factor present in newborn sympathetic ganglia has the same biological effect on neuroblastoma cell lines. PC12 cells and sympathetic ganglia are both of neural crest origin; possibly both secrete the same trophic factor.
The nervous system affects immune regulation. We permanently ablated the sympathetic nervous system (SNS) of CBA mice with 6-OHDA at birth. Function of splenic natural killer (NK) cells in the sympathectomized mice was equivalent to controls at 2 weeks, but rose significantly above control levels at 4 weeks. NK cell function decreased below control values thereafter. NK cell numbers paralleled these changes in NK cell function. Our data suggest that the SNS may regulate the number and function of splenic NK cells during development.
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C-6 glioma cells possess beta-adrenergic receptors on the cell surface. Activation of beta-adrenergic receptors with beta-adrenergic agonists increases intracellular levels of cAMP and leads to differentiation of C-6 glioma cells in vitro. The present study shows that growth of C-6 glioma tumor in rats with ablated sympathetic nervous system is augmented as compared to controls. Lack of normal noradrenergic stimulation of C-6 glioma cells may lower intracellular cAMP and allow unrestricted growth of this tumor.
The sympathetic nervous system modulates the growth of C-1300 mouse neuroblastoma in vivo and in vitro. We now report that a mitogenic/trophic factor that augments growth of C-1300 neuroblastoma and of the S-20 neuroblastoma clonal line is present in freshly excised sympathetic cervical ganglia from newborn rats, but is not detectable in homogenates from sympathetic ganglia obtained from adult rats.
The sympathetic nervous system modulates the growth of C-1300 mouse neuroblastoma (C-1300 NB) in vivo. We now report that the presence of sympathetic cervical ganglia in cultures containing C-1300 NB or dispersed S-20 neuroblastoma (S-20 NB) cells augments growth of these tumors in vitro. Sympathetic ganglia-conditioned medium increases proliferation and survival of S-20 NB cells, indicating that nervous system-derived growth factors can exert an effect on neoplastic cells.
Ablation of the peripheral sympathetic nervous system by treatment of adult (axotomy) and neonatal (sympathectomy) mice with 6-hydroxydopamine hydrobromide produced significant changes in the distribution of cell surface molecules detected on spleen lymphocyte populations. The surface molecules that were studied consisted of the beta-adrenergic receptor and the Thy-1.2 and Lyt-2 surface antigens associated with lymphocyte subpopulations. beta-Adrenergic receptor density, as measured by 3H-dihydroalprenolol binding, was found to be significantly higher on control mouse splenic B cells than on T cells. beta-Adrenergic receptor density was seen to increase in both T and B spleen cell populations after axotomy. The Thy-1.2 and Lyt-2 surface antigens present on cell populations from mouse spleens were labeled using fluorescent monoclonal antibodies and quantitated using a fluorescence-activated cell sorter. A significant increase in the percentage of Thy-1.2 positive cells represented among the total spleen lymphocyte population was detected in axotomized mice. A corresponding increase in the representation of Lyt-2-positive cells, a subset of the Thy-1.2-positive population, was also found. In contrast, while the percentage of Thy-1.2-positive cells per total spleen lymphocyte population were not found to differ between control and sympathectomized mice, a significantly lower percentage of Lyt-2 positive cells within the Thy-1.2-positive population appeared in sympathectomized mice. Suppressor/cytotoxic cell function, as well as properties relating to the recognition of major histocompatibility complex antigens, have been associated with the Lyt-2 antigen. The relative distributions of lymphocyte subpopulations, as indicated by surface markers, and their beta-adrenergic receptors may play an important role in the physiologic functions and interactions between lymphocytes that respond to sympathetic nervous system innervation.
The sympathetic nervous system exerts a trophic-mitogenic influence on C-1300 mouse neuroblastoma. We now report that sympathetic axotomy suppresses growth of the S-20 clonal line of neuroblastoma but does not influence the growth in vivo of two other clonal lines, NIE-115 and C-46. Sympathetic ganglia-conditioned medium significantly increases proliferation of S-20 cells in vitro. Growth of NIE-115 and C-46 clonal neuroblastoma lines is not influenced by sympathetic ganglia-conditioned medium. We postulate that the sympathetic nervous system secretes a mitogenic-trophic factor that favors growth of C-1300 neuroblastoma in vivo. Sensitivity to this factor varies between neuroblastoma clonal lines.
A girl with Eaton-Lambert syndrome had symptoms beginning at the age of 9 years. An extensive search for underlying neoplasm or definable autoimmune disease gave negative findings.