Biomedical subjects

A Toscas

Publications and source records attributed to A Toscas.

6 recordsLinked to original sources

PubMed1997

Role of interferons in demyelinating diseases.

IFN beta-1b reduces the frequency of major multiple sclerosis attacks by 50 percent. Serial MRI scanning over the course of the clinical trial that led to approval of the agent revealed a significant lessening both in disease activity and in accumulating burden of disease in IFN beta-1b-treated patients compared to placebo-treated controls. The mechanism by which IFN beta-1b exerts its beneficial effect in multiple sclerosis is unknown. T suppressor cell function fails during MS attacks and is persistently subnormal in multiple sclerosis patients with progressive disease. IFN beta-1b partially restores suppressor function in multiple sclerosis patients. IFN beta-1b also inhibits release of lymphotoxin, tumor necrosis factor, and interferon gamma, at least in vitro. All three cytokines are toxic to oligodendrocytes. In contrast; production of transforming growth factor beta-1 (TGF beta 1) is increased by IFN beta-1b. TGF beta 1 is an immunosuppressive cytokine. All of the above listed actions of IFN beta-1b could contribute to its beneficial effect. Perhaps all do.

Demyelinating Diseases↗

PubMed1996

Global inhibition of IL-2 and IFN-gamma secreting T cells precedes recovery from acute monophasic experimental autoimmune encephalomyelitis.

Actively induced experimental autoimmune encephalomyelitis (EAE) in the PL/J mouse is a monophasic disease. We isolated mononuclear cells (MNC) from the central nervous system (CNS), lymph node (LN), blood, and spleen over the course of EAE and counted the number of cells secreting IL-2, IFN-gamma or IL-4 in response to polyclonal stimulation. IL-2 secreting cells were present in the CNS at disease onset but absent at disease peak and at recovery. A profound transient drop in IL-2 secreting cells also occurred in LN, blood, and spleen at disease peak and during recovery. IFN-gamma secreting cell number decreased in all compartments as disease evolved. In contrast, IL-4 secreting cell number was greatest in the CNS at disease peak, i.e. IL-4 secreting cells rose as IL-2 and IFN-gamma secreting cells fell. IL-4 secreting cell number did not change appreciably in LN, blood, and splenic MNC as disease evolved. CNS MNC at disease peak failed to proliferate in response to anti-CD3 mAb but did so in response to IL-2. LN, blood and splenic MNC did proliferate in response to anti-CD3 mAb at disease peak and this proliferation was augmented by exogenous IL-2. After prolonged culture, proliferative response of CNS MNC to anti-CD3 mAb was restored. These results indicate that during monophasic EAE global suppression of naive T cell and Th1 T cell cytokine synthesis occurs but that T cell proliferative responsiveness is selectively inhibited in the CNS.

Acute Disease↗

PubMed1993

Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis.

Interferons (IFN) are biological molecules with anti-viral, anti-proliferative and immunomodulatory actions. There is evidence that IFN-gamma increases the frequency of exacerbations of multiple sclerosis (MS) whereas IFN-beta may reduce their frequency. Here we present evidence that IFN-beta significantly decreases concanavalin A (Con A)-induced proliferation of peripheral blood mononuclear cells (PBMC) of MS patients and healthy individuals. Similar results were obtained when PBMC were activated through the T cell receptor (TcR) by anti-CD3 monoclonal antibody or independently of it by phorbol ester and Ca2+ ionophore. These effects of IFN-beta were also noted when IFN-gamma and IFN-beta were added together. Furthermore, IFN-beta decreased proliferation when added to cells that were already pre-activated. Activated CD4+ and CD8+ T cells were downregulated to approximately the same extent. Analysis of cytokine production showed that IFN-gamma production by Con A activated PBMC was increased in MS when compared to controls. IFN-beta significantly decreased IFN-gamma production in MS patients and control individuals. Con A activated cultures treated with IFN-beta showed decreased IL2R expression and accumulation of IL2. These results show that IFN-beta decreases T cell activation and IFN-gamma production in vitro, effects that may be beneficial in MS.

Adult↗

PubMed1992

Contrasting effects of alpha, beta, and gamma interferons on nonspecific suppressor function in multiple sclerosis.

Interferons are biological molecules with antiviral, antiproliferative, and immunomodulatory actions. Interferon alpha (IFN-alpha) and -beta are potentially useful in the treatment of multiple sclerosis (MS). IFN-gamma, in contrast, increases the frequency of exacerbations of MS. In this study, we compared the effect of recombinant human IFN-alpha, -beta, and -gamma on suppressor function in patients with MS. Nonspecific suppressor cell function, measured in a concanavalin A suppressor assay, was significantly decreased in 16 patients with progressive MS (mean percent suppression +/- SEM, 14.4 +/- 5.5 in patients with MS, 33.5 +/- 4.8 in 16 normal subjects; p less than 0.001). Recombinant human IFN-beta augmented suppressor function in MS to 45.4 +/- 5.1% (p less than 0.001) and in control subjects to 56.8 +/- 3.8% (p less than 0.001). Similarly, recombinant human IFN-alpha improved suppression in MS to 43.0 +/- 5.6% (p less than 0.001) and in control subjects to 51.1 +/- 5.9% (p less than 0.001). In contrast, recombinant human IFN-gamma had no effect on suppressor function in patients with MS and in control subjects. This study shows that IFN-alpha and -beta augment deficient suppressor function in MS, whereas IFN-gamma has no effect on suppressor function in the progressive phase of the disease.

Adult↗

PubMed1992

Preferential increase of IL-2R+ CD4+ T cells and CD45RB- CD4+ T cells in the central nervous system in experimental allergic encephalomyelitis.

We examined lymphocytes isolated from the spinal cord (SC), peripheral blood (PB) and lymph nodes (LN) draining the immunization site of Lewis rats with acute experimental allergic encephalomyelitis (EAE). Cells were analysed for T cell subset markers CD4 (mAb W3/25) and CD8 (mAb OX8), for IL-2R (mAb OX39), and for high molecular mass leukocyte common antigen (LCA, CD45RB) expression (mAb OX22). T cells expressing high (CD45RB+) or low (CD45RB-) molecular mass LCA are of different maturational stages and/or separate lineages. CD4+ T cells were more predominant in SC than in PB and LN; CD8+ T cells were scarce in SC but common in PB and LN. Activated CD4+ T cells (IL-2R+) were common in the SC and LN but infrequent in blood. CD4+ T cells that were CD45RB+ were scarce in the SC. In contrast, the majority of CD4+ T cells in the PB and LN were CD45RB+. The preferential accumulation of IL-2R+ CD4+ T cells and of CD45RB- CD4+ T cells in the central nervous system (CNS) indicates that a selective mechanism directs cell egress into CNS lesions in EAE.

Animals↗

PubMed1990

Interferon beta augments suppressor cell function in multiple sclerosis.

Suppressor cell function has been previously reported to be decreased in patients with progressive multiple sclerosis (MS). The abnormality could not be corrected in vitro and was present even after patients were treated with immunosuppressive agents. We now report that interferon beta augments suppressor cell function in vitro in progressive MS. Nonspecific suppressor cell function as measured in a concanavalin A (Con A) suppressor assay was reduced in 24 MS patients (mean percent suppression, 19.6 +/- 2.2) when compared to 19 normal subjects (mean percent suppression, 35.0 +/- 3.3). The data are highly significant (p less than 0.001). When recombinant human interferon beta (10(3) units/ml) was added to lymphocyte cultures with Con A, suppressor activity improved significantly. The mean percent suppression improved from 19.6 +/- 2.2 to 37.8 +/- 2.6 in MS (p less than 0.001) and from 35.0 +/- 3.3 to 46.2 +/- 3.5 (p less than 0.025) in control subjects. This study shows that recombinant interferon beta improves suppressor function in humans, an effect that is particularly significant in progressive MS.

Adult↗