Partial safety of the new COX-2 inhibitor rofecoxib in NSAIDs high sensitive patients.
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Adolescent↗
Biomedical subjects
A Matucci
Publications and source records attributed to A Matucci.
Highly Th2-skewed cytokine profile of beta-lactam-specific T cells from nonatopic subjects with adverse drug reactions.
A positive lymphocyte transformation test to beta-lactams (beta-L) was found in 12 of 29 subjects with adverse drug reaction (ADR) to beta-L, irrespective of either the type of clinical manifestation or the presence of specific serum IgE. Short-term T cell lines specific for penicillin G, amoxicillin, and ampicillin could be generated only from subjects with ADR (eight with positive and one with negative lymphocyte transformation test), while streptokinase and Dermatophagoides pteronyssinus group 1 (Der p 1)-specific T cells were obtained from all these subjects, from 7 atopic Der p-sensitive donors without history of ADR and 17 healthy nonatopic donors. Streptokinase-specific T cells from all subjects showed intracellular expression of IFN-gamma with poor or no IL-4, whereas Der p 1-specific T cells exhibited IFN-gamma but low or no IL-4 expression in nonatopics, and remarkable IL-4 expression in atopic donors. By contrast, all penicillin G-, ampicillin-, and amoxicillin-specific short-term T cell lines showed high intracellular expression of IL-4, IL-5, and IL-13, but poor or no expression of IFN-gamma, thus exhibiting a clear-cut Th2 profile. Accordingly, most penicillin G-specific T cell clones derived from two subjects with ADR released high concentrations of IL-4 alone or IL-4 and IFN-gamma. These data suggest that cytokines produced by Th2 cells play an important role in all beta-L-induced ADR, even when late clinical manifestations occur and an IgE-mediated mechanism is apparently indemonstrable.
Allergens↗
Source of IL-4 able to induce the development of TH2-like cells.
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Animals↗
[Bronchial asthma: pathogenetic mechanisms and genetic aspects].
At present there is a general consensus on the inflammatory nature of bronchial asthma. The main immunological features of the atopic state are represented by the ongoing expansion of Th2-like cells and production of IgE antibodies. IL-4 seems to represent the key factor for the differentiation of Th2-like cells, even though other cytokines have been recently proposed to play a some role. The possible genetic alterations which lead to the deregulated overexpression of IL-4 gene and of other genes of the same family in atopics are under active investigation. The existence of a polymorphism at level of IL-4 gene distal and proximal promoter has directly been shown. Even though IL-4 is required for the development and maintenance of atopic state, IL-5 certainly plays an essential role in the pathogenesis of bronchial inflammation in atopic, intrinsic and occupational asthma. On the basis of the findings emerged from new experimental models, it appears that there are different pathways by which T cell responses can develop bronchial eosinophilic inflammation but all the pathways have to lead to obligatory ongoing production of IL-5. The future research can be also addressed either to clarify the cytokines and/or other factors able to induce the differentiation and ongoing expansion of T cells prevalently producing IL-5, possibly involved in the pathogenesis of intrinsic asthma, either to understanding the nature of stimuli acting as etiologic factors. On the basis of the present acquisitions, IL-5 could represent the most important target of the new approaches to asthma therapy.
Animals↗
Plasminogen activator and receptor in osteoarthritis.
Evidence indicates that breakdown of articular cartilage resulting in the loss of normal joint function is the distinctive feature of osteoarthritis. Degradation of cartilage extracellular matrix components involves the action of at least 2 classes of proteinases: serine proteinases and metalloproteinases. Receptors have been described on a wide range of cell lines for many such proteinases [urokinase-type plasminogen activator (u-PA), plasminogen/plasmin, collagenase], which subsequently activate each other on the solid phase of the cell surface, leading to cartilage destruction. We review the leading role of u-PA and its receptor (u-PAR) in cartilage degradation.
Cartilage, Articular↗
Control of the chondrocyte fibrinolytic balance by the drug piroxicam: relevance to the osteoarthritic process.
OBJECTIVE: Since the plasminogen activator [PA/plasminogen activator inhibitor (PAI) system is believed to be involved in a breakdown of articular cartilage in osteoarthritis (OA), we studied the modulation of single components of the fibrinolytic system (urokinase-type plasminogen activator, u-PA; plasminogen activator inhibitor-1, PAI-1; the surface receptor for u-PA, u-PAR) in human chondrocytes in the presence of piroxicam. METHODS: The drug was added to the chondrocyte culture medium either directly or by supplementing chondrocyte cultures with synovial fluid (SF) from patients with OA treated with piroxicam. We have shown u-PAR M(r) 55000 Da on human chondrocytes in suspension culture by cross linking chondrocyte lysates with 125I-labelled amino-terminal fragment (ATF) of human u-PA, which frames the sequence that specifically interacts with u-PAR. RESULTS: Such receptors decrease upon incubation of chondrocytes with piroxicam or with SF from patients treated with piroxicam. The culture medium of treated chondrocytes showed decreased fibrinolytic activity when compared with untreated controls, while PAI activity was increased in both SF chondrocyte culture medium following piroxicam treatment. At the same time, internalization of u-PA/u-PAR complexes increased after incubation of chondrocytes with piroxicam or PAI-1 rich SF. CONCLUSION: Our results indicate that the drug induces the surface clearance u-PAR by internalization of u-PA/PAI-/u-PAR complexes. Thus piroxicam reduces both the soluble fibrinolytic activity of human chondrocytes (increase of PAI activity and decrease of released u-PA) and the cell associated u-PA activity (clearance of u-PAR by internalization). The drug dependent changes in the fibrinolytic system suggest that piroxicam may be useful in preventing or limiting perilacunar cartilage damage in OA.
Autoradiography↗
The importance of Th2-like cells in the pathogenesis of airway allergic inflammation.
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Allergens↗
New joint imaging tools in osteoarthritis. I--Validation and preliminary experience with GGGS treatment.
In the pathology of joints, the main aim is an early diagnosis. In osteoarthritis (OA), where laboratory support is particularly poor, traditional radiology is informative only when the pathologic process is so advanced that prevention is difficult, either by changing life habits or by treating with chondroprotective drugs. Therefore an ideal diagnostic imaging tool should be sensitive, specific, reproducible and not invasive. In our opinion, Nuclear Magnetic Resonance (NMR) has all these characteristics and in particular can show meaningful pictures of cartilage and subchondral bone. We therefore compared NMR and traditional radiology to the gross pathology shown by arthroscopy at an early stage of OA, before and after treatment with glycosamino-glucuron-glycan-sulphate (GGGS) or placebo. Our results suggest that NMR is quite meaningful and can detect early OA joint modifications. With this technique the placebo-treated OA patients showed a natural increase in their pathologic picture, while the GGGS-treated patients seemed to experience a retardation in the progression of the disease.
Aged↗
[Autoimmunity and organic disease].
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Autoantibodies↗
[Primary antiphospholipid antibody syndrome: clinical features and analysis of personal cases].
We studied 11 patients with primary antiphospholipid syndrome (PAPS), basing our diagnosis on Harris's clinical and serological criteria. Analysis of these cases brought to light a number of symptoms that have a statistically significant association with PAPS. Although these symptoms have not yet been recognized internationally as diagnostic criteria, we anticipate that they will be included on a revised and lengthened list of clinical symptoms used for the diagnosis of PAPS. There was a high incidence of neurological symptoms in our case group: disorders were often observed before the onset of full-blown disease and could be confirmed by means of cerebral NMR and SPECT analysis. We believe that further investigation will enable researchers to determine the predictive value of these PAPS-related neurological disorders.
Adult↗
T cells, cytokines, IgE and allergic airways inflammation.
Great progress in the knowledge of the cellular and molecular signals involved in IgE antibody synthesis and in the induction of allergic inflammation has been achieved. A great deal of data support the view that Th-2-like cells are the main type of cells required for IgE production and are able to orchestrate allergic tissue inflammation. In particular, a reciprocal role for IL-4 (positive)- and IFN-gamma (negative)-producing CD4+ Th cells in the regulation of human IgE synthesis has been proven. However, a physical membrane interaction between T and B cells is required for IL-4-dependent IgE synthesis. The analysis of cytokine production by allergen-specific T cells has demonstrated that the great majority of these cells, derived from the peripheral blood of atopic patients, express a Th-2/Th-0 phenotype. Furthermore, in atopic subjects, aberrant in vitro production of IL-4 and IL-5, even in response to bacterial antigens, is displayed by CD4+ T cell clones. There is a general consensus on the accumulation of Th-2-like cells at the level of the target tissues of allergic inflammation such as the respiratory mucosa during allergic rhinitis and asthma, and at the level of the skin during atopic dermatitis. Even in other forms of bronchial asthma (intrinsic and occupational asthma), particular subsets of T cells, able to produce IL-2 and IL-5 but not IL-4, may play an important role. A great effort on the characterization of the factors that may favor the development in atopics of Th cells into Th-2-like cells has been made.(ABSTRACT TRUNCATED AT 250 WORDS)
Allergens↗
[Cellular and molecular mechanisms of allergic respiratory tract inflammation].
Knowledge of the cellular and molecular aspects of allergic airway inflammation has increased greatly. It is now clear that the type of specific immune response is determined by the preferential activation of CD4+ T cell subsets which secrete defined patterns of cytokines, and it has been suggested that Th2-like cells, able to produce IL-4 and IL-5, but not IFN-gamma, play an important role in the induction and maintenance of allergic airway inflammation. It has been demonstrated, moreover, that mast cells can secrete cytokines which are analogous to those produced by Th2-like cells. It is thus possible that both mast cells and Th2-like cells are involved in the induction and maintenance of allergic airway inflammation. We review here the genetic and environmental factors predisposing to allergic respiratory diseases, especially those potentially favoring the development of Th2-like cells. Particular attention is paid to the possible role of the antigen presenting cells, HLA class II molecules, T cell repertoire, and microenvironmental cytokines. We also discuss the crucial role that IL-4 plays in the development of Th2-like cells from their precursors as well as hypotheses concerning the possible molecular alterations responsible for the overexpression of the IL-4 gene in atopic subjects. This new information certainly facilitates the planning of preventive and treatment tactics for bronchial asthma.
Antigen-Presenting Cells↗
Cellular and molecular basis of airway allergic inflammation.
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Animals↗
[Current views on the etiopathogenesis of type-I diabetes mellitus].
In the last few years the improvement of our knowledge of the pathogenesis of type I diabetes mellitus has been possible mainly because of the development of studies of the role played by genetic factors and the better definition of lesion mechanisms. The availability of experimental models such as "non obese diabetic (NOD)" mice and "Bio-Breeding (BB)" rats, which develop a form of type I diabetes similar to that of humans, has provided many data regarding the relevance of T lymphocytes in the pathogenesis of the disease, and made it possible to anticipate the immunopathological steps leading to pre-insulitis, insulitis and, finally, to pancreatic beta-cell destruction. The analysis of sera of patients with type I diabetes has demonstrated the presence, also in the preclinical states, of several autoantibodies directed against specific autoantigenic structures of beta cells, which have come to be useful for early diagnosis and in the monitoring of the disease. However, hard evidence for a relevant role of these autoantibodies in the pathogenesis of the disease does not exist. At present, we can affirm that the expansion of autoreactive T lymphocytes specific for membrane antigens of beta cells is the most relevant immunological event for the induction and sustenance of insular lesions. Autoreactive T lymphocytes may be able to activate several effector systems of lesions through the production of multiple combinations of cytokines. The aetiology of the disease is certainly multifactorial and involves both genetic and environmental factors. With respect to the former, the most accurate studies have been performed on the HLA system. It has been clearly shown that type I diabetic patients more frequently display HLA DR3 and DR4 specificities. The results obtained by the application of molecular techniques have suggested considering as risk factors the occurrence of DQB1 0302 DQB1 0201 alleles, the presence of a neutral amino acid residue in position 57 of the DQ beta chain instead of aspartic acid, as well as an arginine residue in position 52 of the DQ alpha chain. With regard to acquired aetiological factors, the hypothesis that primary lesions of pancreatic islets could be due to some viral infections capable of triggering, through several undefined mechanisms, persistent and self-sustaining autoimmune reactions, has gained some credit.
Animals↗
[Current advances in various aspects of chronic obstructive bronchopneumopathy and in the pathogenesis of bronchial asthma].
The continuing interest of researchers in chronic obstructive pulmonary disease (COPD) is due not only to its increasing socio-economic impact, but also to the rapid advances made in the comprehension of various mechanisms of this disease, advances made feasible chiefly by a broader interdisciplinary approach to the subject. The most significant progress has been made through the study of bronchial asthma: researchers have confirmed that a particular inflammation of the bronchial mucosa is the common feature of all asthmatic syndromes. IgE antibodies specific for allergens as well as Th2 type T cells seem to play a central role in allergic bronchial asthma. Other types of T cells producing different combinations of cytokines, chiefly IL-5, may be involved in the pathogenesis of intrinsic and professional asthma. It is hoped that this recently gained knowledge will enable improvement in the prevention and therapy of asthma and other COPD syndromes.
Asthma↗
[Cortisone-resistant bronchial asthma].
There is general agreement on the inflammatory pathogenesis of bronchial asthma: an accumulation of activated eosinophils, degranulated mast cells, T lymphocytes and in very severe forms, granulocytes has constantly been found in the bronchial mucosa. In allergic bronchial asthma, inflammation seems to be orchestrated predominantly by a subset of T lymphocytes, with a phenotype similar to the Th2 subset able to produce IL-4 and IL-5. Although corticosteroids are the most potent therapeutic agents used for this disease, their anti-inflammatory effect differs from patient to patient. Some criteria which can be used to define steroid-resistant bronchial asthma are listed here. This review analyzes various molecular alterations responsible for the deficient response to corticosteroid treatment observed in steroid-resistant bronchial asthmatic subjects. New knowledge on the mechanism of steroid resistance may have important implications for the treatment of chronic asthma and other diseases.
Adrenal Cortex Hormones↗
IL-4 as a key factor influencing the development of allergen-specific Th2-like cells in atopic individuals.
In the last years Th2-like cells, able to produce IL-4, IL-5, IL-6 and IL-10, have been shown to play an important role in the pathogenesis of allergic diseases. They are absolutely required for IgE production by B-cells and are expanded at the level of target tissues of atopic patients. Very recently, much attention has been focused on the genetic and environmental factors responsible for the differentiation and ongoing expansion of allergen-specific Th2-like cells in atopic subjects. In this review possible cellular sources of IL-4 in the primary, secondary and ongoing responses to allergens are discussed. In atopics, Th cell precursors themselves could be proposed as a main source of IL-4 in the primary responses to allergens. However, there is extensive evidence for the role of other cells such as mast cells, basophils and eosinophils as important sources of IL-4 the secondary and ongoing responses to allergens.
Allergens↗
New advances in the pathogenesis and therapy of bronchial asthma.
At present, general consensus exits on the inflammatory nature of bronchial asthma. Advances in the knowledge of pathogenetic mechanisms of bronchial asthma are certainly to be ascribed to the use of immunobiological, molecular and genetic approaches for studying experimental models and human bronchial asthma. The histopathological hallmark of bronchial asthma consists in the constant presence, at the level of bronchial mucosa, even in the mild and intermittent syndromes, of epithelial lesions, thickening of basement membrane, and inflammatory infiltration consisting of activated eosinophils, Th2 lymphocytes and degranulated mast cells. Cellular and molecular alterations responsible for this typical bronchial inflammation and the subsequent patho-physiological and clinical characteristics of bronchial asthma have been identified. It has been shown that interleukin-4 is the principal cytokine necessary for Th2 lymphocyte differentiation and expansion and IgE production. Interleukin-5 acts specifically on eosinophil activation, terminal differentiation, and survival. As only eosinophils primed by interleukin-5 as well as by interleukin-3 and granulocyte macrophage-colony stimulating factor can express all the membrane receptors and integrins, they become able to bind to adhesion molecules overexpressed on the mucosal microvascular endothelial cells and of being selectively chemoattracted by a particular subgroup of beta-chemokines, which bind to their membrane CC-receptor-3. The amplification and maintenance of airway inflammation and the clinical exacerbations and chronicity of bronchial asthma depend on complex mechanisms. Tumor necrosis factor-alpha and interleukin-1 beta play a fundamental role in the induction of multiple cellular and molecular interactions. Molecular approaches are now being used to define genetic predisposition. Candidate genes have been located on different chromosomes. In addition to bronchodilator medication to relieve symptoms, the most important purpose of asthma therapy must be based on anti-inflammatory agents to reduce airway inflammation and airway hyperreactivity. Corticosteroids appear able to interfere with almost all components of inflammation. New inhaled steroids have radically modified therapeutic principles of bronchial asthma. Even cromones and anti-leukotrienes have been recommended as anti-inflammatory agents. Some developing therapeutic strategies involve use of anti-IgE antibodies, interleukin-4 and interleukin-5 inhibitors and chemokine receptor antagonists.
Animals↗