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P Dore-Duffy

Publications and source records attributed to P Dore-Duffy.

At least 19 recordsLinked to original sources
PubMed1995

Circulating, soluble adhesion proteins in cerebrospinal fluid and serum of patients with multiple sclerosis: correlation with clinical activity.

Soluble adhesion protein intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule (E-selectin) were measured in serum and cerebrospinal fluid (CSF) of patients with relapsing-remitting multiple sclerosis (RRMS) in remission and in exacerbation, as well as patients with chronic progressive MS, stable MS, and in patients with other neurological and inflammatory diseases (ONDs). Serum ICAM-1 and E-selectin were significantly elevated in patients with MS over those with ONDs and controls. CSF VCAM-1 and E-selectin were found to be elevated over control and disease control samples. No increase in CSF ICAM-1 was observed. Results were analyzed longitudinally and by MS category. In paired CSF and serum samples from patients in exacerbation, elevated VCAM-1 correlated with increased serum VCAM-1 in 5 of 7 patients. Elevated CSF E-selectin did not correlate with elevations in serum E-selectin.

Analysis of Variance↗
PubMed1994

Expression of immunologically relevant endothelial cell activation antigens on isolated central nervous system microvessels from patients with multiple sclerosis.

Activation of the vascular endothelium is thought to be an important facet of inflammation, thrombosis, and vasculitis. Activated endothelial cells express a number of immunologically relevant surface markers not expressed by normal endothelial cells. Many of these surface antigens are thought to augment adhesion reactions and migration. Our results show that endothelial activation may play a central role in the pathogenesis of multiple sclerosis (MS). Normal human central nervous system microvessels isolated from autopsy material do not express endothelial cell activation markers, including the adhesion proteins vascular cell adhesion molecule-1 (VCAM-1) and endothelial cell leukocyte adhesion molecule-1 (E-selectin/ELAM-1). They exhibit little to no constitutive expression of immunoreactive intercellular adhesion molecule-1 (ICAM-1) or the urokinase plasminogen activator receptor. Control microvessels exhibit no major histocompatibility complex (MHC) class II antigen. MS microvessels express significant levels of MHC class II antigens, ICAM-1, VCAM-1, and urokinase plasminogen activator receptor. E-selectin was expressed by 3 of 5 MS brains tested. Histologically unaffected areas of MS brain expressed less VCAM-1, ICAM-1, and E-selectin than did microvessels from periplaque zones. However, MHC class II antigens and urokinase plasminogen activator receptor were increased in areas exhibiting little to no evidence of leukocyte infiltration. When microvessels were examined for dual expression of activation markers, we found that in periplaque areas, 50% of microvessels coexpressed HLA-DR and VCAM-1, 28% of microvessels coexpressed HLA-DR and urokinase plasminogen activator receptor, and 43% of microvessels coexpressed HLA-DR and ICAM-1.

Adolescent↗
PubMed1994

Cytokine-mediated activation of cultured CNS microvessels: a system for examining antigenic modulation of CNS endothelial cells, and evidence for long-term expression of the adhesion protein E-selectin.

Much of what is known of endothelial responses to cytokines has been derived from in vitro studies using cultured human umbilical vein endothelial cells (EC). Less is known of CNS EC responses and whether intact endothelium responds similarly to cultured cells. We have used techniques by which rat CNS microvessels can be isolated, then cultured in vitro, to study the response of intact endothelium to activation with cytokines. These microvessels are composed of viable EC and perivascular cells, predominantly pericytes. Expression of EC activation antigens in multicellular systems such as cultured microvessels can be assessed quantitatively using immunofluorescence laser cytometry. Interferon gamma increased immunologically reactive major histocompatibility complex class II antigens (< 300 to 2,398 +/- 225 average fluorescence intensity), while tumor necrosis factor alpha induced an increase in vascular cell adhesion molecule-1 (2,167 +/- 171) and E-selectin (1,628 +/- 315). CNS EC appeared to respond similarly to cultured EC with the exception that E-selectin expression was not transiently expressed but was maintained by microvessel EC for 24 and 48 h. Cultured CNS microvessels provide a good system for studying EC activation.

Animals↗
PubMed1992

Production of soluble autocrine inhibitory factors by human glioma cell lines.

Gliomas in vitro exhibit density-limited growth upon the attainment of confluency, an effect usually attributed to cell-cell contact inhibition. Since gliomas have been demonstrated to secrete an array of soluble factors which can enhance tumor growth, we undertook this study to ascertain whether production of soluble factors by the tumor may also inhibit growth in an autocrine manner, and whether production of such factors is associated with the growth phase of the glioma. We observed that cell-conditioned medium (supernatants) from non-confluent glioma cultures induced growth, while confluent culture supernatants produced pronounced growth suppression. These latter supernatants enhanced proliferation of non-transformed astrocytes. Supernatants derived from all stages of confluency produced inhibition of lymphocyte proliferation. To characterize these factors, dialyzed supernatant was tested and found to continue to produce lymphocyte suppression but no glioma growth limitation. Growth of tumors in indomethacin or in acetylsalicylic acid to abolish prostanoid synthesis abrogated the inhibitory influence on glioma growth but only partially reversed the lymphocyte suppressive capacity. These studies suggest that gliomas do produce a growth phase dependent autocrine inhibitory factor(s), and that the production of these small molecular weight factors is at least partially under control of the cyclooxygenase pathway.

Adult↗
PubMed1992

Expression of monocyte activation antigen Mo3 on the surface of peripheral blood monocytes from patients with multiple sclerosis.

Exposure of human peripheral blood monocytes (PBM) to phorbol esters, bacterial products, and cyclic adenosine monophosphate agonists is known to stimulate expression of a plasma membrane antigen ([Ag]; Mo3). Mo3 is recognized by two monoclonal antibodies, Mo3e (IgM), and Mo3f (IgG). Surface Mo3 is barely detectable by indirect immunofluorescence flow cytometry in nonstimulated monocytes. Mo3-positive monocytes have been found in inflammatory tissues, but increased surface expression of Mo3 in PBM has not been seen in any patient group. We report that PBM from patients with chronic progressive MS (CPMS) express increased Mo3. PBM from patients with other neurologic diseases and healthy controls express little measurable Mo3. No difference was seen in class II major histocompatibility complex Ag expression and in Mo2 (CD14) expression. Exposure of PBM to lipopolysaccharide (10 mg/ml) enhanced Mo3 expression in both MS patients and controls. Mo3 expression on CPMS PBM was not dependent on culture conditions. Taken together, our observations suggest that monocytes from patients with MS are stimulated in vivo to express activation Ag Mo3, but that Mo3-positive monocytes need not be upregulated for HLA-DR.

Cell Separation↗
PubMed1991

Malignant glioma modulation of immune function: relative contribution of different soluble factors.

We analyzed a series of human glioma cell lines with regard to establishing what variables may contribute to their overall functional immunomodulating capability. We observed that supernatants derived from the gliomas, but not those from non-malignant human astrocyte cultures, suppressed lymphocyte proliferation. The extent of suppression elicited differed between tumors and for the same tumor depending upon its growth phase. For individual gliomas, supernatants from cultures approaching or at confluency elicited maximal lymphocyte suppression. For the series of tumors, levels of production of the immunosuppressive molecules transforming growth factor beta 2 and prostanoids (prostaglandin E2) did not correlate with the levels of functional suppression observed at any of the different growth phases. In some cases, glioma cultures grown in the presence of indomethacin to abolish prostanoid synthesis resulted in supernatants with net stimulatory activity. Our results indicate that malignant transformation of astrocytes is associated with acquisition of immunosuppressive capability which is determined by the combined effect of multiple immunomodulatory soluble factors, inhibitory or enhancing, and is dependent on the growth phase of the tumor.

Dinoprostone↗
PubMed1991

Functional desensitization of monocytes from patients with multiple sclerosis due to prostaglandin E.

We previously showed that monocytes from patients with multiple sclerosis (MS) produce increased prostaglandin E (PGE) in tissue culture. In this paper we show that monocytes from patients with chronic progressive MS are less sensitive to agents which stimulate PGE synthesis than healthy controls. MS cells are equally sensitive to PG inhibitors. MS monocytes have increased levels of cellular cyclic AMP and are less sensitive to PGE-mediated increases in cAMP. Depressed monocyte natural cytotoxicity was found to be correlated with cellular cAMP. Functional desensitization of monocytes and decreased sensitivity to PGE signals may be related to chronic exposure to prostaglandin E.

Aspirin↗
PubMed1991

Cerebrospinal fluid eicosanoid levels: endogenous PGD2 and LTC4 synthesis by antigen-presenting cells that migrate to the central nervous system.

We analyzed CSF from patients with multiple sclerosis, patients with other neurologic diseases, and healthy controls for the presence of prostaglandin (PG) E2, F2 alpha, D2, I, A, and leukotriene (LT) C4. Control CSF had little measurable PGs or LTs. CSF eicosanoids from patients with progressive MS were increased. We found PGD2 only in MS CSF. CSF monocytes from patients in active disease produced significantly increased PGD, PGE, and LTC4 than paired peripheral blood monocytes and monocytes from healthy controls. We saw no significant difference in LTC4 production between MS and control peripheral blood monocytes.

Antigen-Presenting Cells↗
PubMed1989

Essential fatty acid and lipid profiles in plasma and erythrocytes in patients with multiple sclerosis.

This study was conducted to investigate the possible differences in erythrocyte lipid composition, which might account for the previously reported increase in erythrocyte membrane zinc levels in patients with multiple sclerosis (MS). Compared with healthy control subjects, plasma lipids in patients with MS contained less sphingomyelin but more phosphatidylserine and the cholesterol-phospholipid ratio was 42% higher in the plasma from MS patients (p less than 0.01). In erythrocytes from MS patients, phosphatidylinositol was lower and erythrocyte cholesterol per milligram protein was significantly lower than concentrations in healthy control subjects (p less than 0.01). Among the long-chain fatty acids, the omega-3 fatty acids were lower in plasma from MS patients and linoleic acid was lower in erythrocyte ghosts from MS patients (p less than 0.01). We conclude that altered levels of cholesterol in plasma and erythrocytes from MS patients may contribute to increased erythrocyte-membrane Zn in MS patients. It cannot be stated with certainty whether the altered fatty acid profiles in MS patients were a function of the disease or of altered fatty acid intake.

Cholesterol↗
PubMed1988

Synthesis of prostaglandin E by peritoneal macrophages from NZB/W mice.

Peritoneal macrophages from NZB/W (murine lupus) mice spontaneously produce less prostaglandin E (PGE) than peritoneal macrophages from immunologically normal mice. Reduced PGE synthesis is seen as early as 2 months of age and becomes more profound as disease progresses. It is suggested that impaired production of PGE by peritoneal macrophages from NZB/W mice may account in part for abnormal macrophage function observed in these animals.

Age Factors↗
PubMed1987

Age-related differences in lymphocyte adherence to myelinated tissue in multiple sclerosis.

Human peripheral blood lymphocytes were obtained from patients with MS and from healthy controls. Comparisons were made between the adherence of lymphocytes from donors of varying ages to myelin from donors of different age groups at the time of death. The adherence of control lymphocytes was maximum with lymphocytes from donors in their 30s. No obvious maximum for lymphocyte age was found for adherence of MS lymphocytes. However, MS adherence levels were significantly higher than control levels at most ages tested. Maximum adherence levels were observed for both MS and control cells with myelin from donors who were 20 to 45 years of age at the time of death. No significant difference between MS and control adherence to myelin from elderly donors was observed. Possible age-related changes in myelin and the relationship of maximum adherence to the peak age of onset of MS discussed.

Adolescent↗
PubMed1986

Zinc in multiple sclerosis. II: Correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis.

Previous studies have shown that zinc levels in erythrocytes are significantly elevated in patients with multiple sclerosis (MS). To examine the correlation between erythrocyte Zn levels and disease activity, we measured erythrocyte Zn levels longitudinally. Levels were dramatically decreased during a clinically documented exacerbation of MS. To determine the localization of increased Zn levels in MS erythrocytes, we employed standard techniques for the isolation of nonhemoglobin erythrocyte membrane ghosts. Patients with MS had three times more Zn in ghost material than did controls. Chloroform-methanol extraction in erythrocyte ghosts followed by determination of Zn levels indicated that most of the membrane-bound Zn was associated with the lipid-soluble fraction. Non-lipid-associated Zn and total membrane protein concentration were similar in MS and control samples. Results suggest that mechanisms which govern cellular availability, compartmentalization of Zn, or the binding of Zn to cell surface membranes may be altered in patients with MS, and that these mechanisms vary with disease activity.

Adult↗
PubMed1986

Lymphocyte adherence in multiple sclerosis: role of the cytoskeleton and prostaglandin E.

Human peripheral blood lymphocytes from patients with multiple sclerosis (MS) form significantly greater numbers of rosettes with virus infected cells than healthy controls. Because increased lymphocyte adherence in MS may be important to the disease process, we have investigated the mechanisms governing lymphocyte adherence in healthy control volunteers. We have previously shown that prostaglandins E1, E2 (PGE2), and dibutyryl cyclic AMP (db cAMP) and colchicine increase control lymphocyte adherence in healthy control volunteers. Colchicine treatment enhances PGE synthesis in control cells. We now report that colchicine (10(-5) + 10(-7) M) treatment of mononuclear cells does not enhance PGE synthesis in cells from patients with multiple sclerosis. Colchicine treatment did not affect MS lymphocyte adherence.

Aspirin↗
PubMed1986

Lymphocyte adherence to myelinated tissue in multiple sclerosis: correlation with disease activity.

Human peripheral blood T-lymphocytes adhere to myelinated sections of human and nonhuman brain tissue. No lymphocyte adherence is seen to gray matter. Lymphocytes from patients with MS adhere more than control lymphocytes. Lymphocyte adherence in patients with stable MS and in healthy controls did not vary more than 15%. Lymphocyte adherence in MS patients was decreased significantly during exacerbation. Values rose to pre-exacerbation levels in remissions. Results suggest that T cells that adhere to myelin may migrate from the peripheral blood during exacerbation.

Cell Adhesion↗
PubMed1986

Prostaglandin release in multiple sclerosis: correlation with disease activity.

Release of prostaglandin E (PGE) was examined in leukocyte cultures from patients with definite MS who had had at least one recent exacerbation, others with chronic progressive or stable MS, and healthy controls. MS patients had higher baseline levels of PGE than did controls. Patients with active symptoms exhibited a sharp increase in PGE release early in or just before the onset of clinical symptoms. Levels dropped early in exacerbation immediately after the burst in PGE synthesis activity. Values gradually increased to control levels and then to preexacerbation levels. Similar rises and falls were not seen in stable MS. MS patients may have a circulating population of activated leukocytes that produce PGE.

Acute Disease↗
PubMed1986

Serum 13-14-diOH-15-keto-prostaglandin F2 alpha and airway response to meclofenamate and metaproterenol in relation to the menstrual cycle.

In order to evaluate whether adverse reactions to a nonsteroidal antiinflammatory agent (NSAIA) were related to variations in prostaglandin levels during the menstrual cycle, we measured 13-14-diOH-15-keto-prostaglandin F2 alpha in serum and the effect on airways of a single dose of 100 mg oral meclofenamate and 1.5 mg inhaled metaproterenol during the early (follicular phase) and late (luteal phase) menstrual cycle. Among 24 women with premenstrual asthma (PMA), four women with regular asthma (REA), and four healthy women, the 13-14-diOH-15-keto-PGF2 alpha averaged 140.9 +/- 68.4 pg/0.1 ml during the follicular phase but only 14.4 +/- 2.2 pg/0.1 ml during the luteal phase (p less than 0.0001). Acute asthma reactions to the meclofenamate occurred during the follicular phase in six women with PMA but were never observed during the luteal phase (p = 0.016). These reactions occurred preferentially in patients on corticosteroids (p = 0.004). Conversely, one patient with PMA had 18% improvement in FEV1 with meclofenamate during the luteal phase. A placebo-controlled, double-blind evaluation of the healthy women and the women with REA revealed a trend toward improvement in FEV1 during the luteal phase (0.15 less than p less than 0.10) but no change during the follicular phase. The effect of metaproterenol did not vary with the menstrual cycle, and there was no interaction between the effects of meclofenamate and those of metaproterenol. It appears that meclofenamate causes adverse effects on pulmonary function in asthmatic women primarily during the follicular phase of the menstrual cycle. This effect is associated with corticosteroid treatment and may be related to monthly variation in serum 13-14-diOH-15-keto-PGF2 alpha.

Adult↗
PubMed1984

Generation of phenotypic helper/inducer and suppressor/cytotoxic T-cell lines from cerebrospinal fluid in multiple sclerosis.

The investigation of cell-mediated events in man has been largely limited to the study of the cells in the peripheral circulation. The study of T cells from localized anatomic compartments has been difficult due to the small numbers of cells usually obtainable from these sites. Investigation of such compartmentalized responses theoretically may yield information relating to both normal immunoregulation and autoimmune diseases--information that may not be obtainable through the investigation of the circulating cellular immune system. Utilizing cerebrospinal fluid (CSF) lymphocytes from patients with multiple sclerosis as a model of compartmentalized immunologically relevant cells, the technology for the generation of long-term T-cell lines from compartments both in continuous culture and after cryopreservation and that consist of both helper/inducer and suppressor/cytotoxic phenotypes have been generated. The 10(4) to 10(5) CSF cells obtained initially from individual patients have often been expanded into greater than 10(8) total cells within 4 months. The ability to generate large, stable, cryopreservable helper and suppressor/cytotoxic T-cell lines from limited access compartments will allow for new investigative approaches into both normal immunoregulation and autoimmune diseases in man.

Antigens, Surface↗