Paula Dore-Duffy

Lymphocyte Adherence in Multiple Sclerosis: EFFECT OF ASPIRIN

Peripheral blood lymphocytes from multiple sclerosis (MS) patients form substantially greater numbers of rosettes with measles virus-infected human epithelial cells than do lymphocytes from healthy controls or from patients with other diseases. We have previously shown that prostaglandin E(1)-treated normal lymphocytes exhibit increased lymphocyte adherence, and thus behave like MS lymphocytes in this in vitro system. In this study we describe the effect of prostaglandin synthesis inhibition on lymphocyte adherence in both MS and control patients. Direct addition of aspirin or indomethacin to peripheral blood mononuclear cells from MS patients in vitro reduced lymphocyte adherence to control levels. Ingestion of therapeutic (anti-inflammatory) doses of aspirin (1 g, 4 times daily for 2 d) by MS patients resulted in reduction of lymphocyte adherence to levels seen in healthy controls. A single 325-mg dose of aspirin did not reduce lymphocyte adherence. A dose-dependent reduction in lymphocyte adherence was observed after single doses ranging from 650 mg to 1.3 g; duration of the effect was directly related to the aspirin dose. These observations indicate that treatment of MS patients with aspirin profoundly influences adherence of their lymphocytes to measles virus-infected cells and suggest that the altered cellular response, which results in increased lymphocyte adherence in MS patients, may be mediated by a prostaglandin-sensitive mechanism.

Interferon-mediated inhibition of prostaglandin synthesis in human mononuclear leukocytes

In this study, the question of whether human leukocyte-derived and fibroblast-derived interferon had an effect on prostaglandin metabolism in human peripheral blood mononuclear cells has been considered. Both leukocyte- and fibroblast-derived interferon were potent inhibitors of mononuclear cell prostaglandin synthesis at low physiological concentrations. Inhibition required a minimum incubation of 1 hr. Interferon had no effect on release of arachidonic acid; synthesis of hydroxy fatty acids was slightly increased.

Adherence of Human Peripheral Blood Lymphocytes to Measles-Infected Cells

Abstract We studied the effect of prostaglandins in vitro on an immune reaction mediated by T cells: adherence of lymphocytes to measles-virus-infected human epithelial cells. Normal human lymphocytes adhered to a mean ±S.D. 20.1 ±5.2 per cent of these HEp-2 cells. The percentage positive cells increased to 50.3±5.7 when lymphocytes were incubated with 10-6 M prostaglandin E1 (P<0.01 vs. untreated lymphocytes); 10-8 M and 10-10 M were as effective. Prostaglandin F2α had no effect on lymphocyte adherence. Prostaglandin E1 increased lymphocyte cyclic AMP five to 10 times whereas prostaglandin F2α did not affect cellular levels of this nucleotide. Dibutyryl cyclic AMP (10-8 M) increased lymphocyte adherence: positive human epithelial cells increased from 16.0±2.4 to 38.7±1.1 per cent (P<0.01). Prostaglandin E1 also increased adherence of lymphocytes from patients with systemic lupus erythematosus from 21.8±5.8 to 52.5±9.2 per cent (P<0.01). These results indicate that prostaglandin E1 and cyclic AMP may serv...

Lymphocyte adherence in multiple sclerosis

It has been reported that peripheral blood lymphocytes from patients with multiple sclerosis (MS) adhere to measles-infected human epithelial cells in significantly greater numbers than do lymphocytes from healthy volunteers or patients with other neurologic diseases. We have confirmed this observation in three separate studies, and have investigated the relationship of lymphocyte adherence to the clinical state. Lymphocyte adherence determination values correlated with the degree of certainty of the clinical diagnosis of MS, and lymphocyte adherence values in individual patients increased during clinical exacerbations. Judicious use of this test may facilitate the diagnosis of MS.

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.

Lymphocyte adherence to myelinated tissue in multiple sclerosis.

A small subpopulation of human peripheral blood T lymphocytes has the capacity to adhere selectively to myelinated sections of human and nonhuman brain tissue. Adherence of lymphocytes from patients with multiple sclerosis is significantly greater than adherence of control lymphocytes. Monocytes inhibit binding in controls. This function appears to be lost by multiple sclerosis monocytes.

Adherence of human peripheral blood lymphocytes to virus infected cells: 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) increase control lymphocyte adherence to MS levels. We now report that colchicine (10(-7) M) and nocodazole (10(-7) M) significantly increased control lymphocyte adherence to measles virus infected human epithelial (HEp-2) cells. Lumicolchicine had no effect. Cytochalasins A, B, C, and D also had no effect on lymphocyte adherence. Colchicine (10(-5) + 10(-7) M) treatment of mononuclear cells enhanced PGE synthesis in tissue culture. Cytochalasins had no effect on PGE synthesis. Thus, microtubules appear important to adherence of lymphocytes to virus infected cells perhaps by virtue of their involvement and/or control of PG biosynthesis.

Lymphocyte adherence in multiple sclerosis: Lack of virus specificity

The virus specificity of adherence of peripheral blood mononuclear leukocytes from patients with multiple sclerosis and from age- and sex-matched healthy volunteers to tissue culture cells infected with measles virus, Newcastle disease virus, and vesicular stomatitis virus was studied. Lymphocyte adherence to uninfected cells is uniformly low (5-15% tissue culture cells with greater than 3 lymphocytes adhered). Adherence to cells infected with virus is enhanced 2- to 4-fold in controls and 2- to 10-fold in patients with multiple sclerosis. Virus-specific antigen, antiserum, and receptor, at least in part, inhibited adherence to all cells tested. It is concluded from these studies that increased lymphocyte adherence in multiple sclerosis is not measles virus specific.

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 is discussed.

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.