T LYMPHOCYTE ACTIVATION IN ACUTE SEVERE ASTHMA

doi:10.1016/S0140-6736(88)91951-4

The Lancet

Volume 331, Issue 8595, 21 May 1988, Pages 1129-1132

https://doi.org/10.1016/S0140-6736(88)91951-4 Get rights and content

Abstract

T lymphocyte subsets and lymphocyte activation markers in the peripheral blood were assessed in patients admitted to hospital with acute severe asthma (status asthmaticus). Measurements were made on admission, day 3, and day 7 (or on discharge from hospital if this was sooner). The results were compared with 3 control groups (mild asthma, chronic obstructive airways disease, and normal individuals). The percentages of CD4-positive and CD8-positive T lymphocytes, and the CD4/CD8 ratios, were similar in the patients with acute severe asthma and the control groups, and were within the normal range. In contrast, patients with acute severe asthma had significant increases, compared with control subjects, of three surface proteins associated wtih T lymphocyte activation: interleukin-2 receptor (IL-2R); class II histocompatibility antigen (HLA-DR); and "very late activation" antigen (VLA-1). The IL-2R-positive T lymphocytes were exclusively of the CD4 "helper-inducer" phenotype. The percentages of IL-2R-positive and HLA-DR-positive (but not VLA-1-positive) lymphocytes tended to decrease as the patients were treated and clinically improved, although these values remained raised above control values for the observation period. Cell-mediated immunity may be causally related to the pathogenesis of acute severe asthma.

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This led to a small study in severe asthma but it failed to produce a significant increase in lung function and no further trials have been planned (Kon et al., 1998). Another T cell subtype that has been shown to be increased in the airways of severe asthmatics are CD25 + CD4 + T cells (Corrigan, Hartnell, & Kay, 1988; Walker, Kaegi, Braun, & Blaser, 1991). Daclizumab, a humanized anti-CD25 IgG1 mAb, has been assessed in moderate to severe asthmatics (Busse et al., 2008).
A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby the patient experiences a pronounced worsening of disease symptoms. Moreover, acute exacerbations may also be a marker of insufficient disease management. The underlying cause of an acute exacerbation can be due to insults such as pathogens or environmental pollutants, or the cause can be unknown. For each acute exacerbation, the patient may require medical intervention such as rescue medication, or in more severe cases, hospitalization and ventilation and have an increased risk of death.
Biologics, such as monoclonal antibodies, are being developed for chronic respiratory diseases including asthma, COPD and IPF. This therapeutic approach is particularly well suited for chronic use based on the route and frequency of delivery and importantly, the potential for disease modification. In recent clinical trials, the frequency of acute exacerbation has often been included as an endpoint, to help determine whether the investigational agent is impacting disease. Therefore the significance of acute exacerbations in driving disease, and their potential as a marker of disease activity and progression, has recently received much attention. There is also now a need to standardize the definition of an acute exacerbation in specific disease settings, particularly as this endpoint is increasingly used in clinical trials to also assess therapeutic efficacy. Moreover, specifically targeting exacerbations may offer a new therapeutic approach for several chronic respiratory diseases.
Associations of IL-2 and IL-4 Expression and Polymorphisms With the Risks of Mycoplasma pneumoniae Infection and Asthma in Children
2015, Archivos de Bronconeumologia
El asma es una afección inflamatoria de las vías respiratorias. Las infecciones por Mycoplasma pneumoniae pueden exacerbar los síntomas del asma. Se ha demostrado que la interleucina 2 y la interleucina 4 participan en las reacciones inmunitarias e inflamatorias. Hemos estudiado la relación entre los polimorfismos de la IL2 y la IL4 y su expresión y el riesgo de padecer asma e infección por M. pneumoniae en niños.
Se reclutó a 392 niños asmáticos y 849 controles para el estudio. Se genotiparon 8 polimorfismos en IL2 e IL4 con la plataforma MassARRAY de Sequenom. La infección por M. pneumoniae y el número de copias se establecieron mediante PCR fluorescente. Los niveles séricos de expresión de IL-2 e IL-4 se midieron con ELISA.
Hallamos una relación significativa entre el polimorfismo rs6534349 de IL2 y el aumento de riesgo de sufrir asma (heterocigóticos, p = 0,029; variantes homocigóticas, p = 0,013), así como entre el polimorfismo rs2227284 de IL4 y una reducción del riesgo de padecer asma (heterocigóticos, p = 0,026; variantes homocigóticas, p = 0,001). Además, la relación con otros polimorfismos, excepto el rs2070874, se hizo evidente al agrupar a los niños asmáticos según la clasificación GINA de control y gravedad del asma. Asimismo, los niveles séricos de expresión de IL-2 e IL-4 fueron significativamente mayores en los sujetos no infectados (p = 0,038) e infectados (p = 0,011) por M. pneumoniae, respectivamente. Esta observación también se cumple entre los pacientes asmáticos (p = 0,016 para IL-2 y p = 0,042 para IL-4), pero en los controles no asmáticos solo se cumple en el caso de la IL-4 (p = 0,032). Del mismo modo, observamos que el genotipo GG rs6534349 estaba claramente relacionado con un aumento de las posibilidades de tener una infección con alta carga de M. pneumoniae (p = 0,0376).
La IL2 y la IL4 podrían ser biomarcadores importantes para calcular el riesgo de padecer asma, así como infección por M. pneumoniae, en niños.
Asthma is an inflammatory disorder of the airways and the symptoms of asthma could be exacerbated by Mycoplasma pneumoniae infection. Interleukin-2 and interleukin-4 have been implicated in immune and inflammatory reactions. We examined the associations of IL2 and IL4 polymorphisms and expression with the risks of asthma and M. pneumoniae infection in children.
392 asthmatic children and 849 controls were recruited into the study. Eight polymorphisms in IL2 and IL4 were genotyped with Sequenom MassARRAY platform. M. pneumoniae infection and copy number was determined with fluorescence PCR. IL-2 and IL-4 serum expression levels were determined by using ELISA.
We found a significant association of IL2 rs6534349 polymorphism with increased asthma risk (heterozygotes, P = .029; homozygous variants; P = .013) and of IL4 rs2227284 polymorphism with reduced asthma risk (heterozygotes, P = .026; homozygous variants; P = .001). Besides, the association of other polymorphisms, except rs2070874 polymorphism, became apparent when the asthmatic children were grouped according to GINA classification of asthma control and severity. In addition, IL-2 and IL-4 serum expression levels were significantly higher in M. pneumoniae negative (P = .038) and positive (P = .011) subjects respectively. This observation holds true among asthmatic patients (P = .016 for IL-2 and P = .042 for IL-4), but only the IL-4 observation remained correct among non-asthmatic controls (P = .032). We also observed that the rs6534349 GG genotype was significantly associated with increased odds of getting high load M. pneumoniae infection (P = .0376).
IL2 and IL4 could be important biomarkers for estimating the risks of asthma and M. pneumoniae infection in children.
Therapeutic novelties of inhaled corticosteroids and bronchodilators in asthma
2015, Pulmonary Pharmacology and Therapeutics
Orally inhaled agents are a key therapeutic class for treatment of asthma. Inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthma thus representing the first-line therapy and bronchodilators complement the effects of ICSs. A significant body of evidence indicates that addition of a β2-agonist to ICS therapy is more effective than increasing the dose of ICS monotherapy. In this paper, pharmacological features of available ICSs and bronchodilators will be reviewed with a focus on fluticasone propionate/formoterol fumarate combination which represents the one of the most powerful ICS acting together with the most rapid active LABA.
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Citation Excerpt :
Several of the other biologics under investigation target the cytokines involved in Th2-mediated allergic and asthmatic inflammation, including IL-2, IL-5, IL-4, and IL-13. IL-2 leads to the activation of Th2 cells, and symptomatic asthmatics have long been known to have increased levels of the IL-2 receptor.92 Daclizumab, a monoclonal antibody to the IL-2 receptor, has been shown in phase II trials to improve lung function in adults with moderate to severe asthma on inhaled corticosteroids.93
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Citation Excerpt :
It has been suggested that the commonly used mouse models are of limited relevance to the study of juvenile onset asthma [34]; the immune system physiology at birth is very different in mice and humans, and development to an adult state occurs in a matter of weeks in mice versus years in humans [34,35]. The current view of asthma attributes the main effector role to T lymphocytes, specifically Th2 cells, originally identified in mouse studies [17], but also obtained from studies demonstrating an increase in Th2 cytokines in the lungs of patients [36,37]. Differences also exist within species; the most commonly used mouse strains in experimentally induced models differ sharply in their propensity to cytokine production in response to certain agents [35,38].
The incidence of asthma is on the increase and calls for research are growing, yet asthma is a disease that scientists are still trying to come to grips with. Asthma research has relied heavily on animal use; however, in light of increasingly robust in vitro and computational models and the need to more fully incorporate the ‘Three Rs’ principles of Replacement, Reduction and Refinement, is it time to reassess the asthma research paradigm? Progress in non-animal research techniques is reaching a level where commitment and integration are necessary. Many scientists believe that progress in this field rests on linking disciplines to make research directly translatable from the bench to the clinic; a ‘21st-century’ scientific approach to address age-old questions.

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T LYMPHOCYTE ACTIVATION IN ACUTE SEVERE ASTHMA

Abstract

The pathology of asthma

A cellular abnormality m glucocorticoid-resistant asthma

Clin Exp Immunol

Resistance to methyl prednisolone in cultures of blood mononuclear cells from glucocorticoid-resistant asthmatic patients

Clin Sci

Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) cells in asthma. Relative increases in OKT8 cells in single early responders compared with those in late-phase responders

Am Rev Respir Dis

Ia determinants on human T-cell subsets defined by monoclonal antibodies

J Exp Med

Transient expression of interleukin-2 receptors

J Exp Med