William H. Brooks

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.

Modulation of T-cell function by gliomas.

Patients with primary intracranial tumors (gliomas) exhibit a profound decrease in immunity, the mechanism of which has, until recently, remained obscure. Here Thomas Roszman, Lucinda Elliott and William Brooks reveal that T cells obtained from these patients exhibit defects in interleukin 2 secretion and in expression of the high-affinity IL-2 receptor and they discuss the role played by immunosuppressive factors produced by gliomas in inducing these defects.

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.

Differential compartmentalization of the calpain/calpastatin network with the endoplasmic reticulum and Golgi apparatus

Calpain, a calcium-activated cysteine protease, is involved in modulating a variety of cell activities such as shape change, mobility, and apoptosis. The two ubiquitous isoforms of this protease, calpain I and II, are considered to be cytosolic proteins that can translocate to various sites in the cell. The activity of calpain is modulated by two regulatory proteins, calpastatin, the specific endogenous inhibitor of calpain, and the 28-kDa regulatory subunit. Using velocity gradient centrifugation, the results of this study confirm and greatly expand upon our previous finding that the calpain/calpastatin network is associated with the endoplasmic reticulum and Golgi apparatus in cells. Moreover, confocal microscopy demonstrates that calpain II colocalizes with specific proteins found in these organelles. Additional experiments reveal that hydrophobic rather than electrostatic interactions are responsible for the association of the calpain/calpastatin network with these organelles. Treatment of the organelles with Na2CO3 or deoxycholate reveal that calpain I, 78-kDa calpain II, and the regulatory subunit are “embedded” within the organelle membranes similar to integral membrane proteins. Proteinase K treatment of the organelles shows that calpain I and II, calpastatin, and the regulatory subunit localize to the cytosolic surface of the organelle membranes, and a subset of calpain II and the regulatory subunit are also found within the lumen of these organelles. These results provide a new and novel explanation for how the calpain/calpastatin network is organized in the cell.

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.

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.

Calcium-dependent Signaling Pathways in T Cells POTENTIAL ROLE OF CALPAIN, PROTEIN TYROSINE PHOSPHATASE 1B, AND p130Cas IN INTEGRIN-MEDIATED SIGNALING EVENTS

Engagement of β1 integrin receptors initiates an increase in intracellular calcium concentrations in T cells, potentially affecting calcium-sensitive signaling pathways. The calcium-activated cysteine protease, calpain, regulates a variety of cell functions by calcium-dependent limited proteolysis. To investigate the function of calpain in T cells, we sought to determine the role of this protease in calcium-dependent signaling events. Subsequent to elevations in intracellular calcium concentrations induced by ionomycin or adherence to fibronectin, calpain activity translocated to the cytoskeletal/membrane fraction of T cells. In addition, stimulation of T cells with these agents initiated the proteolytic cleavage of protein tyrosine phosphatase 1B by calpain. Enzymatic cleavage of protein tyrosine phosphatase 1B occurs near the endoplasmic reticulum-targeting sequence and results in the generation of an enzymatically active form of the phosphatase. Furthermore, we show that both the native and the cleaved forms of protein tyrosine phosphatase 1B interact with p130Cas in T cells. This interaction may serve to relocate protein tyrosine phosphatase 1B to sites of focal contact resulting in potential interactions with substrates previously inaccessible to the endoplasmic reticulum-associated phosphatase. Thus, we describe a novel calcium-dependent signaling pathway in T cells that may mediate signals generated by β1 integrin adherence to the extracellular matrix.

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.

Melanin as a component of cerebral gliomas. The melanotic cerebral ependymoma

Even though melanin is found in certain central nervous system neurons and leptomeningeal melanocytes, gliomas rarely possess melanin. A few rare lethal melanotic medulloblastomas found typically in the cerebellar vermis of children have been described, but neuroglial cells have not been observed to contain this pigment. Since glial elements and the melanotic pigmented layer of the retina are derived from the same ciliated epithelium of the embryonic neural tube, recognition of melanin in a cerebral glioma was predictable. Indeed, melanin was observed in a cystic cerebral ependymal glioma from a 30‐year‐old woman, supporting the potential of glial cells to produce melanin.