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W H Brooks

Publications and source records attributed to W H Brooks.

At least 37 records · Page 2Linked to original sources
PubMed1993

Modulation of T cell proliferation by stimulation of the beta-adrenergic receptor: lack of correlation between inhibition of T cell proliferation and cAMP accumulation.

The presence of beta-adrenergic receptors on T cells suggests the potential for modulating T cell function upon binding of an appropriate agonist. Utilizing highly purified human T cells we assessed the proliferative capacity of T cells upon stimulation with immobilized anti-CD3 monoclonal antibody (mAb) in the presence of the beta-adrenergic agonist isoproterenol (ISO). The proliferative response of T cells and their CD4+, CD8+, or CD45RO+ subsets to anti-CD3 mAb was inhibited in a dose-dependent manner by ISO. In parallel experiments, various concentrations of prostaglandin E2 (PGE2) were added to anti-CD3 mAb-stimulated T cells and their subsets. Similar dose-dependent effects were observed with the important exception that PGE2 was considerably more immunosuppressive than ISO. The results also showed that PGE2 was a much more effective inhibitor of anti-CD3 mAb-induced interleukin 2 synthesis by T cells than was ISO. Because both the beta-adrenergic and PGE2 receptors are linked to adenylyl cyclase, the magnitude and kinetics of cAMP accumulation in T cells and their subsets were determined after stimulation with ISO or PGE2. The results show that PGE2 induced a greater and more sustained accumulation of cAMP than ISO. Moreover, these differences could not be ascribed to differential modulation of cAMP phosphodiesterase activity. Correlation of the degree of inhibition of anti-CD3 mAb-induced T cell proliferation by PGE2 or ISO with the level of accumulation of cAMP in these stimulated T cells indicate that, on an equimolar basis, cAMP elicited by PGE2 is more immunosuppressive than that induced by ISO. These results suggest that qualitative differences in cAMP accumulation in T cells have an important role in the subsequent modulation of anti-CD3 mAb-induced T cell proliferation.

CD3 Complex↗
PubMed1992

Suppression of high affinity IL-2 receptors on mitogen activated lymphocytes by glioma-derived suppressor factor.

Previously we have reported that human glial tumor cells secrete a factor(s) which suppresses the mitogen responsiveness of normal human peripheral blood lymphocytes (PBL) in a dose dependent manner. In this study we extend these observations and explore the possible mechanisms by which glioma-derived suppressor factor(s) (GSF) modulates lymphocyte reactivity. Preincubation of lymphocytes with GSF for 2 hrs induces suppression of lymphocyte mitogen responsiveness. GSF also inhibits production of interleukin-2 (IL-2) by mitogen activated human T-cells. Addition of delectinated or recombinant IL-2 to mitogen activated human T-cells in the presence of GSF does not restore the normal proliferative response of these cells. These findings suggest that GSF induces a defect in the expression of the receptor for IL-2 (IL-2R) on activated T-cells. Binding studies with radiolabeled IL-2 demonstrated that GSF suppresses and in some cases completely inhibits the expression of functional high affinity IL-2R on activated T-cells, thereby, preventing association of IL-2R with its receptor and the subsequent progression of the cell into the proliferative stage of the cell cycle. These cellular defects induced by GSF closely parallel the observed defects noted in T-cells obtained from patients with gliomas, indicating that the factors elicited from glial tumors may be responsible for the immunological deficits observed in patients with primary malignant intracranial tumors.

Animals↗
PubMed1990

Inability of mitogen-activated lymphocytes obtained from patients with malignant primary intracranial tumors to express high affinity interleukin 2 receptors.

Patients with primary malignant brain tumors manifest a variety of abnormalities in cell-mediated and humoral immunity. Diminished T cell reactivity has been shown in these patients to be linked to deficiencies in interleukin 2 (IL-2) production that cannot be overcome by exogenous IL-2. In this study, specific binding of radiolabeled IL-2 to PHA-stimulated lymphocytes from brain tumor patients demonstrates that the number of high affinity interleukin 2 receptors (IL-2R) is greatly reduced. FACS analysis indicates that the relative density of the p55 protein (Tac protein) is lower on the mitogen-activated lymphocytes obtained from patients than on comparably treated lymphocytes from normal individuals. These data indicate that mitogen-stimulated lymphocytes obtained from patients have fewer functional high affinity IL-2R principally because of the failure to express sufficient levels of the p55 protein for association with the p75 protein. Northern analysis of total RNA isolated from mitogen-stimulated T cells from patients demonstrates normal levels of steady state mRNA, which codes for the p55 protein. Moreover, there is no defect in the postranslational processing of the primary translation product of this mRNA suggesting that normal levels of the p55 protein are produced in activated T cells from patients.

Brain Neoplasms↗
PubMed1990

Common injuries in horseback riding. A review.

The most common location of horse-related injuries is the upper extremity (24% to 61%) with injuries to the lower extremity second in frequency (36% to 40%). The head and face sustain 20% of horse-related injuries. The most common type of injury is a soft tissue injury (92% to 1%), followed by a fracture (57% to 3%). Concussion is the third most common type of injury (63% to 2%). The most frequent cause of hospitalisation is concussion (38% to 4%) with fracture second. The most common injury which leaves residual impairment is injury to the central nervous system. The age at which most injury occurred is less than 21 years. In the latest NEISS report (1987-1988), injuries have decreased in the younger riders, but have increased in the older riders (above 24 years). More women are injured than men, but over the age of 44 years more men are injured than women, with the difference more marked in the 1987-1988 NEISS report. Previous horse-related injuries are reported frequently (37% to 25%). In mortality studies from Australia and the United States, head injuries caused the majority of deaths (78% and 60%), followed by chest injuries (9%). In the Australian study each sex had 50% of the deaths. In the United States, 60% were male, 40% female. Above the age of 24 years male deaths increasingly predominate, being 15 male deaths to 1 female above the age of 64. Concussion is divided into 3 divisions of severity which require different medical evaluation and treatment: mild in which rider is stunned or disoriented for a brief period; moderate in which there is loss of consciousness for less than 5 minutes; and severe in which there is a loss of consciousness for more than 5 minutes. Investigative need is cited in the areas of previous horse-related injury, lessons, experience vs knowledge, epilepsy, drowning, gender, deaths, safety helmets, stirrups, and body protectors. No horse is a safe horse; some are safer than others but the horse is a potentially lethal animal. Prevention of accidents and injuries is dependent upon using knowledge previously obtained from studying horse activities. Much more information is available than in the past through the medical studies that have been done and the recommendations made by these investigators. The medical community has a responsibility to educate the horse riding public and to participate in investigations requested by the horse organizations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Neurotransmitter-lymphocyte interactions: dual receptor modulation of lymphocyte proliferation and cAMP production.

Stimulation of the beta-adrenergic receptor on lymphocytes can decrease the proliferative response of these cells to mitogens. We have found that simultaneous stimulation of T cells with the beta-adrenergic agonist isoproterenol and mitogens (phytohemagglutinin (PHA) and OKT3 monoclonal antibody) results in a 2- to 4-fold increase in cAMP production compared to cells exposed to isoproterenol alone. Mitogens alone have little effect on cAMP synthesis, but do activate the phosphatidylinositol (PI) cycle, suggesting that interactions may be occurring between the second messenger systems resulting in a cAMP synergy. Further experiments suggest that calcium may be involved in inducing the cAMP synergy observed in T cells. It is proposed that the synergy between beta-adrenergic and mitogenic stimulation of T cells for cAMP may be involved in the mechanism of catecholamine modulation of lymphocyte function.

Cyclic AMP↗
PubMed1988

Specific uptake of serotonin by murine macrophages.

In view of the reported immunomodulatory properties of the monoaminergic neurotransmitter, serotonin (5HT), this study aimed to assess whether 5HT specifically associates with immunocompetent cells. Although murine splenocytes appear to lack high-affinity membrane binding sites for 5HT, they do possess a specific, active, 5HT uptake system similar in affinity (Km = 40 nM) to that described in platelets. This uptake system appears to be confined to macrophages. Further, macrophages rapidly metabolize 5HT to its 5-hydroxyindole acetic acid metabolite. Specific uptake of serotonin by macrophages may thus constitute an important mechanism whereby this amine is able to regulate immune function.

Animals↗
PubMed1987

Modulation of T-suppressor cell activity by central nervous system catecholamine depletion.

This study extends our previous findings, which indicate that depletion of CNS catecholamines has a marked inhibitory effect on humoral immune responsiveness. These data show that depletion of CNS catecholamines by injection of 6-hydroxydopamine (6-OHDA) into the cisterna magna in conjunction with immunization enhances the activity of a population of splenic T-suppressor cells as evidenced by the transfer of these cells to normal recipients. Increased suppressor cell activity does not result solely from 6-OHDA treatment, but rather requires concomitant immunization. Further characterization shows that these suppressor cells are not antigen specific. Hypophysectomy abrogates the effects of 6-OHDA injection suggesting that catecholamine depletion modulates immune function via the release of pituitary hormones. Thus, depletion of CNS catecholamines impairs immune responsiveness by inducing enhanced T-suppressor cell activity, providing additional evidence of the involvement of the CNS in regulation of immune responsiveness.

Animals↗
PubMed1987

Activation of immunoregulatory lymphocytes obtained from patients with malignant gliomas.

The responsiveness of T cells and their subsets (T-helper cells and T-suppressor cells) obtained from patients with malignant gliomas was evaluated in an effort to further define the mechanism of their impaired host immunocompetence. This study demonstrates that peripheral blood lymphocytes obtained from these patients have impaired responsiveness to a variety of mitogens including phytohemagglutinin, concanavalin A, pokeweed mitogen, and anti-T3 monoclonal antibody. The impaired lymphocyte responsiveness does not result from the inability of these cells to express receptors for a specific mitogen or antibody. The mitogenic responsiveness of purified T cells is markedly reduced when compared to values obtained from control subjects. Therefore, the decreased T cell reactivity of patients with malignant gliomas does not result simply from a diminution in the absolute number of potentially responding lymphocytes. The mitogen reactivity of the T cell subsets, CD4+ helper cells, and CD8+ cytotoxic/suppressor cells was also investigated. These results demonstrate that the responsiveness of the CD4+ T-helper cell subset obtained from these patients is consistently diminished as compared to control values. In contrast, the reactivity of the CD8+ T cell subset was not nearly as dramatically impaired. Thus, these results indicate that the proliferative defect observed in T cells obtained from patients is located predominantly in the T-helper cell subset. Functional deficiencies in this important subpopulation of T lymphocytes may explain, in part, the presence of depressed immune responsiveness in patients with malignant glial tumors.

Adolescent↗
PubMed1987

Inhibition of lymphocyte responsiveness by a glial tumor cell-derived suppressive factor.

The results of this study demonstrate the presence of suppressive factor(s) in the tissue culture supernatants of cloned and freshly explanted malignant glioma cells. Culture supernatants obtained from these glial cell lines were demonstrated to have potent suppressive activity as evidenced by their ability to inhibit the proliferative response of normal human peripheral blood lymphocytes induced by phytohemagglutinin and anti-OKT3 monoclonal antibodies. The results further demonstrate the existence of a dose-response relationship between these supernatants and inhibition of mitogen-induced lymphocyte activation. Maximum production of suppressive activity by glial tumor cells was dependent on: 1) the number of tumor cells seeded in culture, 2) whether fetal calf serum was present, and 3) the duration of culture. The production of the suppressive factor(s) was not inhibited by the addition of inhibitors of prostaglandin E synthesis. Experiments designed to determine at what time during lymphocyte activation the suppressive factor was most effective demonstrated that the culture supernatants must be added during the first 24 hours of culture to exhibit inhibitory properties. Finally, proliferation of both the T-helper and T-suppressor/cytotoxic subsets was equally well inhibited by the glial tumor cell culture supernatants.

Brain Neoplasms↗
PubMed1986

Neuroimmunomodulation: impairment of humoral immune responsiveness by 6-hydroxydopamine treatment.

Previous studies from this laboratory and others show that perturbations of the central nervous system modulate immune function. In addition, reports from several investigators indicate that depletion of the neurotransmitter norepinephrine (NE) in peripheral nerves by injecting the neurotoxin 6-hydroxydopamine (6-OHDA), can enhance or suppress the antibody response. However, immunocompetence following brain depletion of catecholamines has not been investigated. In this study, we investigated the effects of injecting 6-OHDA into the cisterna magna of male CBA/J mice, and determined the effects of this treatment on both the IgM and IgG antibody responses to sheep red blood cells (SRBC). Both responses are suppressed compared to saline-injected control or normal animals. Animals treated with 6-OHDA have decreased levels of NE in the midbrain, pons-medulla and hypothalamus, while dopamine levels did not change in these brain regions but was decreased in the striatum. The percentage of splenic T cells and B cells was not affected by 6-OHDA treatment. Although there is a marked increase in plasma corticosterone levels in 6-OHDA-treated mice, saline-injected control animals have equivalent increases in plasma corticosterone without concomitant impairment of the immune response. Thus, the decline in immune responsiveness following 6-OHDA treatment does not result from corticosterone-induced immunosuppression. Analysis of the kinetics of the primary IgG response following 6-OHDA treatment indicates that the magnitude, but not the kinetics, of the response decreases. Experiments to determine the effects of 6-OHDA on the afferent and efferent phrases of the response demonstrate that it is effective only when administered prior to immunization, and thus must inhibit early events involved in the initiation of the response. Additional experiments show that mice can be immunized 2 weeks following brain catecholamines depletion and still exhibit a decreased antibody response. However, the response returns to normal levels if immunization is delayed 4 weeks after injection. Further experiments demonstrated that 6-OHDA treatment has no effect on the secondary antibody response, but does inhibit the development of immunological memory. Collectively, these results indicate that 6-OHDA treatment has a profound inhibitory effect on the induction of the primary antibody response and immunological memory development, but is without effect on the secondary antibody response. The data further substantiate the existence of a link between the brain and the immune response.

Animals↗
PubMed1985

Neural modulation of immune function.

In this report we review our hypotheses and approaches to the study of the relationship between the central nervous and immune systems. Discussed are results pertaining to the modulation of immune parameters resulting from perturbations of the brain employing electrolytic lesions and the neuroleptic 6-hydroxydopamine. Experiments describing the central and peripheral effects of serotonin on in vivo and in vitro immune responses are also discussed.

Animals↗
PubMed1985

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↗
PubMed1985

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↗