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Biomedical subjects

E McCrea

Publications and source records attributed to E McCrea.

8 recordsLinked to original sources
PubMed2005

Upregulation of TRAIL expression on human T lymphocytes by interferon beta and glatiramer acetate.

We measured the in vivo and in vitro effects of interferon (IFN)beta and glatiramer acetate (GA) on the expression of the regulatory molecule, tumor necrosis factor related apoptosis inducing ligand (TRAIL), in patients with multiple sclerosis (MS). We confirmed the prior observation that TRAIL is enhanced on anti-CD3 activated T cells by the in vitro addition of IFNbeta. T cells from IFNbeta-treated patients stimulated with anti-CD3 only, had higher levels of TRAIL than untreated patients, suggesting that in vivo IFNbeta exposure has an effect on TRAIL expression in association with T cell activation. In vitro IFNbeta-induced TRAIL upregulation on anti-CD3 or phytohemagglutinin-activated T cells was comparable for IFNbeta-treated and non-treated MS patients and controls, indicating that IFN receptors were neither saturated nor down-regulated by current IFNbeta therapy. Although GA in vivo or in vitro did not induce TRAIL, the IFNbeta +GA combination in vitro enhanced TRAIL expression to higher levels than IFNbeta alone on CD4+ T cells obtained from MS patients, regardless of GA treatment status, and healthy donors, and on GA reactive T cell lines derived from GA-treated patients or controls. Whether any observed therapeutic effects of GA/IFNbeta combination therapy will correlate with TRAIL expression and function remains to be determined.

Adjuvants, Immunologic↗
PubMed2000

Superantigen presenting capacity of human astrocytes.

We found that human fetal astrocytes (HFA) are able to support superantigen (SAG) staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1)-induced activation of immediately ex vivo allogenic human CD4 T cells. Using radiolabelled toxins, we demonstrate that both SEB and TSST-1 bind with high affinity to MHC class II antigen expressing astrocytes; binding is displaceable with excess cold toxin. Competition experiments further indicate that TSST-1 and SEB at least partially compete with each other for binding to astrocytes suggesting they bind to the same HLA-DR region on these cells. Our study supports the hypothesis that SAG would be capable of stimulating immune responses within the human CNS and contribute to persistence or recurrence of inflammatory responses within this compartment.

Antigen-Presenting Cells↗
PubMed1999

Interferon-gamma secretion by peripheral blood T-cell subsets in multiple sclerosis: correlation with disease phase and interferon-beta therapy.

Interferon-gamma (IFN-gamma) is implicated as a participant in the immune effector and regulatory mechanisms considered to mediate the pathogenesis of multiple sclerosis (MS). We have used an intracellular cytokine staining technique to demonstrate that the proportion of ex vivo peripheral blood CD4 and CD8 T-cell subsets expressing IFN-gamma is increased in secondary progressing (SP) MS patients, whereas the values in untreated relapsing-remitting (RR) MS patients are reduced compared with those of controls. Patients treated with interferon-beta (IFN-beta) have an even more significant reduction in the percentage of IFN-gamma-secreting cells. The finding that the number of IFN-gamma-expressing CD8 cells is increased in SPMS patients, a group with reduced functional suppressor activity, and is most significantly reduced by IFN-beta therapy, which increases suppressor activity, indicates that IFN-gamma secretion by CD8 T cells and functional suppressor defects attributed to this cell subset in MS can be dissociated.

Adult↗
PubMed1998

Non-MHC-restricted cell-mediated lysis of human oligodendrocytes in vitro: relation with CD56 expression.

Oligodendrocytes and their myelin membranes are the apparent target of the autoimmune response that characterizes the human adult central nervous system-demyelinating disease multiple sclerosis. Human oligodendrocytes do not express MHC class II molecules, a requirement for MHC-restricted injury mediated by myelin-reactive CD4+ T cells, the cell type implicated in initiating the disease process. In this study we observed that human adult central nervous system-derived oligodendrocytes can be susceptible to non-MHC-restricted lysis mediated by myelin basic protein-reactive CD4+ T cell lines. Cytotoxicity was significantly greater (37 +/- 4 vs 7 +/- 3%) with cell lines in which a high proportion of cells (mean, 28 +/- 6%) expressed CD56 compared with cytotoxicity mediated by low CD56 cell lines (8 +/- 2%). High CD56 cell lines, when rested in IL-2, lost cytotoxic activity and had reduced expression of CD56 (mean, 5 +/- 2%). CD4+ T cells isolated from short term (3-day) anti-CD3/IL-2-activated mononuclear cell cultures did not express CD56 and were not cytotoxic to oligodendrocytes unless lectin was added. In contrast, an enriched population of non-T cells extracted from the same activated MNC cultures expressed CD56 as well as other NK cell-associated surface molecules and was cytotoxic. These results indicate the potential susceptibility of human oligodendrocytes to non-MHC-restricted injury mediated by both Ag-reactive and nonspecific cellular immune effector cells, with CD56 expression being a common feature of the effector cells.

Adult↗
PubMed1995

Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury.

We examined whether oligodendrocytes, neurons, and astroglia derived from the human central nervous system differ in susceptibility to injury mediated by tumor necrosis factor (TNF)-alpha and by activated CD4+ T cells acting via a TNF-independent mechanism. Injury was assessed either as cell membrane-directed (lysis), measured by 51chromium (Cr) or lactate dehydrogenase (LDH) release, or nucleus-directed (apoptosis), measured by morphologic features based on propidium iodide (PI) staining and by DNA fragmentation measured by a terminal transferase (TdT)-mediated dUTP biotin nick end labeling technique (TUNEL). TNF did not induce 51Cr or LDH release in any cell targets, but did induce nuclear (66 +/- 2% of cells) and DNA (68 +/- 2% of cells) fragmentation selectively in the oligodendrocytes over 96 hr. At this time, there was no significant loss of oligodendrocyte cell number. Nuclear injury could be induced in neurons by serum deprivation and in malignant astrocytes by the combination of TNF and low serum. CD4+ T cells activated with phytohemagglutin (pha) or anti-CD3 plus interleukin-2 induced significant 51Cr and LDH release in all target cells tested; only pha-activated CD4+ T-cell cocultures showed reduced target cell numbers. Significant nuclear fragmentation was observed only for glioma cells (22 +/- 1% of cells). Differences in susceptibility to different immune effector mechanisms and in the nature of the injury response to the same effector mediator among human CNS-derived neural cells will need to be considered in design of therapeutic strategies aimed at protecting or limiting target cell injury consequent to disease or trauma.

Apoptosis↗
PubMed1994

T cell-mediated cytotoxicity of human gliomas: a tumor necrosis factor-independent mechanism.

Cellular immune effector mechanisms are implicated as potential therapies for malignant gliomas. We have examined the potential for anti-CD3-activated human peripheral blood-derived CD4+ and CD8+ T cells to induce lysis of human glioma cell lines in vitro, the mechanism of action of these cells, and the capacity of the glioma to inhibit the effect. We found that activated CD4+ and CD8+ T cell preparations containing less than 5% natural killer cells could induce significant lysis of the glioma cell line U251, as measured by an 18-hour, but not 5-hour, chromium-51 or lactate dehydrogenase release assay. This effect was not reproduced using recombinant tumor necrosis factor or inhibited with antitumor necrosis factor antibody. Anti-lymphocyte functional antigen-1 and anti-intercellular adhesion molecule antibodies also did not inhibit the effect. Glioma-derived supernatant could inhibit the proliferation of the T cells but not the cytotoxic effect. Human fetal astrocytes were also susceptible to the cytotoxic effect of the activated T cells. These results indicate that activated T cells can induce glioma cytotoxicity via a mechanism independent of tumor necrosis factor. The therapeutic potential of this effector mechanism will depend on its capacity to deliver these cells or their specific effector molecules to the tumor site or to augment the activity of such cells, which accumulate naturally in gliomas.

Brain Neoplasms↗
PubMed1983

Chemotherapy for metastatic basal cell carcinoma.

Metastatic basal cell carcinoma is a rare, malignant neoplasm associated with poor survival. A 63-year-old woman had an extensive primary keratinizing basal cell carcinoma of the scalp, with metastases to the regional lymph nodes of the neck. Disease in the primary site and in the regional lymph nodes was controlled by surgery and irradiation. However, skeletal metastases that responded to therapy with three courses of cisplatin and bleomycin sulfate and then to ten courses of cyclophosphamide, methotrexate, and fluorouracil developed. Subsequent progressive metastases failed to respond to a combined cisplatin and cyclophosphamide regimen as well as to etoposide and doxorubicin hydrochloride used as single agents.

Antineoplastic Agents↗