Neuroanatomic and neurotransmitter influences on immune function.
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Amygdala↗
Biomedical subjects
T L Roszman
Publications and source records attributed to T L Roszman.
Pokeweed mitogen-induced immunoglobulin secretion by peripheral blood lymphocytes from patients with primary intracranial tumors. Characterization of T helper and B cell function.
We have previously demonstrated that patients with primary malignant brain tumors have impaired in vivo and in vitro cell-mediated immunity. The purpose of the present research was to employ pokeweed mitogen (PWM)-induced secretion of immunoglobulin (Ig) by peripheral blood lymphocytes (PBL) to further investigate impaired lymphocyte function in these patients. The PWM response of PBL from normal individuals averaged 8384 plaque-forming cells (PFC) per 10(6) cells, whereas the response of PBL from patients averaged 1590 PFC/10(6). The decreased PWM response of PBL patients could not be improved by varying the number of PBL placed in culture or employing different concentrations of PWM. Co-culture experiments to detect the presence of suppressor cells in PBL and purified T cell preparations from patients demonstrated that enhanced suppressor cell activity was not evident. Next, experiments were performed to assess the T-helper cell activity present in purified T cell preparations obtained from patients. The results demonstrated that T cells from patients lacked the ability to provide adequate helper activity in the PWM response. Moreover, studies with monoclonal antibodies directed against T cell subsets revealed that PBL from patients have a reduced percentage of T-helper cells (40%) as compared with normal values (55%). In concert with T-helper cell anomalies, B cell function in these patients also is diminished. Thus, these observations indicate that a combined T-helper and B cell defect may contribute to the broad impairment of host immunocompetence observed in patients with primary gliomas.
Adolescent↗
Influence of serotonin on the immune response.
The present study investigates the influence of pharmacological agents known to regulate biosynthesis of the neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) on the primary antibody response to sheep red blood cells (SRBC) in the CBA mouse. Systemic administration of 5-HT (4-100 mg/kg) or its precursor, 5-hydroxytryptophan (5-HTP, 50-400 mg/kg), 30-60 min before immunization resulted in dose-dependent suppression of both the IgM and IgG plaque-forming cell (PFC) response to SRBC. Conversely, para-chlorophenylalanine (PCPA, 250 mg/kg), which inhibits the rate-limiting enzyme (tryptophan hydroxylase) in 5-HT biosynthesis, markedly enhanced IgM and IgG antibody production when injected 48 hr prior to antigen. Effects of these drugs on immune processes appeared independent of observed changes in plasma corticosterone levels. Further, immune function was preserved following selective depletion of brain serotonin through intracisternal injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) in mice pretreated with desmethylimipramine (DMI). Thus, immunomodulation by serotonin appears to be mediated via peripheral mechanism(s).
5,7-Dihydroxytryptamine↗
T-lymphocyte heterogeneity in the rat: separation of distinct rat T-lymphocyte populations which respond in syngeneic and allogeneic mixed lymphocyte reactions.
These experiments were designed to determine if separate subpopulations of T cells were involved in the syngeneic and allogeneic mixed lymphocyte reaction. Rat lymph node T cells were separated into W3/25+ and W3/25- subpopulations by panning with the monoclonal antibody W3/25 and tested for their ability to proliferate in both syngeneic (SMLR) and allogeneic (MLR) mixed lymphocyte responses, as well as to develop cytotoxicity against allogeneic, syngeneic, and trinitrophenol (TNP)-modified syngeneic targets. The W3/25+ T cells reacted strongly in the SMLR and the MLR whereas the W3/25- fraction proliferated only in response to allogeneic stimulation and with a kinetic pattern distinct from W3/25+. Furthermore, addition of W3/25 monoclonal antibody directly to the cultures was shown only to inhibit the proliferation of the W3/25+ T-cell fraction. The W3/25- subpopulation contained cytotoxic T cells (CTLs) against both allogeneic determinants and TNP-modified self. However the requirements for the activation of allospecific CTLs were distinct from those for CTLs for TNP-self in that W3/25- allospecific CTLs required no detectable help from W3/25+ T cells but generation of the CTL response against TNP-self required the presence of W3/25+ helper T cells (Th). These data suggest that in the rat, there exist subsets of T cells recognized by their cell surface phenotype that distinguish between self and nonself determinants and the requirements for activation are different for each of these populations.
Animals↗
Role of spontaneous interstitial cell testicular tumors on the mitogen reactivity of spleen cells from aged male Fischer-344 rats.
Virtually all aged, male, Fischer-344 rats have testicular tumors. The influence of this tumor on lymphocyte reactivity from aged Fischer-344 rats is unknown. In this report we demonstrate that neither the presence of this tumor nor the serum concentration of luteinizing hormone has an effect on the splenic mitogen reactivity of old animals.
Aging↗
Neuromodulation of lymphocyte reactivity in aged rats.
Numerous reports indicate that both central nervous system (CNS) and immune system functions decline with age. We have previously shown that the CNS can modulate both mitogen-induced spleen cell proliferation and NK activity in young Fischer 344 rats. In the present study we have determined the effects of AHT lesions on the lymphocyte reactivity of aged Fischer 344 rats. These data show that lesions in the AHT of aged rats cannot modulate splenic mitogen responsiveness, however, NK activity is impaired. This differential effect may be due to multiple factors including enhanced splenic suppressor cell activity, the inability of the brain to send modulatory signals following lesioning, or the failure of the immune system to receive a neural signal and react to it.
Animals↗
Cytokinetic basis for the impaired activation of lymphocytes from patients with primary intracranial tumors.
Patients with malignant brain tumors have a variety of immunologic abnormalities, including the impaired responsiveness of peripheral blood lymphocytes (PBL) to mitogens and alloantigens. We further investigated this impairment of lymphocyte reactivity by employing the techniques of limiting dilution analysis and cytokinetic analysis. PBL preparations from patients have approximately six times fewer phytohemagglutinin (PHA)-responsive cells than PBL from normal subjects. Similar results were obtained with purified T cell preparations. Cytokinetic analysis of PHA-induced [3H]thymidine incorporation employing colchicine blocking of mitosis demonstrated that the number of first generation cells entering the S-phase of mitosis for each 24-hr period was less for PBL from patients than for PBL from normal individuals. First generation responding cells from patients and normal subjects entered DNA synthesis at the same time (48 to 72 hr). Cytokinetic analysis over a period of 168 hr demonstrated that whereas PBL from normal individuals demonstrated second generation responding cells, PBL from the majority of patients did not, thus indicating a defect in their ability to undergo clonal expansion. Measurement of interleukin 2 (IL 2) activity in culture fluids from PHA-activated PBL from normal subjects and patients revealed significantly lower IL 2 levels in culture fluids from PBL from patients. The addition of various concentrations of lectin-free IL 2 to PBL from patients stimulated with PHA did not restore responsiveness to normal values. There was no difference between the levels of interleukin 1 (IL 1) produced by lipopolysaccharide-activated monocytes from normal subjects and patients. Overall, these results suggest that an intrinsic defect exists in T cells obtained from brain tumor patients that renders them unable to enter into normal mitogen-induced blastogenesis.
Adolescent↗
Hypothalamic-immune interactions: neuromodulation of natural killer activity by lesioning of the anterior hypothalamus.
Placement of bilateral electrolytic lesions in the preoptic-anterior hypothalamic area (AHT) of Fischer 344 rats results in decreased splenic NK activity as compared to control and normal animals. Animals with AHT lesions have a decrease in NK activity 4 and 7 days after lesion placement, with a return to normal activity by day 14. Fractionation of spleen cells on glass bead columns results in nonadherent and adherent cell fractions with NK activity. AHT lesions affect NK activity only in the adherent cell fraction. The removal of macrophages from this cell fraction did not restore NK activity. Moreover, this NK activity is not the result of cytotoxic macrophages. Hypophysectomy decreases NK activity in lesioned and non-lesioned animals, suggesting the influence of pituitary factors. These data indicate that the anterior hypothalamus is capable of modulating the cytotoxic activity of NK cells. Thus, neuroimmunomodulation may be a potential factor in susceptibility to some disease states such as viral infections and neoplasia.
Animals↗
Immunobiology of primary intracranial tumors. VI. Suppressor cell function and lectin-binding lymphocyte subpopulations in patients with cerebral tumors.
Peripheral blood lymphocytes obtained from patients with primary intracranial tumors were assessed for the presence of Concanavalin-A-activated, glass-adherent, and spontaneous, nonspecific suppressor cells. Additionally, the effect of indomethacin on phytohemagglutinin (PHA)-induced blastogenesis was determined. No significant differences in cellular suppressor mechanisms in these patients and normal controls were observed. However, shifts in lymphocyte populations were demonstrable when cells were separated according to quantification of PHA-L surface binding sites by flow microfluorometry. Therefore, although impaired cellular responsiveness in patients with cerebral neoplasms does not appear to be due to alterations in suppressor-cell function, changes in lymphocyte subpopulations occur that may be induced as an immunobiological consequence of primary central nervous system neoplasia and contribute to suppressed host immunocompetence.
Adult↗
Neuroimmunomodulation: neural anatomical basis for impairment and facilitation.
Rats with bilateral electrolytic lesions of specific limbic nuclei show alterations in lymphoid cell number and in lymphocyte activation induced in vitro by concanavalin A (Con A). The number of splenocytes decreases after lesioning in the anterior hypothalamus (p less than 0.001), ventromedial hypothalamus (p less than .0.2), and mamillary bodies (p less than. 0.001). The number of thymocytes decreases after lesioning of the anterior hypothalamus (p less than 0.001) and increases after hippocampal lesioning (p less than 0.001). Spleen cell responsiveness to con A decreases subsequent to lesioning of the anterior hypothalamus, whereas reactivity was enhanced after lesion placement in the mamillary bodies (p less than 0.002), hippocampus (p less than 0.001), and amygdaloid complex (p less than 0.001). Thymocyte mitogen reactivity is increased by lesions of the hippocampus (p less than 0.001) and amygdaloid complex (p less than 0.001). These effects manifest themselves maximally 4 days after lesioning, with a return to normal by day 14. These preliminary data indicated that quantitative and qualitative lymphocyte functions are altered by ablation of selected brain nuclei, thereby suggesting the presence of neural modulation of immune function.
Amygdala↗
Hypothalamic-immune interactions. Effect of hypophysectomy on neuroimmunomodulation.
Electrolyte destruction of certain nuclei of the brain cause specific structural and functional changes in the immune system. Lesions in the preoptic-anterior hypothalamic area result in thymic involution and a decrease in the number and blastogenic reactivity of splenocytes. In contrast, lesions in the hippocampus increase thymic and splenic mitogenic responsiveness and cellularity. Hypophysectomy abrogates all changes in splenocyte number and function induced by hypothalamic and limbic lesions. The effects of ablating the hippocampus and amygdaloid complex on thymocyte number and function also are abolished. Hypothalamic lesions in hypophysectomized animals result in an increase in the number of thymocytes but suppressed mitogenic activity. These data indicated that neuroimmunomodulation is mediated predominantly but not exclusively by the pituitary gland.
Animals↗
Hypothalamic-immune interactions. II. The effect of hypothalamic lesions on the ability of adherent spleen cells to limit lymphocyte blastogenesis.
Animals with electrolytic pre-optic and anterior hypothalamic (AHT) lesions show impaired mitogen-induced lymphocyte blastogenesis which is restored by removal of a population of spleen cells with macrophage-like properties. Although suppressor macrophages are detectable in normal and control rats, substantially more activity is present following AHT destruction. Abrogation of lymphocyte activation does not result from increased numbers of splenic macrophages. These data indicate that one mechanism by which neuroimmunomodulation occurs is by induction of a qualitative alteration in the function of naturally occurring suppressor macrophages.
Animals↗
T-lymphocyte heterogeneity in rat: role of adherent T-cell subpopulation in the regulation of cytotoxic T-cell response to alloantigens.
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Animals↗
Immunobiology of primary intracranial tumors. Part 5: Correlation of a lymphocyte index and clinical status.
Long-term assessment of general host immunocompetence of patients with primary malignant brain tumors indicates that although isolated determinations of nonspecific responsiveness are not clinically useful, sequential analyses utilizing a linear combination of in vitro lymphocyte probes are capable of predicting tumor recurrence prior to clinical deterioration.
Adult↗
Lymphocyte subpopulations and responsiveness in rats bearing intracranial tumors induced by avian sarcoma virus.
The mitogenic responsiveness of peripheral blood lymphocytes obtained from Fischer 344 rats inoculated with avian sarcoma virus was studied. In addition, quantitative alterations in lymphocyte subpopulations were determined in these animals. Only peripheral blood lymphocytes from rats bearing astrocytomas had significantly diminished responses to concanavalin A when compared to control responses. The percentage of lymphocyte subpopulations detected in either the peripheral blood or spleen of tumor-bearing rats did not differ from values obtained with control rats. However, rats bearing astrocytomas had a marked decrease in the absolute number of the various lymphocyte subpopulations as a result of lymphopenia. Neither the sarcoma-bearing rats nor the virus-inoculated rats that did not develop tumors exhibited this lymphopenia. In addition, sera from rats bearing astrocytomas diminished the concanavalin A reactivity of spleen cells obtained from normal rats. The results of this study establish the avian sarcoma virus-induced rat astrocytoma model as a useful immunological parallel for the human disease.
Animals↗
Hypothalamic-immune interactions. I. The acute effect of anterior hypothalamic lesions on the immune response.
Rats with electrolytic anterior hypothalamic lesions show changes in lymphoid tissue cellularity and a decrease in the response to concanavalin A (Con A). This effect manifests itself maximally 4 days after lesioning, with a return to normal by day 14. The changes are not mediated through the release of corticosteroids. These data indicate the presence of a neuroendocrine pathway that is capable of modulating immune function.
Animals↗
Immunobiology of primary intracranial tumours. III. Demonstration of a qualitative lymphocyte abnormality in patients with primary brain tumours.
Peripheral blood lymphocytes obtained from patients with primary intracranial tumours respond poorly when stimulated with phytohaemagglutinin (PHA) as compared to lymphocytes from control subjects. This defect could not be corrected by employing purified thymus-derived lymphocytes (T cells) obtained from the peripheral blood of these patients. Moveover, neither increasing the number of lymphocytes placed in culture nor the duration of culture (3-6 days) corrected the defect. Preincubation of these lymphocytes for 24 hr in media supplemented with human AB sera followed by stimulation with PHA did not result in an increase in blast transformation when compared to cells which were not preincubated. However, when the percentage of sheep red blood cell rosetting lymphocytes was determined in a similar type of experiment a marked decrease in the ability of lymphocytes from patients with brain tumours to form rosettes was noted. Quantitation of the number of L-PHA binding sites on lymphocytes from patients with brain tumors revealed that these lymphocytes had approximately twice as many receptor sites per cell as did control lymphocytes suggesting either membrane alterations or changes in lymphocyte subpopulations.
Adult↗