Inseon S. Choi

Therapeutic effects of BCG vaccination in adult asthmatic patients: a randomized, controlled trial

BACKGROUND Bacille Calmette-Guérin (BCG) vaccination in humans induces Th1 immune responses. Th1 and Th2 cells are reciprocally regulated. OBJECTIVE To examine whether BCG vaccination of adult patients with asthma, a Th2-associated allergic disease, is clinically effective. METHODS Forty-three moderate-to-severe asthma patients were randomly assigned into groups that received percutaneous injection of 58.2 x 10(7) CFUs BCG (n = 22) or placebo (n = 21) in a double-blinded fashion, on the first day of a 12-week treatment period. Medications were adjusted every 4 weeks to maintain optimal asthma control. Spirometric measurements were performed before treatment and at weeks 4, 8, and 12 after vaccination. The daily peak expiratory flow rate values, asthma symptoms, and medications were also recorded. Tuberculin skin tests, and sputum inflammatory cell and cytokine analyses were carried out before treatment and 12 weeks after vaccination. RESULTS BCG vaccination significantly increased forced expiratory volume in 1 second and forced expiratory flow rate 25% to 75% at weeks 4, 8, and 12. Morning peak expiratory flow rate was significantly increased only during the first 4 weeks. Although the asthma symptom scores were not significantly changed, the weekly medication scores were significantly decreased. Tuberculin skin reactivities were significantly increased without significant alterations in induced sputum profiles. In contrast, medication scores and sputum eosinophils were significantly increased, and the interferon-gamma:interleukin-4 ratio in sputum was significantly decreased in the placebo group. CONCLUSIONS BCG vaccination improved lung function and reduced medication use in adults with moderate-to-severe asthma. This amelioration was accompanied by a suppressed Th2-type immune response, suggesting that BCG vaccination might be an effective therapeutic modality against asthma.

Genome-Wide and Follow-Up Studies Identify CEP68 Gene Variants Associated with Risk of Aspirin-Intolerant Asthma

Aspirin-intolerant asthma (AIA) is a rare condition that is characterized by the development of bronchoconstriction in asthmatic patients after ingestion of non-steroidal anti-inflammatory drugs including aspirin. However, the underlying mechanisms of AIA occurrence are still not fully understood. To identify the genetic variations associated with aspirin intolerance in asthmatics, the first stage of genome-wide association study with 109,365 single nucleotide polymorphisms (SNPs) was undertaken in a Korean AIA (n = 80) cohort and aspirin-tolerant asthma (ATA, n = 100) subjects as controls. For the second stage of follow-up study, 150 common SNPs from 11 candidate genes were genotyped in 163 AIA patients including intermediate AIA (AIA-I) subjects and 429 ATA controls. Among 11 candidate genes, multivariate logistic analyses showed that SNPs of CEP68 gene showed the most significant association with aspirin intolerance (P values of co-dominant for CEP68, 6.0×10−5 to 4.0×10−5). All seven SNPs of the CEP68 gene showed linkage disequilibrium (LD), and the haplotype of CEP68_ht4 (T-G-A-A-A-C-G) showed a highly significant association with aspirin intolerance (OR  = 2.63; 95% CI  = 1.64–4.21; P = 6.0×10−5). Moreover, the nonsynonymous CEP68 rs7572857G>A variant that replaces glycine with serine showed a higher decline of forced expiratory volume in 1s (FEV1) by aspirin provocation than other variants (P = 3.0×10−5). Our findings imply that CEP68 could be a susceptible gene for aspirin intolerance in asthmatics, suggesting that the nonsynonymous Gly74Ser could affect the polarity of the protein structure.

Association of angiotensin I‐converting enzyme gene polymorphisms with aspirin intolerance in asthmatics

Background Aspirin‐intolerant asthma (AIA) refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin or other non‐steroidal anti‐inflammatory drugs (NSAIDs). Angiotensin I‐converting enzyme (ACE), a membrane‐bound peptidase present in the lung, plays a pivotal role in the metabolism of the endogenous peptides involved in the pathogenesis of asthma.

Seasonal Difference in the Occurrence of Exercise-Induced Bronchospasm in Asthmatics: Dependence on Humidity

Background: Most studies on the effects of temperature and humidity on exercise-induced bronchospasm (EIB) in asthmatics have been carried out under indoor conditions. However, any asthmatic patient is exposed to varying climatic conditions. Objective: To investigate whether temperature or relative humidity plays a more important role in determining the degree of EIB in asthmatics under naturally exposed climate conditions. Methods: To exclude the effects of pollen on EIB, we enrolled 69 subjects with perennial asthma (mean ± SD: 20.1 ± 1.5 years). The subjects performed outdoor free running tests. They were divided into winter (n = 25), spring/autumn (n = 22), and summer (n = 22) groups according to the season when they performed the tests. Initial spirometry and skin prick tests were performed. Methacholine bronchial challenge testing and, one day later, the free running tests were done. Results: There were significant differences in temperature and relative humidity among the three groups: However, the relative humidity in winter did not differ from that in spring/autumn. There were no differences in pulmonary functions, airway responsiveness, and atopy score among the three groups. The percentage of cases of positive EIB – fall in forced expiratory volume in 1s FEV1 of >15% from baseline – in winter (84%, p < 0.05) or spring/autumn (86.4%, p < 0.05) was higher than that in summer (50%). However, the percentage of subjects with a positive EIB in winter did not differ from that in spring/autumn. The maximal percent fall in FEV1 after exercise in winter did not differ from that in spring/autumn. Conclusions: The occurrence of EIB is associated with environmental temperature and humidity. Under such climatic conditions as in Korea, relative humidity may be a more important factor than temperature in contributing to EIB in patients with perennial asthma.

Effects of BCG revaccination on asthma

In a study conducted 1 year ago, we found that Th1 immune enhancement following Bacille Calmette–Guérin (BCG) vaccination effectively suppressed human asthma. To investigate whether revaccination would further improve lung function, BCG vaccine was given again. Current lung function tended to improve in the Repeated BCG group (n = 9), but not in the Single BCG group (previously the placebo group) (n = 11), compared with that 1 year ago. The BCG vaccination improved lung function in both groups, and the Repeated BCG group showed a significant increase in the peripheral blood interferon γ/interleukin 4 ratio. These findings suggest that repeated BCG vaccinations might be effective in asthma therapy.

BCG Infection in Allergen-Presensitized Rats Suppresses Th2 Immune Response and Prevents the Development of Allergic Asthmatic Reaction

Recent investigations demonstrate that bacille Calmette–Gu´erin (BCG), a potent inducer of Th1 response, infection prior to allergen sensitization inhibits Th2 immune responses to the allergen. However, it is not clear whether BCG infection in allergen-presensitized rats switches off Th2 response and prevents allergic asthmatic reaction to the subsequent allergen exposure. In this study we investigate whether BCG infection in ovalbumin (OVA)-presensitized Sprague-Dawley rats suppresses airway hyperresponsiveness and eosinophilic inflammation induced by OVA and Th2 cytokine production. BCG infection in OVA-presensitized rats significantly inhibited not only the sensitivity of airway smooth muscle to electrical field stimulation and acetylcholine but also absolute eosinophil counts in bronchoalveolar lavage fluid. As a correlate, interleukin-4 (IL-4) production significantly decreased and interferon-γ (IFN-γ) slightly increased, resulting in a markedly decreased ratio of IL-4–IFN-γ in OVA-presensitized rats with BCG infection. These results indicate that BCG infection in pre-sensitized rats suppresses allergic asthmatic reaction and Th2 immune response. It is possible from these findings that BCG vaccine may be used as an immunomodulating agent for the sensitized host with preestablished Th2 memory.

Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity.

Objective Aspirin affects interleukin-4 (IL-4) synthesis; however, the genetic role of IL-4 has not been evaluated in asthmatics with aspirin hypersensitivity. The objective of the study was to examine the influence of single nucleotide polymorphisms (SNPs) in IL-4 gene on aspirin hypersensitivity in asthmatics at the genetic and molecular levels. Methods Aspirin-intolerant (AIA, n=103) and aspirin-tolerant asthmatics (n=270) were genotyped and functional promoter assays were performed. Results Of 15 SNPs tested, seven (−589T>C (rs2243250) in promoter, −33T>C (rs2070874) in the 5′-untranslated region, +4047A>G (rs2243266), +4144C>G (rs2243267), +4221C>A (rs2243268), +4367G>A (rs2243270), and +5090A>G (rs2243274) in introns) were significantly associated with AIA risk. The frequency of the rare allele (C) of −589T>C was higher in the AIA group than in the aspirin-tolerant asthmatic group (Pcorr=0.016), and a gene dose-dependent decline in forced expiratory volume in 1 s was noted after an aspirin challenge (P=0.0009). Aspirin unregulated IL-4 mRNA production in Jurkat T and K562 leukemia cells. A reporter plasmid assay revealed that aspirin augmented IL-4 promoter transactivation with the −589T>C C and −33T>C C alleles, compared with that bearing the −589T>C T and −33T>C T alleles. Further, electrophoretic mobility shift assay showed the formation of nuclear complexes with −33T>C and −589T>C allele-containing probes; this was augmented by aspirin. The complexes formed with the −33T>C and −589T>C probes were shifted by treatment with anti-CCAAT-enhancer-binding proteins &bgr; and anti-nuclear factor of activated T-cells antibodies, respectively, indicating the inclusion of these transcription factors. Conclusion Aspirin may regulate IL4 expression in an allele-specific manner by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, leading to aspirin hypersensitivity.

Nitric oxide metabolites in induced sputum: a marker of airway inflammation in asthmatic subjects

The role of nitric oxide (NO) needs to be further clarified in allergic inflammation. This study was designed to investigate the relationships between NO metabolites and eosinophil count, eosinophil cationic protein (ECP), interleukin (IL)‐5 in induced sputum from asthmatics.

Gender-Specific Asthma Treatment

Because genetic characteristics vary among subjects, the therapeutic effects of a certain drug differ among patients with the same disease. For this reason, special interest has focused on tailored treatments. Although it is well known that sex is genetically determined, little attention has been paid to sex differences in the clinical features and treatment of asthma. Females are more likely to suffer allergic asthma, to have difficulty controlling asthma symptoms, and to show adverse effects to drugs. As asthma symptoms show cyclic changes depending on female hormone levels in many women of child-bearing age, the use of contraceptives may specifically help to treat female patients with asthma such as those with perimenstrual asthma and severe asthma. Generally, testosterone seems to suppress asthma, and dehydroepiandrosterone (DHEA), a less virilizing androgen, may be effective for treating asthma. Evidence exists for a therapeutic and steroid-sparing effect of DHEA. However, further studies on the optimal dose and route of DHEA for each sex are needed. Monitoring of the serum DHEA-S level is necessary for patients with asthma on inhaled steroid treatment, and at minimum, replacement therapy for patients with a low level of DHEA may be helpful for treating their asthma.

Additive Effect of Diesel Exhaust Particulates and Ozone on Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

Allergic airway diseases are related to exposure to atmospheric pollutants, which have been suggested to be one factor in the increasing prevalence of asthma. Little is known about the effect of ozone and diesel exhaust particulates (DEP) on the development or aggravation of asthma. We have used a mouse asthma model to determine the effect of ozone and DEP on airway hyperresponsiveness and inflammation. Methacholine enhanced pause (Penh) was measured. Levels of IL-4 and IFN-γ were quantified in bronchoalveolar lavage fluids by enzyme immunoassays. The OVA-sensitized-challenged and ozone and DEP exposure group had higher Penh than the OVA-sensitized-challenged group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone exposure group. Levels of IFN-γ were decreased in the OVA-sensitized-challenged and DEP exposure group and the OVA-sensitized-challenged and ozone and DEP exposure group compared to the OVA-sensitized-challenged and ozone exposure group. Levels of IL-4 were increased in the OVA-sensitized-challenged and ozone exposure group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone and DEP exposure group compared to OVA-sensitized-challenged group. Co-exposure of ozone and DEP has additive effect on airway hyperresponsiveness by modulation of IL-4 and IFN-γ suggesting that DEP amplify Th2 immune response.