RESUMO
While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines.
Assuntos
Hipersensibilidade/imunologia , Hipersensibilidade/terapia , Tolerância Imunológica/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Dessensibilização Imunológica/métodos , HumanosRESUMO
BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a "cytokine storm" or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs. CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.
Assuntos
Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Imunoglobulina E/efeitos adversos , Imunoglobulina E/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Receptores de IgE/metabolismo , Animais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/metabolismo , Linhagem Celular Tumoral , Receptor 1 de Folato/imunologia , Humanos , Imunoglobulina E/administração & dosagem , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Camundongos , Modelos Animais , Neoplasias/patologia , Ligação Proteica , Ratos , Estatísticas não Paramétricas , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangueRESUMO
Toluene diisocyanate (TDI)-induced asthma is a frequent occupational airway disease. To determine whether a calibrated dosage of oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by TDI, we examined six asthmatic subjects who developed a late or a dual asthmatic reaction after TDI inhalation challenge. We administered oral slow-release theophylline or placebo to each subject for 7 days according to a double-blind, randomized, cross-over study design. When the subjects received a placebo, TDI caused a late or a dual asthmatic reaction. When the subjects received theophylline. TDI caused significantly reduced late asthmatic reactions. Mean serum theophylline concentrations were within the therapeutic range. Theophylline neither modified the baseline airway responsiveness to methacholine, nor the increase of airway responsiveness to methacholine induced by TDI. These results suggest that slow-release theophylline may improve TDI-induced late asthmatic reactions, but it does not change the baseline airway responsiveness to methacholine and the increase of airway responsiveness to methacholine induced by TDI.
Assuntos
Asma/tratamento farmacológico , Teofilina/uso terapêutico , Tolueno 2,4-Di-Isocianato/antagonistas & inibidores , Administração por Inalação , Administração Oral , Análise de Variância , Asma/induzido quimicamente , Testes de Provocação Brônquica , Método Duplo-Cego , Humanos , Placebos , Teofilina/administração & dosagem , Teofilina/sangueRESUMO
PURPOSE: The clinical significance of VEGF-A expression in gastric cancer (GC) has been reported with contradicting results. We analyzed the expression and clinical significance of VEGF-A in a wide Italian cohort of GC specimens. METHODS: VEGF-A expression was tested by immunohistochemistry in 507 patients with GC of all clinical stages. The impact of VEGF-A on overall survival (OS) was evaluated in conjunction with clinical and pathological parameters. RESULTS: In the Italian cohort we studied VEGF-A was not an independent prognostic factor neither at the univariate nor at multivariate analysis. CONCLUSIONS: Although frequently expressed, in our study VEGF-A was not able to discriminate between groups of patients with different risk.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias Gástricas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenocarcinoma/mortalidade , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Itália , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/mortalidadeRESUMO
We report the sudden death of a 16 yr old boy with asthma. At presentation, the patient had symptoms of active asthma, mild bronchoconstriction, severe airway hyperresponsiveness to methacholine, and increased variability of peak expiratory flow records. After the patient was placed on inhaled beclomethasone (1 mg b.i.d preceded by inhaled fenoterol 0.4 mg b.i.d) he rapidly felt better, lung function improved, but airway responsiveness remained severe. Four months later, on the day he died, he was well until a fatal attack of asthma occurred around midnight without identifiable precipitating factors. Taken to hospital, he was dead on arrival. Necroscopy and microscopy showed the characteristic features of asthma death. This case report suggests that; a) asthma death may occur suddenly and unexpectedly; b) asthma death may not be prevented by long-term treatment with high-dose inhaled beclomethasone; c) severe bronchial hyperresponsiveness, even in the presence of stable peak flow records, may identify asthmatic patients at risk of sudden death.
Assuntos
Asma/fisiopatologia , Morte Súbita/etiologia , Adolescente , Asma/complicações , Asma/tratamento farmacológico , Beclometasona/uso terapêutico , Brônquios/fisiopatologia , Fenoterol/uso terapêutico , Humanos , MasculinoRESUMO
To determine whether circulating platelets alter during asthmatic reactions induced by allergens, we studied nine subjects previously shown to develop an early or dual asthmatic reaction after inhalation challenge with extracts of house dust mite or grass pollen. In each subject, FEV1, circulating platelets and leucocytes were measured before, 15, 30 and 60 min, and 2, 4, 6 and 8 hr after inhalation of allergen and diluent control administered in a single-blind, randomized fashion. The same procedure was repeated in six of the nine subjects after bronchoconstriction induced by methacholine. Each subject developed an early asthmatic reaction after allergen inhalation challenge, which was followed by a late asthmatic reaction in six subjects and by an equivocal late asthmatic reaction in two of them (fall in FEV1 of 15 and 17% respectively). Compared with the control day, circulating platelets significantly decreased during the allergen-induced early asthmatic reaction (P less than 0.025, at 30 min). Platelet counts returned to baseline values within 4 hr and remained steady thereafter both in subjects who did and did not develop a late asthmatic reaction. No changes in platelet counts occurred after bronchoconstriction induced by methacholine. Diurnal increase of leucocyte numbers occurred after challenge with both allergen and diluent control. These results suggest that platelets may be involved in the pathogenesis of allergen-induced asthmatic reactions.
Assuntos
Asma/complicações , Trombocitopenia/etiologia , Adolescente , Adulto , Animais , Asma/sangue , Asma/fisiopatologia , Testes de Provocação Brônquica , Feminino , Volume Expiratório Forçado , Humanos , Contagem de Leucócitos , Leucocitose/etiologia , Masculino , Cloreto de Metacolina , Compostos de Metacolina , Pessoa de Meia-Idade , Ácaros , Contagem de Plaquetas , PólenRESUMO
In asthmatic subjects, the degree of bronchial hyperresponsiveness correlates with the severity of asthma and the amount of treatment required to control asthma. Both in normal and in asthmatic subjects, the degree of airway responsiveness may increase after viral infections, exposure to oxidant pollutants and allergens or sensitizing agents; however, airway hyperresponsiveness is quite stable in the absence of exposure to inflammatory stimuli, suggesting that there are at least two components in airway hyperresponsiveness: a transient component, caused by airway inflammation, and a long-lasting one, unrelated to exposure to acute inflammatory stimuli, which is hypothesized to be due to changes in the autonomic innervation or in the smooth muscle itself.
Assuntos
Asma/fisiopatologia , Brônquios/fisiopatologia , Animais , Testes de Provocação Brônquica , Bronquite/fisiopatologia , Cães , HumanosRESUMO
To determine whether inhaled beclomethasone, both at low and at high doses, inhibits late asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 9 sensitised subjects. Low dose beclomethasone (200 micrograms bid), high dose beclomethasone aerosol (1000 micrograms bid), and placebo were administered for 7 days before TDI inhalation challenge to each subject, according to a double-blind, crossover study design. The washout period between the treatments was at least 1 week. When the subjects were treated with placebo, forced expiratory volume in 1 sec (FEV1) markedly decreased after exposure to TDI. By contrast, high dose beclomethasone prevented the late asthmatic reaction and the low dose partially inhibited the reaction. With placebo the mean (+/- SE) value of FEV1 4 h after exposure to TDI was 2.6 +/- 0.17 L, which went to 3.3 +/- 0.12 after low dose beclomethasone, and to 3.5 +/- 0.15 L after high dose of beclomethasone (significant difference in the decrease of FEV1 in the 8 h after exposure to TDI, between treatments: F = 9.87, (P less than 0.001), After treatment with placebo or with low dose beclomethasone, airway responsiveness to methacholine increased 8 h after exposure to TDI. With placebo, the PD20 decreased from 0.66 mg (Geometric Standard Error of the Mean [GSEM], 1.38) to 0.18 mg (GSEM, 1.46); with low dose inhaled beclomethasone, the PD20 decreased from 0.93 mg (GSEM, 1.42) to 0.36 mg (GSEM, 1.63).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Asma/tratamento farmacológico , Beclometasona/uso terapêutico , Compostos de Metacolina/farmacologia , Tolueno 2,4-Di-Isocianato/farmacologia , Administração por Inalação , Adulto , Asma/fisiopatologia , Beclometasona/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We report the case of a 43-yr-old car painter who died within 1 h of exposure to a polyurethane paint in the workplace. A diagnosis of asthma induced by toluene diisocyanate (TDI) had been established 6 yr before, when he underwent inhalation challenges with carbachol and with TDI. The subject had airway hyperresponsiveness to carbachol (PD20FEV1 carbachol = 0.32 mg; normal value greater than 1.0 mg) and developed an early and long-lasting asthmatic reaction after exposure to TDI in the laboratory. Although it was recommended that he change his job or stop using paints containing isocyanates, he continued to work as a car painter, taking antiasthmatic drugs both at work and at home to control asthma symptoms. On Monday, October 6, 1986, at 11:30 A. M., he developed a severe attack of asthma while he was mixing the 2 components of a polyurethane paint. Taken to hospital, he was dead on arrival. Autopsy showed no evidence of cardiac or brain disease; lungs were overinflated, the cut surface showed grey glistening mucous plugs in in the airways. Histologic examination showed denudation of airway epithelium and thickening of the basement membrane with infiltration of the lamina propria by polymorphonuclear leukocytes, mainly eosinophils, and diffuse mucous plugging of bronchioles. Bronchial smooth muscle appeared hyperplastic and disarrayed, and lung parenchyma showed focal areas of alveolar destruction adjacent to areas of perfectly intact alveolar walls.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Asma/induzido quimicamente , Cianatos/efeitos adversos , Tolueno 2,4-Di-Isocianato/efeitos adversos , Adulto , Asma/imunologia , Asma/mortalidade , Espasmo Brônquico/induzido quimicamente , Espasmo Brônquico/fisiopatologia , Espasmo Brônquico/terapia , Exposição Ambiental , Humanos , Pulmão/patologia , Masculino , Pintura/efeitos adversos , Poliuretanos/efeitos adversos , Tolueno 2,4-Di-Isocianato/imunologiaRESUMO
To determine whether 4 drugs used in the treatment of asthma inhibit the late asthmatic reaction and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 24 sensitized subjects divided into 4 groups. Beclomethasone aerosol (1 mg bid), slow-release theophylline (6.5 mg/kg bid), slow-release verapamil (120 mg bid), and cromolyn (20 mg qid via spinhaler), were administered for 7 days, respectively, to 1 of the 4 groups, according to a double-blind, crossover, placebo-controlled study design. When the subjects were treated with placebo, verapamil, or cromolyn, FEV1 markedly decreased and airway responsiveness increased after exposure to TDI. By contrast, beclomethasone prevented the late asthmatic reaction and the associated increase in airway responsiveness to methacholine induced by TDI. Slow-release theophylline partially inhibited both the immediate and the late asthmatic reactions but had no effect on airway hyperresponsiveness to methacholine. These results suggest that only high-dose inhaled steroids can completely block TDI-induced late asthmatic reactions.
Assuntos
Asma/tratamento farmacológico , Cianatos/efeitos adversos , Imunização , Pulmão/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/efeitos adversos , Asma/induzido quimicamente , Asma/fisiopatologia , Beclometasona/administração & dosagem , Testes de Provocação Brônquica , Ensaios Clínicos como Assunto , Cromolina Sódica/administração & dosagem , Preparações de Ação Retardada , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Cloreto de Metacolina , Compostos de Metacolina , Placebos , Distribuição Aleatória , Sistema Respiratório/efeitos dos fármacos , Teofilina/administração & dosagem , Fatores de Tempo , Verapamil/administração & dosagemRESUMO
In order to determine whether treatment with ketotifen inhibits asthmatic reactions induced by toluene di-isocyanate (TDI), we studied six sensitized subjects with previously demonstrated dual or late asthmatic reaction after inhalation challenge with TDI. Ketotifen (1 mg b.i.d., orally) or placebo was administered for 7 days to the examined subjects, according to a double-blind, cross-over, placebo-controlled study design. When the subjects were treated with either ketotifen or placebo, FEV1 markedly decreased after exposure to TDI. These results suggest that the anti-asthmatic agent ketotifen is not effective in TDI-induced asthma and suggest that it should not be used in the prophylaxis of asthmatic reactions induced by TDI in sensitized subjects.
Assuntos
Asma/prevenção & controle , Cianatos/antagonistas & inibidores , Cetotifeno/farmacologia , Tolueno 2,4-Di-Isocianato/antagonistas & inibidores , Asma/induzido quimicamente , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Hipersensibilidade Tardia , Imunização , Cetotifeno/administração & dosagem , Cloreto de Metacolina , Compostos de Metacolina/imunologia , Distribuição Aleatória , Tolueno 2,4-Di-Isocianato/efeitos adversosRESUMO
To determine whether oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by allergens, we examined six asthmatic subjects who developed a dual asthmatic reactions after allergen bronchoprovocation with Dermatophagoides pteronyssinus or with grass pollen. We gave oral slow-release theophylline and placebo to each subject for seven days in two series of experiments in a double-blind, randomized, crossover study. The individual daily dose of theophylline (4.7 to 16.6 mg/kg/day, divided into two doses) was calculated for each subject by measuring individual theophylline clearance and optimal daily dosage. During treatment with placebo, the subjects developed dual asthmatic reactions, ie, FEV1 decreased from 4.1 +/- 0.17 L before bronchoprovocation to 3.2 +/- 0.14 L at 15 minutes and to 3.2 +/- 0.19 L at seven hours after allergen bronchoprovocation. By contrast, during active treatment FEV1 decreased from 4.2 +/- 0.28 L to 3.9 +/- 0.26 L at 15 minutes, and to 3.8 +/- 0.13 L at seven hours (both cases, P less than .03 compared with placebo). Mean serum theophylline concentration was 13.2 +/- 0.6 mg/L. Although 1 week's treatment with slow-release theophylline did not modify significantly either prechallenge airway responsiveness to methacholine or its increase after allergen inhalation challenge, in five out of six subjects theophylline significantly inhibited the increase of airway responsiveness to methacholine induced by allergens compared to placebo and control day (P less than .05). These results suggest that slow-release theophylline may inhibit allergen-induced asthmatic reactions and the associated increase of airway responsiveness, suggesting some antiinflammatory effects for this drug.
Assuntos
Alérgenos/efeitos adversos , Asma/prevenção & controle , Teofilina/uso terapêutico , Administração Oral , Adolescente , Adulto , Asma/tratamento farmacológico , Asma/etiologia , Testes de Provocação Brônquica , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Cloreto de Metacolina/farmacologia , Cloreto de Metacolina/uso terapêutico , Teofilina/administração & dosagem , Teofilina/sangueRESUMO
To determine whether treatment with aerosolized dexamethasone isonicotinate inhibits asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied six sensitized subjects with previously demonstrated dual or late asthmatic reaction after inhalation challenge with TDI. Dexamethasone isonicotinate (four puffs bid for seven days, ie, 0.5 mg bid for seven days; last four puffs 30 minutes before TDI) was administered for seven days before the inhalation challenge with TDI (0.010 to 0.015 ppm for 10 to 30 minutes) to each subject, according to a single-blind study design. When the subjects received no treatment, FEV1 markedly decreased and airway responsiveness increased after exposure to TDI. By contrast, when the subjects were treated with dexamethasone-isonicotinate, FEV1 decreased significantly less, but airway responsiveness still significantly increased after exposure to TDI. These results suggest that aerosolized dexamethasone isonicotinate may be used in the prophylaxis of TDI-induced late asthmatic reactions.
Assuntos
Asma/prevenção & controle , Brônquios/fisiologia , Testes de Provocação Brônquica , Cianatos/farmacologia , Isonicotinato de Dexametasona/uso terapêutico , Dexametasona/análogos & derivados , Tolueno 2,4-Di-Isocianato/farmacologia , Adulto , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Nocturnal asthma reflects the severity of the disease, and thus its pharmacologic prevention represents one on the main goals of asthma management. SUBJECTS AND METHODS: To determine whether controlled-release theophylline inhibits the development of airway obstruction and/or airway hyperresponsiveness early in the morning, we examined 18 subjects reporting recurrent nocturnal asthma. In each subject, after five days' treatment with an 8 PM increasing dose of oral controlled-release theophylline, up to 10 +/- 1 mg/kg or placebo the night before the study day, we measured serum theophylline, FEV1 and PC20FEV1 at 6 AM, 2 PM and 10 PM. RESULTS: At 6 AM, both FEV1 and PC20FEV1 were significantly higher on theophylline than on placebo (3.52 +/- 0.22 versus 3.17 +/- 0.25 L; P < .005 and 2.76 divided by 3.61 versus 1.55 divided by 3.73 mg/mL; P < .05, respectively). At 2 PM and 10 PM FEV1, but not PC20FEV1, was higher on theophylline than on placebo (3.73 +/- 0.21 versus 3.54 +/- 0.25 L; P < .05 and 3.40 +/- 0.22 versus 3.24 +/- 0.24 L; P < .05). Serum theophylline was 12.8 +/- 1.1 micrograms/ml, 8.9 +/- 0.77 and 9.5 +/- 0.85 at 6 AM, 2 PM and 10 PM, respectively. CONCLUSIONS: We conclude that an evening dose of controlled-release theophyl line inhibits early morning airway obstruction and hyperresponsiveness, and that it may be helpful in the prevention of nocturnal asthma.