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T L Roszman

Publications and source records attributed to T L Roszman.

At least 37 records · Page 2Linked to original sources
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

Transplantation of pituitary grafts fail to restore immune function and to reconstitute the thymus glands of aged mice.

There is evidence to indicate that the neuroendocrine and immune systems can interact. Thus, neuroendocrine hormones can modulate a variety of immune functions and there have been attempts to manipulate the neuroendocrine system of aged animals to enhance immune function. We have previously shown that the transplantation of a syngeneic pituitary gland under the kidney capsule of young adult mice elevates serum prolactin and enhances immune responsiveness. In the present study pituitary glands were transplanted under the kidney capsule of 22-month-old mice to determine if this maneuver can enhance a number of immunologic parameters. The results demonstrate that aged animals bearing transplanted pituitary grafts for 10 days did not exhibit any enhancement in their primary antibody response to sheep red blood cells, splenic T or B-cell mitogen responsiveness or restoration of thymic architecture. When these immunologic assessments are performed on animals bearing pituitary grafts for 28 days, the IgM and IgG primary antibody responses and splenic T-cell responsiveness are enhanced but repopulation of the thymus still does not occur. Importantly, this enhancement does not restore immunocompetence to levels observed in young mice.

Aging↗
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↗
PubMed1989

Potentiation of antibody responsiveness after the transplantation of a syngeneic pituitary gland.

Transplantation of a pituitary graft under the kidney capsule and the resulting elevation of serum prolactin enhances the primary humoral antibody response to sheep red blood cells. Enhancement of the response is not due to marked changes in the percentage of T-cells and their subsets, B-cells, or the number of nucleated spleen cells. Quantitation of serum prolactin levels correlates well with the proportion of enhancement as mice with two grafts and higher levels of prolactin have increased responsiveness compared to mice with one graft. Systemic administration of mouse prolactin at the time of immunization also enhances the humoral immune response; however, if prolactin treatment is delayed and given 24 h after immunization, no potentiation of the response occurs. Thus, prolactin is enhancing the immune response by affecting an early afferent event in the induction of the immune response.

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↗
PubMed1988

Central catecholamine depletion impairs in vivo immunity but not in vitro lymphocyte activation.

We have previously shown that depletion of central nervous system (CNS) catecholamines by injecting the neurotoxin 6-hydroxydopamine (6-OHDA) into the cisterna magna of C57B1/6 mice markedly impairs the humoral immune response to sheep red blood cells. This work extends these observations by showing that 6-OHDA treatment also inhibits the humoral antibody response to the T-cell-dependent antigen trinitrophenyl-keyhole limpet hemocyanin, but does not affect the response to the T-independent antigen trinitrophenyl-lipopolysaccharide. This treatment also impairs humoral responsiveness at peripheral lymphoid sites in addition to inhibiting natural killer cell activity. However, 6-OHDA treatment in vivo does not affect in vitro mixed lymphocyte responsiveness, mitogen-induced lymphocyte activation or antigen presentation by macrophages.

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

Some parameters of conditioned immunosuppression: species difference and CS-US delay.

Three experiments were conducted in which an illness-inducing immunosuppressant, cyclophosphamide (an unconditioned stimulus, US) was associated with a previously presented saccharin solution conditioned stimulus (CS). In each experiment, reexposure to the CS produced a conditioned suppression of the plaque-forming-cell response in the experimental groups. Experiment I demonstrated this result with Fisher 344 rats. Experiment II replicated the effect with Balb/c mice. In Experiment III conditioned immunosuppression was demonstrated when mice received CS-US delays as long as 6 hours. No evidence of a delay gradient was present in either the behavioral or the immunologic data. These parallel findings offer no support for the idea of a dissociation between the taste aversion and conditioned immunosuppression processes.

Analysis of Variance↗
PubMed1986

Booster effect in delayed hypersensitivity skin testing.

After a pilot study had suggested that a drug augmented delayed hypersensitivity, we conducted a control study in which 19 normal volunteers had the same skin test battery applied as in the pilot study, on two occasions one month apart with no intervening treatment. No change was observed in delayed hypersensitivity response to PPD, Candida, or tetanus antigens. However, a significant decrease in response to mumps antigen was observed, and there was a marked "booster" or augmented response to SKSD antigen. These observations have implications for studies of immunomodulation and the mechanism of action of delayed hypersensitivity response.

Antigens↗
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

Failure of cimetidine as an immunomodulator in cancer patients and normal subjects.

Our pilot study of cimetidine as an immunomodulator in cancer patients showed no effect at clinically used doses on total blood, neutrophil, lymphocyte, or monocyte count, quantitative immunoglobulin, percentage of E-rosetting cells, phytohemagglutinin responses or delayed hypersensitivity responsiveness. We concluded that in clinically used doses, cimetidine produces no significant immunomodulation either in vivo or in vitro.

Adenocarcinoma↗