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Biomedical subjects

J E Merrill

Publications and source records attributed to J E Merrill.

At least 55 records · Page 3Linked to original sources
PubMed1991

Natural and induced cytotoxicity of oligodendrocytes by microglia is inhibitable by TGF beta.

Blood macrophages and brain macrophages (microglia) have been implicated in demyelination and destruction of the oligodendrocyte in multiple sclerosis (MS), a disease affecting primarily white matter of the central nervous system (CNS). In this study, we demonstrate that at high effector to target cell ratios, normal rat microglia exhibit a natural cytotoxicity against normal rat oligodendrocytes in vitro. The killing is not mediated by the release of soluble factors. The cytotoxic activity is upregulated by pretreatment of microglia with interferon gamma (IFN gamma) or phorbol myristate acetate (PMA). Both the natural and induced cytotoxicities are inhibitable by transforming growth factor beta (TGF beta). The increase in numbers and apposition of primed or activated microglia to oligodendrocytes in MS lesions may give rise to natural or induced killing from which oligodendrocytes may be protected by TGF beta.

Animals↗
PubMed1991

Bellini, Carpaccio, and receptors in the central nervous system.

With the convergence of science from the fields of neurobiology and immunology, many exciting and challenging surprises have emerged regarding cytokines, neuroendocrine hormones, neuropeptides, excitatory amino acids, and their receptors. For some time neurobiologists have known that subsets of neural cells had different receptors for the same ligand. Those subsets of cells could be as different as neurons and astrocytes and as closely related as astrocytes from different lineages or anatomical areas. The neurobiological puzzle has been to determine the functional meaning of these differences. Immunologists in contrast have long understood the clear cut differences between T and B lymphocytes or T helper/inducer and T cytotoxic/suppressor cells and their response to cytokines. However, it is only very recently that they have discovered preferential use by these cells of different receptors for an identical cytokine ligand. Indeed, identical cytokines in the central nervous system and immune response may induce their pleiotropic responses by utilizing different receptors in these two systems. Immunologic paradigms may help neurobiologists predict the existence of subsets of neural cells and their function. Likewise, neurobiology may enable immunologists to predict roles for receptors in gene families as well as the existence of as yet unidentified receptors.

Animals↗
PubMed1991

Lymphokines and immunoregulatory molecules in subacute sclerosing panencephalitis.

Frozen brain specimens from six patients with subacute sclerosing panencephalitis (SSPE) were analyzed immunohistochemically for the presence of leukocyte subpopulations and specific cytokines. In brain regions demonstrating perivascular cell infiltration and gliosis, CD4 and CD8 positive cells were identified within the brain parenchyma. Cytokine analysis revealed cells staining positively for tumor necrosis factor-alpha and interferon-gamma. These results were similar to those observed in multiple sclerosis (MS) and progressive rubella panencephalitis tissue and were different from other predominantly noninflammatory neurologic diseases and normal controls. Although SSPE and MS differ significantly in their etiology and histopathology, the similarities in leukocyte and cytokine staining patterns suggest a common mechanism of disease progression.

Adolescent↗
PubMed1991

Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate.

Intercellular Ca2+ signaling in primary cultures of glial cells was investigated with digital fluorescence video imaging. Mechanical stimulation of a single cell induced a wave of increased [Ca2+]i that was communicated to surrounding cells. This was followed by asynchronous Ca2+ oscillations in some cells. Similar communicated Ca2+ responses occurred in the absence of extracellular Ca2+, despite an initial decrease in [Ca2+]i in the stimulated cell. Mechanical stimulation in the presence of glutamate induced a typical communicated Ca2+ wave through cells undergoing asynchronous Ca2+ oscillations in response to glutamate. The coexistence of communicated Ca2+ waves and asynchronous Ca2+ oscillations suggests distinct mechanisms for intra- and intercellular Ca2+ signaling. This intercellular signaling may coordinate cooperative glial function.

Animals↗
PubMed1991

HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease.

Hallmarks of central nervous system (CNS) disease in AIDS patients are headaches, fever, subtle cognitive changes, abnormal reflexes, and ataxia. Dementia and severe sensory and motor dysfunction characterize more severe disease. Autoimmune-like peripheral neuropathies, cerebrovascular disease, and brain tumors are also observed. Histological changes include inflammation, astrocytosis, microglial nodule formation, and diffuse de- or dysmyelination. Focal demyelination can also be seen. It is clear that AIDS-associated neurological diseases are correlated with greater levels of HIV-1 antigen or genome in tissues. In AIDS dementia, macrophages and microglial cells of the CNS are the predominant cell types infected and producing HIV-1. However, manifestations of the disease make it unlikely that direct infection by HIV-1 is responsible. It seems more likely that the effects are mediated through secretion of viral proteins or viral induction of cytokines that bind to glial cells and neurons. HIV-1 induction of such cytokines as interleukin 1 (IL 1) and tumor necrosis factor-alpha (TNF alpha) may lead to an autocrine feedback loop involving further productive virus replication and induction of other cytokines such as interleukin 6 (IL 6) and granulocyte-macrophage colony-stimulating factor (GMCSF). Interleukin 1 and TNF alpha in combination with IL 6 and GMCSF could account for many clinical and histopathological findings in AIDS nervous system diseases. As HIV-1 infected patients produce elevated levels of IL 1, TNF alpha, and IL 6, it will be important to make a formal connection between the presence of these factors in the CNS, which are all products of activated macrophages, astroglia, and microglia, their in vivo induction directly by virus or indirectly by virus-induced intermediates, and the clinical and pathological conditions seen in the nervous system in this disease.

AIDS Dementia Complex↗
PubMed1991

Effects of interleukin-1 and tumor necrosis factor-alpha on astrocytes, microglia, oligodendrocytes, and glial precursors in vitro.

Microglia and astrocytes undergo proliferative and differentiative changes in vivo after trauma or diseases such as multiple sclerosis (MS). Oligodendrocytes are destroyed in lesions in MS. Interleukin-1 (IL1) and tumor necrosis factor-alpha (TNF alpha) are involved in inflammation of the central nervous system and are elevated in MS. We have investigated the changes in cell morphology and cell number induced by IL1 and TNF alpha in purified and mixed populations of primary rat brain microglia, astrocytes, oligodendrocytes, and glial precursors. Depending on the target population, proliferation, differentiation, or inhibition of cultured cells was observed. The data also suggest that interactions among cell populations occur and support the hypothesis that IL1 and TNF alpha effects may be indirect, possibly through induction of other factors.

Animals↗
PubMed1990

Failure to detect human T-cell leukemia virus-related sequences in multiple sclerosis blood.

We tested 11 patients with multiple sclerosis for the presence of human T-cell leukemia virus type I (HTLV-I)- or type II (HTLV-II)-related sequences. DNA from blood mononuclear cells was analyzed by the polymerase chain reaction utilizing three different oligonucleotide primer pairs. Two of these primer pairs detect sequences shared between HTLV-I and HTLV-II in either p24, gag protein, or in p21, env transmembrane protein. The third primer pair was synthesized based on regions in the pol gene where amino acid sequences are conserved between HTLV-I, HTLV-II, and the related bovine leukemia virus. The multiple sclerosis samples were consistently negative while appropriate control samples were positive. We conclude that viruses related to HTLV-I, HTLV-II, or bovine leukemia virus are not present in the blood of patients with multiple sclerosis and, therefore, that HTLV-bovine leukemia virus-related viruses are not likely to be involved in the pathogenesis of multiple sclerosis.

Amino Acid Sequence↗
PubMed1989

Tumor necrosis factor identified in multiple sclerosis brain.

Frozen brain specimens from patients with multiple sclerosis (MS) and other neurologic diseases were analyzed using immunocytochemical techniques for the presence of TNF. In brain lesions in MS, and subacute sclerosing panencephalitis, TNF+ cells were demonstrated. At the lesion site in MS, TNF+ staining is associated with both astrocytes and macrophages. These observations were not made in Alzheimer's disease or normal brain tissue. The presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.

Astrocytes↗
PubMed1989

In vitro study of mediators of inflammation in multiple sclerosis.

Prostaglandin E levels have previously been demonstrated to be elevated in multiple sclerosis (MS). We have further investigated other products of activated macrophages related to inflammation. We report here on prostaglandin E and its relationship to interleukin 1, tumor necrosis factor, and leukotriene B4 produced by macrophages from blood and cerebrospinal fluid of MS patients and controls in vitro. Interleukin and tumor necrosis factor are elevated significantly after stimulation in MS, while leukotriene B4 production by blood macrophages is depressed compared to other neurological disease and normal healthy controls. In 40% of MS patients tested, peripheral blood macrophages spontaneously produced elevated levels of interleukin 1. All mediators of inflammation are produced in increased amounts by MS cerebrospinal fluid leukocytes after stimulation. Macrophages from MS blood are not as sensitive as controls to nonsteroidal inhibitors specific for lipoxygenase or cyclo-oxygenase pathways. Positive correlations of elevations in production of such mediators of inflammation as prostaglandin E, interleukin 1, and tumor necrosis factor in MS were significant. Elevated production of these mediators in combination with insensitivity to inhibitors of inflammation suggests a role for activated macrophages in the demyelination process.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

T cell lines established from multiple sclerosis cerebrospinal fluid T cells using human retroviruses.

Cerebrospinal fluid (CSF) lymphocytes from patients with multiple sclerosis (MS) were transformed with human T cell leukemia/lymphoma virus (HTLV I and HTLV II) and the resulting cell lines characterized by cell surface phenotyping and functional assessment. The lines were predominantly of the CD4 helper/induce phenotype although the HTLV II lines contained 10-20% CD8+ cells. The lines appeared to be activated cells; the majority were TA1+, HLA-DR+, and TAC+ (CD25+). Interestingly, they were OKT10- (CD38-). Functionally, the lines contained no natural killer (NK) activity and were modestly cytotoxic in the antibody-dependent cellular cytotoxicity (ADCC) assay. They were poor proliferative responders to antigens and mitogens though the HTLV II lines did respond to interleukin 2 (IL2). The HTLV I lines were either nonresponsive to or were suppressed by IL2. Early passages of two of the lines produced IL2 but this was lost as the cells were passed in culture. The cell lines were capable of either directly or indirectly suppressing pokeweed mitogen (PWM)-driven immunoglobulin production by normal B cells. In addition, the lines were capable of producing gamma-interferon (IFN-gamma), lymphotoxin (LT), an interleukin 1 (IL1)-like factor, glial growth promoting factor (GGPF), and IL6. The advantage of these lines over clones or cell lines developed using other techniques is their growth in the absence of feeder layers or IL2 and their ability to be cloned and to grow in culture indefinitely.

B-Lymphocytes↗
PubMed1989

Interleukin-1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor.

Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) are important in normal immune processes. In this study, we demonstrate that human immunodeficiency virus type 1 (HIV-1) virions induce normal peripheral blood mononuclear phagocytes to produce both IL-1 and TNF within a few hours after their exposure to virus. The induction of these cytokines by HIV-1 does not require a productive infection. Blocking studies with soluble CD4 indicate that the effect is mediated through the CD4 molecule. In addition, the treatment of mononuclear phagocytes with OKT4A monoclonal antibody mimics the effects of HIV-1. Thus, these results indicate that induction of IL-1 and TNF alpha can occur via signals mediated through the CD4 molecule on mononuclear phagocytes. TNF has been shown by other investigators to induce HIV-1 expression. Therefore, TNF alpha may play a role in autocrine and paracrine regulation of HIV-1 expression. In addition, the induction of IL-1 and TNF by HIV-1 may also contribute to some of the neurologic and physiologic disorders associated with acquired immunodeficiency syndrome.

Antibodies, Monoclonal↗
PubMed1988

Response of human glioblastoma cells to recombinant interleukin-2.

We investigated the ability of glioma cells to respond to T cell-derived lymphokines. The growth of astrocytoma and mixed glioblastoma cell lines, as assessed by DNA synthesis, was inhibited in the presence of supernatants derived from mitogen-stimulated human T cells, an HTLV-II-transformed human T cell line, Mo, and human interleukin-2 (IL-2). The mixed glioblastoma cell line, 138-MG-C, was subjected to limiting dilution analysis, and two cell lines (5D7, 5C5) were derived which were homogeneous with respect to staining for galactocerebroside (GalC) (100%). These two GalC+ glioblastoma cell lines proliferated in the presence of high concentrations of recombinant human interleukin-2 (RIL-2). Additionally, these cell lines bear receptors for the IL-2 molecule as determined by immunofluorescent staining with various anti-IL-2 receptor antibodies.

Brain Neoplasms↗
PubMed1987

Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms.

Human immunodeficiency virus (HIV) is the causative agent of the acquired immune deficiency syndrome (AIDS). A large number of AIDS patients show evidence of neurologic involvement, known as AIDS-related subacute encephalopathy, which has been correlated with the presence of HIV in the brain. In this study, two genetically distinct but related viruses were isolated from one patient from two different sources in the central nervous system: brain tissue and cerebrospinal fluid. Both viruses were found to replicate in peripheral blood lymphocytes, but only virus from brain tissue will efficiently infect macrophage/monocytes. The viruses also differ in their ability to infect a brain glioma explant culture. This infection of the brain-derived cells in vitro is generally nonproductive, and appears to be some form of persistent or latent infection. These results indicate that genetic variation of HIV in vivo may result in altered cell tropisms and possibly implicate strains of HIV with glial cell tropism in the pathogenesis of some neurologic disorders of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Remyelination by oligodendrocytes stimulated by antiserum to spinal cord.

The new synthesis of myelin and the proliferation of oligodendrocytes was stimulated by serum from syngeneic mice immunized with homogenized spinal cord (SCH). Treatment with this antiserum produced a 10-fold increase in the area of remyelination in spinal cords that had become demyelinated previously as a result of infection by Theiler's murine encephalomyelitis virus. Inflammation was decreased in regions of white matter that showed remyelination. Oligodendrocytes exposed to anti-SCH in vitro incorporated three to five times more [3H]thymidine than resting cells did and expressed more myelin basic protein in their cytoplasm, suggesting stimulation of myelinogenesis. Thus, there is a factor present in anti-SCH antiserum that stimulates central nervous system-type remyelination. This finding may provide clues for the therapy of patients with demyelinating disorders such as multiple sclerosis.

Animals↗
PubMed1987

Regulation of antibody-dependent cellular cytotoxicity in multiple sclerosis by central nervous system hormones.

Using oligodendrocytes from primary brain cultures as targets in an antibody-dependent cellular cytotoxicity (ADCC) assay, we have examined the effects of insulin and histamine on killer cells in multiple sclerosis (MS) and other neurological disease (OND) controls compared to normal healthy controls. The effects were shown to be specific for effectors by preincubation experiments. MS patients' ADCC to primary oligodendrocytes was depressed, but could be boosted to normal control levels by histamine binding to the H1 receptor. Significant elevation of MS ADCC by cimetidine alone suggested that endogenous histamine production and H2 receptor binding could be mediating a suppressive effect on MS ADCC to oligodendrocytes. In addition, MS ADCC could be boosted significantly by insulin. MS killer cells were more sensitive in vitro to the boosting effects of both histamine and insulin than either OND or normal controls, both in dose response and magnitude of the increased ADCC.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1986

Immunoregulatory molecules and IL 2 receptors identified in multiple sclerosis brain.

Frozen brain specimens from eight multiple sclerosis (MS) patients were examined for the presence of leukocytes and their cell products by using a panel of monoclonal antibodies. The results presented here demonstrated that in the MS lesion, there was a marked accumulation of HLA-Dr-positive (Ia-positive) cells. These Ia-positive cells were identified as being glial fibrillary acidic protein positive by using double staining methods. Furthermore, the cells in the MS lesion expressed the interleukin 2 (IL 2) receptor, as identified by the anti-TAC monoclonal antibody. The cells in the region of the plaque also exhibited positive staining with antibodies to IL 1, IL 2, and prostaglandin E. Neither normal brain nor brain specimens from progressive multifocal leukoencephalopathy or Alzheimer's disease showed such patterns of staining. These results suggest that stimulated cells are present in the MS brain, thus implicating an active immune mechanism in the pathogenesis of MS.

Adolescent↗
PubMed1986

Quantitation of myelination and demyelination by the measurement of myelin basic protein by ELISA.

Utilizing a competitive inhibition enzyme-linked immunosorbent assay (ELISA) we measured the amount of myelin basic protein (MBP) in brain, liver, and kidney of newborn mouse and compared these values with myelinated cerebellar explant cultures under various conditions. Explant cultures demyelinated with anti-myelin serum showed a 90% decrease in MBP when compared with controls. These results correlated with myelination and demyelination as observed by light microscopy. Newborn tissues including brain showed only negligible activity for MBP. This technique provides a sensitive and objective method for quantitating in-vitro demyelination.

Animals↗