Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor.

Tumor immunity in patients with primary intracranial tumors was assessed in relation to the general status of host immunocompetence. Lymphocyte sensitization to tumor-specific membrane antigens was demonstrated by the proliferative response of lymphocytes in the presence of autochthonous tumor cells. Paradoxically, one-half of the patients could not be sensitized to a primary antigen, dinitrochlorobenzene; existing delayed hypersensitivity was also depressed, as measured by skin tests and lymphocyte transformation in response to common antigens. A heat-stable factor in patients' sera blocked cell-mediated tumor immunity. In addition, these "enhancing" sera consistently suppressed the blastogenic response of autologous and homologous lymphocytes to phytohemagglutinin and to membrane antigens on allogeneic cells in the one-way mixed lymphocyte culture. When patients' leukocytes were washed and autologous plasma replaced with normal plasma, reactivity in the mixed lymphocyte culture increased to normal values. In vitro immunosuppressive activity in patients' plasma or sera correlated with depressed delayed hypersensitivity. After removal of the tumor, suppressor activity disappeared. IgG fractions of patient sera contained strong immunosuppressive activity. These data suggest that the suppressor factor may be an isoantibody elicited by the tumor that also binds to receptors on the lymphocyte membrane. In addition to specifically blocking cell-mediated tumor immunity, enhancing sera may broadly depress host immunocompetence.

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.

General immunocompetence of rats bearing avian sarcoma virus-induced intracranial tumors.

The mitogenic responsiveness of spleen cells obtained from avian sarcoma virus-inoculated Fischer 344 rats was studied. Sixty % of the rats had astrocytomas, 13% had sarcomas, 7% had mixed gliosarcomas, and 20% had no evidence of tumors. Only spleen cells from rats bearing astrocytomas had significantly diminished responses to phytohemagglutinin and concanavalin A (Con A) when compared to control responses. The decreased responsiveness observed with phytohemagglutinin was limited to the optimal concentration range (10 and 20 microgram) while a broader concentration of Con A (0.01 to 50 microgram) induced significant suppression. Moreover, a more profound immunosuppression was observed with Con A. The results also demonstrated that spleen cells from rats with the largest astrocytomas exhibited the greatest suppression. From the results of this study, it appears the avian sarcoma virus-induced astrocytoma in rats is an immunological parallel of the human disease based on the loss of general immunological competence as assessed by responsiveness of lymphocytes to phytohemagglutinin and Con A.

Epigenetic modifications in salivary glands from patients with Sjögren's syndrome affect cytokeratin 19 expression.

Sjögren's syndrome (SS) is a chronic autoimmune epithelitis, and several lines of experiments indicate that multifactorial factors contribute to salivary gland epithelial cells (SGEC) dysfunctions including a combination of environmental factors, lymphocytic infiltrations, genetic predispositions as well as epigenetic defects. Such statement is reinforced by the observation that global DNA methylation (5MeCyt) is altered in minor salivary glands from pSS patients and that such defect is associated cytokeratin 19 (KRT19) overexpression. An epigenetic deregulation of the KRT19 gene was further tested by treating the human salivary gland (HSG) cell line with the DNA demethylating agent 5-azacytidin, and with the histone acetylase inhibitor trichostatin A. Blocking DNA methylation, but not histone acetylation, with 5-azacytidin was associated with KRT19 overexpression at both transcriptional and protein level. Next, analysis of the CpG genome-wide methylome array in the KTR19 locus from long term cultured SGEC obtained from 8 pSS patients revealed a more reduced DNA methylation level in those patients with defective global DNA methylation. Altogether, our data, therefore, suggest that alteration of DNA methylation in SGEC may contribute to pSS pathophysiology in part by controlling the expression of KRT19.

Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital.

OBJECTIVES: The goal of this study was to determine whether carotid angioplasty and stenting (CAS) is equivalent to carotid endarterectomy (CEA) in patients with symptomatic carotid stenosis >70% by a randomized, controlled trial in a community hospital. BACKGROUND: Carotid angioplasty and stenting has been suggested to be as effective as CEA for treatment of symptomatic carotid artery stenosis. METHODS: A total of 104 patients presenting with cerebrovascular ischemia ipsilateral to carotid stenosis were selected randomly for CEA or carotid stenting and followed for two years. RESULTS: Stenosis decreased to an average of 5% after CAS. The patency of the reconstructed artery remained satisfactory regardless of the technique as determined by sequential ultrasound. One death occurred in the CEA group (1/51); one transient ischemic attack occurred in the CAS group (1/53); no individual sustained a stroke. The perception of procedurally related pain/discomfort was similar. Hospital stay was similar, although the CAS group tended to be discharged earlier (mean = 1.8 days vs. 2.7 days). Complications associated with CAS prolonged hospitalization when compared with those sustaining a CEA-related complication (mean = 5.6 days vs. 3.8 days). Return to full activity was achieved within one week by 80% of the CAS group and 67% of the patients receiving CEA. Hospital charges were slightly higher for CAS. CONCLUSIONS: Carotid stenting is equivalent to CEA in reducing carotid stenosis without increased risk for major complications of death/stroke. Because of shortened hospitalization and convalescence, CAS challenges CEA as the preferred treatment of symptomatic carotid stenosis if a reduction in costs can be achieved.

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.

Treatment for patients with cerebral metastases.

To establish the effectiveness of treatment of patients with intracranial metastatic neoplasms, a retrospective study of survival of patients who had surgical excision, irradiation, or chemotherapy was compared with survival of patients who received no treatment. Our results indicate that although any form of therapy was superior to no treatment, no modality was clearly better than another. Furthermore, the prognosis for survival of patients with solitary lesions from a known primary was only slightly better than that of patients with numerous metastases. The prognosis was slightly improved when the cerebral lesion was detected before finding the primary site of origin. These observations should be considered when planning treatment for patients with brain metastases.

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.

A heat-stable blocking factor in the plasma of patients with subacute sclerosing panencephalitis.

The possible role of a defective cell-mediated immune response in the pathogenesis of subacute sclerosing panencephalitis remains unclear. Cell-mediated immunity has been investigated in nine patients with this disorder. In eight patients, a heat-stable blocking factor in the plasma inhibited normal lymphocyte transformation to phytohemagglutinin and mixed lymphocyte cultures. The degree of blocking increased as the disease progressed. The nature of the blocking factor is unknown and is currently under investigation. A heat-stable blocking factor has not been described previously in subacute sclerosing panencephalitis, althouth a heat-labile blocking factor has been reported in a total of five patients.

Effects of preincubating human peripheral blood lymphocytes on their ability to bind sheep red blood cells.

The effect of preincubating human peripheral lymphocytes at 37 degrees C or 4 degrees C various lengths of time on their subsequent ability to form rosettes with sheep red blood cells (SRBC) was investigated. Lymphocytes suspended in either medium or medium containing fetal calf serum (FCS) and preincubated at 37 degrees C for 30 min exhibited marked decrease in rosette formation with a return to normal values by 120 min. However, neither lymphocytes suspended in medium and preincubated at 4 degrees C nor lymphocyte suspended in medium containing normal human serum (HS) and preincubated at 37 degrees C exhibited this phenomenon.

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.

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.

cAMP accumulation in T-cells inhibits anti-CD3 monoclonal antibody-induced actin polymerization.

The results presented in this report offer a novel explanation for how stimulation of the beta-adrenergic receptor (beta AR) inhibits the ability of T cells to proliferate after interaction with immobilized anti-CD3 monoclonal antibody (mAb). Accordingly, T cells binding to immobilized anti-CD3 mAb but not anti-CD4 mAb undergo time-dependent F-actin assembly with concomitant formation of pseudopodia. This process is completely inhibited in the presence of isoproterenol (ISO) indicating that stimulation of the beta AR on T cells interferes with the biochemical processes responsible for the assembly of actin. To confirm these observations, we quantitated the formation of F-actin in T cells stimulated with immobilized anti-CD3 mAb in the presence of cAMP elevating agents. The results show that stimulation of the beta AR on T-cells, as well as the addition of forskolin or dibutyryl cAMP, abrogates the formation of F-actin.

Immune defects observed in patients with primary malignant brain tumors.

Malignant glioblastomas (gliomas) account for approximately one third of all diagnosed brain tumors. Yet, a decade of research has made little progress in advancing the treatment of these tumors. In part this lack of progress is linked to the challenge of discovering how glial tumors are capable of both modulating host immune function and neutralizing immune-based therapies. Patients with gliomas exhibit a broad suppression of cell-mediated immunity. The impaired cell-mediated immunity observed in patients with gliomas appears to result from immunosuppressive factor(s) secreted by the tumor. This article reviews what has been elucidated about the immune defects of patients harboring glioma and the glioma-derived factors which mediate this immunosuppression. A model involving systemic cytokine dysregulation is presented to suggest how the immune defects arise in these individuals.

Insulin-like growth factors (IGF) enhance three-dimensional (3D) growth of human glioblastomas.

Human glioblastomas (gliomas) are characterized as rapidly growing brain tumors which are highly invasive but rarely metastatic. Human gliomas synthesize and secrete increased levels of insulin-like growth factors (IGFs) as well as expressing increased numbers of IGF receptors when compared to normal brain tissue. These observations suggest the existence of an IGF-mediated autocrine mechanism for glioma growth regulation. The purpose of this study was to examine the effect of human recombinant IGF (hrIGF) treatment on the in vitro growth of human glioma monolayer and three-dimensional (3D) multicellular spheroid cultures. The data demonstrate that hrIGF-I treatment of glioma cell lines slightly enhanced tumor monolayer proliferation as measured by [(3)H]thymidine incorporation. In contrast, treatment of glioma spheroids with hrIGF-I or hrDes(1-3)IGF-I, the truncated brain form of IGF-I, dramatically enhanced 3D tumor growth with a 1.5-2-fold reduction in spheroid doubling time (FRSDT). In addition, IGF-treated glioma spheroids were more densely packed than spheroids grown in media alone with no observed necrosis. These data suggest that IGFs will dramatically enhance glioma proliferation when 3D cell-cell contact occurs. This observed enhancement suggests that IGFs both synthesized in the brain and systemically support rapid proliferation of gliomas in vivo.

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.

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.

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)

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.

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.