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Biomedical subjects

P Miossec

Publications and source records attributed to P Miossec.

At least 109 records · Page 6Linked to original sources
PubMed1993

[Anti-inflammatory properties of interleukin-4].

Interleukin 4 (IL4) is a cytokine produced by T cells and mast cells/basophils. IL4 has a key role in IgE production and in the pathogenesis of atopic diseases. Disorders such as rheumatoid arthritis are characterized by increased production of proinflammatory cytokines and reduced production of IL4. Furthermore, rheumatoid T cells are of the TH 1 type, not producing IL4. In contrast, circulating IL4 has been detected in scleroderma patients, whose T cells are of the TH 2 type, producing IL4. Since IL4 inhibits the production of proinflammatory cytokines such as IL1, IL6, TNF alpha and IL8, we hypothesized that a deficit in IL4 production might be related to the pathogenesis of rheumatoid arthritis. Addition of IL4 strongly reduced the production of proinflammatory cytokines and expression of corresponding mRNA by synovial membrane pieces from RA patients. RA synovitis is also associated with marked proliferation of synoviocytes. Studies of synoviocytes showed that IL4 inhibited the growth promoting effect of PDGF and IL1 beta. IL4 also inhibited production of IL6 by juxta-articular bone pieces. IL4 was found to reduce disease activity and progression in various arthritis models. These anti-inflammatory and anti-proliferative properties suggest that IL4 may be of potential clinical value in RA. Conversely, as IL4 induces dermal fibroblasts to secrete collagen, IL4 might be involved in the pathogenesis of scleroderma.

Arthritis, Rheumatoid↗
PubMed1992

Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis.

OBJECTIVE: To assess the spontaneous production of proinflammatory cytokines and immunoglobulins in rheumatoid arthritis (RA) synovitis and modulation by interleukin-4 (IL-4). METHODS: We developed an ex vivo model of RA synovitis using pieces of RA synovium, and have studied the regulation of the production of IL-1 beta, IL-6, tumor necrosis factor alpha (TNF alpha), IgM, and IgG. RESULTS: Spontaneous production of proinflammatory cytokines in vitro was active, with prolonged cytokine gene transcription and translation. IL-6 was produced at higher levels than either IL-1 beta or TNF alpha, and explants produced more IgG than IgM. In contrast, IL-4 and interferon-gamma were undetectable. When pieces of synovium were incubated in the presence of IL-4, reduction of spontaneous proinflammatory cytokine and Ig production was observed. CONCLUSION: These results extend the observations of the antiinflammatory properties of IL-4 to an ex vivo situation, and provide the rationale for the clinical use of IL-4 in RA.

Adult↗
PubMed1992

Interleukin 4 inhibits polyclonal immunoglobulin secretion and cytokine production by peripheral blood mononuclear cells from rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is associated with T- and B-cell dysfunction. Immunoglobulin (Ig) production is under the control of T cells and their derived cytokines such as interleukin 2 (IL-2) and IL-4. Herein we studied the regulation of the production of immunoglobulins and cytokines by peripheral blood mononuclear cells from RA patients and controls. In the controls, IL-4 inhibited Ig production in response to Staphylococcus aureus and pokeweed mitogen stimulation. IL-2 induced maximal Ig production in association with Staphylococcus aureus, whereas it inhibited pokeweed mitogen-induced production. In patients, levels of Ig production in response to mitogens and cytokines were reduced, particularly for the response to IL 2. The inhibitory effect of IL-4 on mitogen-induced Ig production was observed in RA patients as in the controls. Spontaneous production of IL-6 was increased in RA patients. These levels were correlated with indicators of active disease such as sedimentation rate and Ritchie index. IL-4 inhibited the production of IL-6, IL-1 beta, and tumor necrosis factor alpha (TNF alpha) by both controls and rheumatoid patients. Thus as first described for the T-cell response, mononuclear cells from RA patients display a reduced response to mitogens and cytokines which induce their B-cell differentiation into Ig-screening cells. However, IL-4 was able to inhibit Ig and cytokine production, properties suggesting a potential antiinflammatory role for this cytokine.

Adolescent↗
PubMed1992

Cytokine abnormalities in inflammatory arthritis.

Cytokines are soluble molecules which control communication between cells of the immune and non-immune systems. Studies on their role in the pathogenesis of inflammatory arthritis have been increased with the discovery of new cytokines and the development of assays for their detection. Conditions such as rheumatoid arthritis are characterized by increased production of proinflammatory cytokines in association with reduced control by regulatory cytokines produced by T lymphocytes. The inadequate inhibition of proinflammatory cytokines by anti-inflammatory cytokines and other regulatory mechanisms contributes to this cytokine imbalance. This situation is responsible for the enhanced degradation, without sufficient repair activity. These results have provided the rationale for the use of cytokines as well as for drug targeting of the cytokine network in rheumatoid arthritis. This also includes the modulation of the cytokine network by targeting the level of the receptors as well as the effects and/or the responding cells.

Arthritis↗
PubMed1991

[Soluble interleukin 2 receptors. Clinical value and biological significance].

Increased levels of the soluble form of the low-affinity receptor for interleukin 2 have been found in various clinical situations associated with immune system activation: infections, haematological disorders, autoimmune diseases, graft rejection, etc. Increased levels are usually associated with a higher stage of activity of the disease and correlated with a more severe prognosis. Reduction of levels precedes the treatment-induced clinical improvement. However, the prognostic value of these fluctuations might be limited by the level increases induced by infections. The immunological role of this receptor remains to be demonstrated and is probably not limited to interleukin 2 binding.

Autoimmune Diseases↗
PubMed1991

[Interleukin-1 and other proinflammatory cytokines].

Interleukin 1 (IL 1), tumor necrosis factor or alpha and Interleukin 6 are members of a family of soluble factors or cytokines which have multiple biologic activities and play a major role in host defence and in the pathogenesis of various diseases. They act at a low concentration on specific receptors. Their role includes host defence with fever, inflammatory cell migration, activation of immune cells, destruction of bone and cartilage. IL 1 activities are included in a cytokine network which amplifies and regulates the effects of numerous cytokines. Current research is aimed at obtaining drugs capable of modulating the effects of these cytokines.

Cytokines↗
PubMed1991

Human interleukin 4.

Human IL-4 is a mature 129 AA glycoprotein, mostly secreted by activated T cells. It is a pleiotropic cytokine which acts on T and B lymphocytes, monocytes, polymorphonuclear cells, fibroblasts and endothelial cells. In addition it acts at various stages of cell differentiation and its effects are also dependent on the cytokine environment. In particular, IL-4 blocks some of the effects of IL-2 whereas interferon gamma blocks some of the effects of IL-4. In vitro and in vivo experiments in mouse and in vitro experiments in man have shown that IL-4 plays a crucial role in the induction of IgE production, whereas interferons counteract this effect. Human IL-4 binds to a high affinity receptor which is composed at least of one 130-kDa glycoprotein of 800 AA, a member of the newly described hematopoietin receptor superfamily. IL-4 may prove useful as an antitumoral and antiinflammatory agent.

Animals↗
PubMed1990

T cell receptor expression and activation of synovial lymphocyte subsets in patients with rheumatoid arthritis. Phenotyping of multiple synovial sites.

Two-color flow cytometry analysis of peripheral blood and synovial lymphocytes from rheumatoid arthritis patients was performed using monoclonal antibodies directed against T cell subsets, T cell activation markers, and T cell receptors. The results showed an abnormally high percentage (greater than 15%) of CD3+, CD4-, and CD8- T cells expressing a specific receptor containing a gamma chain. Phenotypic analysis of lymphocytes infiltrating both knee joints of individual rheumatoid arthritis patients revealed very similar subset distribution and activation levels, despite strong differences in the clinical status between the 2 sites.

Arthritis, Rheumatoid↗
PubMed1990

Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis.

Since interleukin-4 (IL-4) displays agonistic effects on both T and B cells, we studied whether this lymphokine is involved in rheumatoid synovitis, a disease characterized by intense T cell infiltration and B cell stimulation. Rheumatoid arthritis synovial fluids (RA SF) contained no (less than 15 pg/ml) or very low amounts (less than 25 pg/ml) of IL-4, as measured by a sensitive and specific enzyme-linked immunosorbent assay. No IL-4 was produced by unstimulated rheumatoid synovial membrane. RA SF were found to inhibit phorbol myristate acetate (PMA)-dependent proliferation of normal peripheral blood lymphocytes (PBL). An inhibitory fraction with an apparent molecular weight of 150 kd was isolated by gel filtration. The inhibitory fraction strongly blocked the proliferation of PBL induced by PMA, PMA + IL-2, or PMA + IL-4. However, this fraction was less effective in blocking the proliferation of PBL induced by PMA + IL-2 + IL-4. High levels of transforming growth factor beta (TGF beta) were found in these RA SF, and an anti-TGF beta antibody was able to partially reduce the inhibitory activity. RA SF were found to inhibit phytohemagglutinin-induced IL-4 production by PBL. These data indicate that IL-4, similar to other T cell lymphokines, cannot be detected in RA SF and that RA SF contains an inhibitory activity, related in part to TGF beta, which blocks mitogen-induced proliferation of PBL, at least in part through an inhibition of T cell-derived lymphokine release.

Antibodies↗
PubMed1990

Functional studies of soluble low-affinity interleukin-2 receptors in rheumatoid synovial fluid.

Since abnormal regulation of interleukin-2 (IL-2) has been demonstrated in rheumatoid arthritis (RA), the functional role of low-affinity soluble IL-2 receptors (sIL-2R) purified from RA synovial fluids (SF) was studied. Picomolar levels of sIL-2R were detected in RA SF using an enzyme-linked immunosorbent assay. Levels were higher in serum and SF from RA patients than in controls (P less than 0.001) and higher in RA SF than in paired RA serum (P less than 0.01). Soluble IL-2R from RA SF had estimated molecular weights of 40-50 kd and 80-100 kd by gel filtration analysis. The 80-100-kd peak is likely to be a dimer of the 40-50-kd peak, since a single 45-kd peak was found after elution from sodium dodecyl sulfate-polyacrylamide gels. Since inhibitory activity for lymphocyte proliferation was found in the 80-100-kd range, the sIL-2R were purified with an anti-CD25 affinity column and further analyzed. The purified fractions did not interfere with the proliferation of mitogen-stimulated lymphocytes or with the binding of radiolabeled IL-2 to CTLL-2 cells, although direct binding of IL-2 was demonstrated. The affinity of sIL-2R from RA SF for binding IL-2 was in the range of 25 nM, which is similar to the affinity of sIL-2R purified from a human T cell clone, indicating that both sIL-2R are low-affinity receptors for IL-2. We conclude that the concentration and binding affinity of low-affinity sIL-2R purified from RA SF render them unable to interfere with IL-2-related activities.

Arthritis, Rheumatoid↗
PubMed1990

Interleukin 2 (IL 2) inhibitor in rheumatoid synovial fluid: correlation with prognosis and soluble IL 2 receptor levels.

A soluble activity inhibiting over 50% of the CTLL-2 cell line response to recombinant human interleukin 2 (IL 2) was found in 17 of 29 (59%) rheumatoid synovial fluids. To study the prognosis value of this activity, 16 rheumatoid synovial fluids were collected before a radiation synovectomy of the knee with 7 mCi of 90Yt. Patients with a good clinical result after the synovectomy had a lower IL 2 inhibitory activity than those with a bad or incomplete result (P less than 0.01). Levels of inhibitory activity and of soluble IL 2 receptors were correlated with each other and with the response of the synovitis to the radiation synovectomy. These results extend the clinical usefulness of soluble IL 2 receptor measurements and indicate a correlation between the immune activation of the rheumatoid synovitis and its clinical activity.

Adult↗
PubMed1988

Interleukin 1 derived from human endothelial cells enhances the binding and chemotactic step of T lymphocyte emigration.

Recent evidence indicates that interleukin 1 (IL-1) from different sources has varying molecular weights, amino acid and gene sequences and biological properties. In previous experiments, it has been shown that monocyte derived IL-1 was chemotactic for lymphocytes and stimulated their binding to endothelial cells (EC). These phenomena are important in the emigration of lymphocytes in inflammatory states. In the present investigation, EC were stimulated with LPS and from the supernatants the IL-1 activity was isolated. After AcA 54 gel filtration, the active 17 kD fraction was further purified by chromatofocusing, yielding active fractions with pI of 7.0 and 5.0. All of these fractions showed T lymphocyte chemotactic activity, stimulated the binding of T cells to EC and the proliferation of fibroblasts. It is concluded, therefore, that EC-derived IL-1 has similar biological activity to that of monocyte-derived IL-1 and that it can exert a true autocrine effect at the blood-tissue endothelial interface.

Cell Division↗
PubMed1988

[Exploration and modulation of the chemotaxis of lymphocytes].

Lymphocytes migrate and concentrate at inflammatory sites in part under the control of chemotactic factors. Lymphocyte chemotaxis has been studied in vitro using direct microscopic observation, the Boyden chamber technique and the migration under agarose or collagen gels. Various chemical compounds such as casein and cytokines such as interleukins 1 and 2 have been found to be chemotactic factors for lymphocytes. In addition, chemotaxis inhibitors have been described. Lymphocyte chemotaxis abnormalities have been described in various conditions: inflammation, auto-immune diseases, cancer. A better understanding of lymphocyte chemotaxis may provide a more specific therapeutic approach of such diseases.

Caseins↗