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L Borish

Publications and source records attributed to L Borish.

At least 19 recordsLinked to original sources
PubMed2000

IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization.

Cytokines play an important role in modulating inflammatory responses and, as a result, airway tone. IL-10 is a regulatory cytokine that has been suggested for treatment of asthma because of its immunosuppressive and anti-inflammatory properties. In contrast to these suggestions, we demonstrate in a model of allergic sensitization that mice deficient in IL-10 (IL-10-/-) develop a pulmonary inflammatory response but fail to exhibit airway hyperresponsiveness in both in vitro and in vivo assessments of lung function. Reconstitution of these deficient mice with the IL-10 gene fully restores development of airway hyperresponsiveness comparable to control mice. These results identify an important role of IL-10, downstream of the inflammatory cascade, in regulating the tone of the airways after allergic sensitization and challenge.

Aerosols↗
PubMed1999

Genetics of allergy and asthma.

LEARNING OBJECTIVES: This article summarizes the latest information regarding the role of genetic influences in the development of allergic disorders and asthma and reviews our current information on some of the most likely genes responsible for these conditions. After reading this article, the reader will have a better understanding of the current molecular biologic techniques that are being used to understand complex genetic disorders such as allergies and asthma. The reader should understand the value of how this genetic insight will lead to the recognition of the presence of specific subtypes of these disorders that require unique therapeutic interventions. This information can also be used to identify genetically at risk children and thereby offer earlier intervention. Finally, understanding the genetic causes of allergies and asthma will lead to the development of the next--hopefully curative--generation of asthma and allergy therapeutics. DATA SOURCES: A detailed literature search was conducted. Studies considered relevant, well performed, and appropriately controlled were used. Only human studies are included and only the English language literature was reviewed. Some of the information presented is based on the author's own research experience. STUDY SELECTION: Material was only taken from peer-reviewed journals and appropriate reviews. RESULTS AND CONCLUSIONS: Asthma and allergic diseases are examples of disorders having an unmistakable genetic predisposition, but in the absence of a classic Mendelian inheritance pattern. These "complex" genetic disorders are caused by the interactions of multiple interacting genes some having protective value and some contributing to disease development and with each gene having its own variable tendency to be expressed. In addition, these disorders require the presence of appropriate environmental triggers for their expression. One approach to identifying the genetic basis for these conditions is to perform a genome-wide search in which the location of the disease-causing gene on a human chromosome is identified and nearby genes that may be responsible are subsequently identified. An alternative approach to identifying heritable components to asthma and allergy is to evaluate disordered structure or regulation within genes known to be involved in these disorders. Using these approaches, studies have suggested that genes within the cytokine gene cluster on chromosome 5 (including interleukins-3, -4, -5, -9, and -13), chromosome 11 (the beta chain of the high affinity IgE receptor), chromosome 16 (the IL-4 receptor), and chromosome 12 (stem cell factor, interferon-gamma, insulin growth factor, and Stat 6 [IL-4 Stat]) may contribute to asthma and allergy development. In addition, data support involvement of genes involved in antigen-presentation (MHC class II genes) and T cell responses (the T cell receptor alpha chain). Finally, disease-contributing alleles may be present on genes for the beta-adrenergic receptor, 5-lipoxygenase, and leukotriene C4 synthase.

Antigen Presentation↗
PubMed1999

Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma.

Recent family-based studies have revealed evidence for linkage of human chromosome 5q31 to the diagnosis of asthma, elevated serum IgE levels, and bronchial hyperresponsiveness. Among the candidate genes in this region is the gene encoding for human interleukin-4 (IL-4). We reasoned that this gene could also serve as a candidate gene with respect to asthma severity as indicated by the FEV(1) measured when bronchodilator treatment was withheld. To test this hypothesis, we examined a large population of patients with asthma (ascertained without respect to genetic characteristics), for associations between a genetic variant in the IL-4 promoter region (C-589T) and asthma severity, as indicated by FEV(1). We used amplification by the polymerase chain reaction followed by BsmF1 restriction digestion to assign genotypes at the IL-4 promoter C-589T locus. We compared genotypes at this locus in 772 Caucasian and African American patients with asthma of varying severity, and we used multiple regression analysis to relate genotypic findings to FEV(1). Among white individuals, the homozygous presence of the C-589T IL-4 promoter genotype (TT) was associated with a FEV(1) below 50% of predicted (p = 0.013; OR, 1.44; 95% CI: 1.09 to 1.90). Subjects with the TT genotype had mean FEV(1) (% predicted) values 4.5% lower than those of subjects with the wild-type (CC) genotype at this locus. FEV(1) values of white patients with a CC or CT genotype were broadly distributed, whereas the TT genotype was associated with a narrow distribution of low FEV(1) values. The frequency of the T allele was significantly greater (p = 1 x 10(-)(23)) among African American asthmatics (0.544) than among white asthmatics (0.183). These data provide the first evidence associating FEV(1) in patients with asthma and genetic determinants at any locus. Our data are consistent with the idea that the FEV(1) in asthma is the result of multiple factors; one of these factors is the genotype at the IL-4 C-589T locus. This locus is associated with a small but significant decrement in pulmonary function among white asthmatic subjects.

Adult↗
PubMed1998

Chronic fatigue syndrome: identification of distinct subgroups on the basis of allergy and psychologic variables.

BACKGROUND: We investigated a role for allergic inflammation and psychologic parameters in the development of chronic fatigue syndrome (CFS). METHODS: The design was a comparison between subjects with CFS and age- and sex-matched control cohorts. Studies were performed on CFS subjects (n = 18) and control cohorts consisting of normal subjects (n = 11), allergic subjects (n = 14), and individuals with primary depression (n = 12). We quantified cytokines at baseline as cell-associated immunoreactive peptides and as transcripts evaluated by means of semiquantitative RNA-based polymerase chain reactions. Psychologic evaluations included administration of the Diagnostic Interview Schedule, the Structured Clinical Interview, and the Symptom Checklist 90-Revised. RESULTS: Increases in tumor necrosis factor (TNF)-alpha were identified in individual subjects with CFS (50.1 +/- 14.4 pg TNF-alpha per 10(7) peripheral blood mononuclear cells [PBMCs]; mean +/- SEM) and allergic subjects (41.6 +/- 7.6) in comparison with normal subjects (13.1 +/- 8.8) (P < .01 and P < .05, respectively). Similar trends were observed for interferon (IFN)-alpha in allergic subjects (3.0 +/- 1.7 pg/10(7) PBMCs) and subjects with CFS (6.4 +/- 3.4) compared with normal subjects (1.9 +/- 1.4). A significant increase (P < .05) in TNF-alpha transcripts was demonstrated between subjects with CFS and depressed subjects. In contrast to these proinflammatory cytokines, both subjects with CFS (2.6 +/- 1.8 pg/10(7) PBMCs) and allergic subjects (3.4 +/- 2.8) were associated with a statistically significant (P < .01) decrease in IL-10 concentrations compared with normal subjects (60.2 +/- 18.2). As shown in other studies, most of our subjects with CFS were allergic (15 of 18) and therefore presumably demonstrated cytokine gene activation on that basis. The seasonal exacerbation of allergy was associated with a further increase in cellular IFN-alpha (from 2.1 +/- 1.2 to 14.2 +/- 4.5 pg/107 PBMCs; P < .05) but no further modulation of TNF-alpha or IL-10. Similarly, self-reported exacerbations of CFS were associated with a further increase in IFN-alpha (from 2.5 +/- 1.0 to 21.9 +/- 7.8; P < .05) and occurred at times of seasonal exposures to allergens. This linkage does not permit making any definitive conclusions regarding a causative influence of either seasonal allergies or the increase in cellular IFN-alpha with the increase in CFS symptoms. The close association between atopy and CFS led us to speculate that CFS may arise from an abnormal psychologic response to the disordered expression of these proinflammatory and antiinflammatory cytokines. Psychologic variables were predictive of immune status within the CFS sample (65.9% of the variance in immune status; F (3,10) = 6.44, P < .05). Specifically, the absence of a personality disorder but greater endorsement of global psychiatric symptoms was predictive of immune activation. CONCLUSIONS: Most of our subjects with CFS were allergic, and the CFS and allergy cohorts were similar in terms of their immune status. However, the CFS subjects could be discriminated by the distinct psychologic profiles among subjects with and without immune activation. We propose that in at least a large subgroup of subjects with CFS who had allergies, the concomitant influences of immune activation brought on by allergic inflammation in an individual with the appropriate psychologic profile may interact to produce the symptoms of CFS. In a psychologically predisposed individual, symptoms associated with allergic inflammation are recognized as illness.

Adult↗
PubMed1998

Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma.

Interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) are inhibitory for B and T cells, IgE production, and mast cell proliferation, and they induce apoptosis in eosinophils. These cytokines are therefore candidate genes which could contribute to the development of asthma or allergies. We investigated the hypothesis that polymorphic nucleotides within the IL-10 and TGF-beta gene promoters would link to the expression of allergies and asthma. DNA taken from families with an asthmatic proband was examined for base exchanges by single-stranded conformational polymorphism (SSCP). We demonstrated the presence of a polymorphism in the promoter region of the IL-10 gene and four in the TGF-beta gene promoters (3 in TGF-beta1 and 1 in TGF-beta2). The IL-10 gene polymorphism was a C-to-A exchange 571 base pairs upstream from the translation start site and was present between consensus binding sequences for Sp1 and elevated total serum. This polymorphism was associated with elevated total serum IgE in subjects heterozygotic or homozygotic for this base exchange (p < 0.009). The base exchange at -509 (from the transcription initiation site) in the TGF-beta promoter also linked to elevated total IgE (p < 0.01). This polymorphism represented a C-to-T base exchange which induced a YY1 consensus sequence and is present in a region of the promoter associated with negative transcription regulation.

Adenine↗
PubMed1997

Nasal immunotherapy in weed-induced allergic rhinitis.

BACKGROUND: Nasal immunotherapy with single allergen extracts, following premedication with cromolyn, has been reported to be effective in treating seasonal and perennial allergic rhinitis. METHODS: We conducted a double-blind, placebo-controlled study to assess the efficacy, tolerability, and mechanism of action of nasal immunotherapy for allergic rhinitis caused by weed pollens from three unrelated families. Twenty-seven weed-allergic patients underwent baseline nasal provocation and titrated skin test with a mixed weed extract containing ragweed, sage, and Chenopod extracts. Patients were randomized to receive either mixed weed extract or placebo. Nasal immunotherapy was self-administered daily to alternate nostrils preceded by 5.2 mg intranasal cromolyn. Beginning with 1:2500 wt/vol the concentration was increased to 1:10 wt/vol over an average period of 36 days. The maintenance dose (1:10 wt/vol) was administered daily for 12 to 16 weeks through the weed pollen season. Patients recorded nasal and eye symptoms and the use of rescue medications throughout the study. A nasal lavage for cytokine levels and nasal scraping with Rhinoprobe for nasal cytology were performed at the peak of the weed season. Nasal provocation and titrated skin tests with mixed weed extract were repeated after the weed season. Nasal lavage and scraping were also performed before and 24 hours after the final nasal provocation. RESULTS: During the peak weeks of the weed season the group receiving mixed weed extract by nasal instillation, compared with those treated with placebo, had significantly lower total nasal symptom scores, total eye symptom scores, and symptom medication scores. There were no significant differences in the nasal cytology or cytokines levels between the two groups, except for elevated IL-10 in the nasal lavage in the treated group at the peak of the season. Nasal symptoms and medication use were higher preseasonally in the active treatment group. CONCLUSION: Nasal immunotherapy with aqueous mixed weed extract administered with cromolyn sodium pretreatment for 17 to 21 weeks was effective in reducing both nasal and ocular symptoms of weed pollen-induced allergic rhinitis. There were increased nasal symptoms in the treated group preseasonally.

Administration, Intranasal↗
PubMed1997

Increased expression of the interleukin-10 gene by alveolar macrophages in interstitial lung disease.

Idiopathic pulmonary fibrosis (IPF) and bronchiolitis obliterans with organizing pneumonia (BOOP) are interstitial lung diseases of unknown pathogenesis. Alveolar macrophages play a major role in the regulation of the inflammatory response in these diseases through their ability to produce cytokines that modify the inflammatory response. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) exhibit proinflammatory and anti-inflammatory actions, respectively, and thus an imbalance in the expression of these cytokines may contribute to the pathogenesis of IPF and BOOP. Therefore, we quantified IL-10 and TNF-alpha mRNA levels in alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with IPF and BOOP and in normal healthy volunteers. The level of TNF-alpha mRNA in macrophages obtained from IPF and BOOP patients was not significantly different from normal healthy subjects. However, macrophages from patients with IPF and BOOP expressed increased levels of IL-10 mRNA compared with healthy controls. In addition, stimulation of alveolar macrophages with lipopolysaccharide in the presence of a neutralizing anti-IL-10 antibody augmented the production of TNF-alpha over that seen in the absence of anti-IL-10 antibody, suggesting that the increased expression of IL-10 by alveolar macrophages may act to control the expression of TNF-alpha. Paradoxically, measurement of IL-10 protein in cell-free BAL fluid revealed lower amounts of the protein in patients with IPF and BOOP compared with healthy controls.

Adult↗
PubMed1997

Genetics of atopy and asthma: the rationale behind promoter-based candidate gene studies (IL-4 and IL-10).

The genetics of atopy and asthma has become a very interesting area for research. Potential candidate genes identified either by the immunopathogenesis of asthma or bronchial hyperresponsiveness, or uncovered by the whole-genome screen, will lead to new and better ways of diagnosing asthma and, more importantly, the potential for drug discovery related to the products of the candidate genes identified in the various genome screening efforts. The candidate gene approach has been applied to the promoter region of a number of cytokine genes, both within and outside of the human 5q33 cytokine gene cluster. As a prototype for both cytokines, work relating to an interleukin (IL)-4 promoter polymorphism and an IL-10 promoter polymorphism will be reviewed as providing a potential molecular mechanism for dysregulation of these cytokine genes in asthma.

Asthma↗
PubMed1996

Theophylline's effect on neutrophil function and the late asthmatic response.

BACKGROUND: The decrement in lung function associated with the late asthmatic response after allergen challenge is believed to be mediated by an inflammatory response in the airways. Theophylline has been shown to inhibit the late asthmatic response, but the mechanisms are not clear. OBJECTIVE: The study was designed to determine whether theophylline would inhibit the late asthmatic response by reducing neutrophil activation and subsequent superoxide production. METHODS: Twelve subjects with asthma underwent treatment in this double-blind, randomized, crossover study. Each subject received theophylline and placebo in random order in two treatment periods of 3 weeks each. Each treatment period was followed by an allergen challenge and blood neutrophil function analysis. RESULTS: At therapeutic levels theophylline increased FEV1 at baseline and during the allergen challenge and increased the percentage suppression of neutrophil superoxide production by adenosine. CONCLUSION: Theophylline improved pulmonary function at baseline and during an allergen challenge, in part perhaps, by increasing the neutrophil's response to feedback inhibition by adenosine. However, theophylline did not decrease the severity and duration of the late asthmatic response.

Adult↗
PubMed1996

Interleukin-10 regulation in normal subjects and patients with asthma.

Interleukin-10 or cytokine synthesis inhibitory factor has important antiinflammatory activities in immune diseases. We speculated that diminished IL-10 production in asthma would permit the unopposed synthesis of proinflammatory cytokines, contributing to the development and severity of asthma. Our data demonstrate constitutive secretion of IL-10 into bronchoalveolar lavage (BAL) fluid of normal, nonasthmatic subjects (130 +/- 61 pg/ml; n = 8). Asthmatic patients' BAL fluid was characterized by diminished concentrations of IL-10 (9 +/- 18 pg/ml; n = 8; p < 0.01 compared with that of normal subjects). By using the RNA-based polymerase chain reaction, we demonstrated that diminished IL-10 occurred as a result of inhibition of transcription. IL-10 transcription, but not protein, was observed at the time of the late asthmatic response. We speculate that the subsequent appearance of IL-10 protein could contribute to the resolution of the late asthmatic response. Similar to what was observed in the BAL fluid, peripheral blood mononuclear cells of patients with asthma demonstrated decreased spontaneous (0.01 +/- 0.01 ng/ml-asthmatic and 0.09 +/- 0.04 ng/ml-normal; p < 0.05) and stimulated (0.60 +/- 0.22 ng/ml-asthmatic and 1.69 +/- 0.49 ng/ml-normal; p < 0.05) IL-10 production compared with normal subjects. In support of the hypothesis that IL-10 mitigates the development of inflammation, we demonstrated that the addition of a neutralizing anti-IL-10 antibody to resting peripheral blood mononuclear cell cultures of normal subjects stimulated the spontaneous production of interferon-gamma (10.4 +/- 4.3 to 152.4 +/- 23.6 ng/ml; p < 0.01). Finally, we reasoned that corticosteroids might exert at least part of their antiinflammatory activity through the induction of IL-10 secretion. However, methylprednisolone inhibited the lipopolysaccharide-stimulated production of IL-10 (2.34 +/- 0.49 ng/ml IL-10 with lipopolysaccharide alone to 1.11 +/- 0.38 ng/ml in the additional presence of 10(-6) mol/L methylprednisolone; p < 0.05).

Adult↗
PubMed1996

Update on cytokines.

Explore the source record for details and available documents.

Allergy and Immunology↗
PubMed1996

Anti-inflammatory effects of theophylline: modulation of cytokine production.

BACKGROUND: The basis for the efficacy of theophylline in the treatment of asthma remains enigmatic. Although commonly classified as a bronchodilator, its ability to dilate smooth muscle is considered fairly poor and clinical responses are often independent of bronchodilation. Recent studies have suggested that immunomodulatory activities may contribute to the therapeutic benefit mediated by theophylline. OBJECTIVE: We performed these preliminary studies to determine whether theophylline modulates cytokine production by peripheral blood mononuclear cells. METHODS: Peripheral blood mononuclear cells were obtained from 24 asthmatic subjects and were left in a resting state or stimulated with either mitogens (phytohemagglutinin, lipopolysaccharide) or antigen (tetanus, cat) with or without the additional presence of theophylline (15 micrograms/dL). Supernatants were collected and evaluated for cytokine concentration by ELISA. RESULTS: Theophylline neither inhibited production of allergenic cytokines such as IL-4 nor modulated the repertoire of cytokines produced by TH cells. A statistically significant inhibition of spontaneous interferon-gamma synthesis was observed (24.5 +/- 8.6 to 13.4 +/- 4.2; P < .05). Theophylline did have anti-inflammatory effects on cytokines primarily produced by mononuclear phagocytic cells. Theophylline mediated a slight inhibition of TNF-alpha production (0.26 +/- 0.08 to 0.21 +/- 0.06; P < .05). Theophylline was also associated with a 2.8-fold increase in spontaneous production of the anti-inflammatory cytokine IL-10 (0.35 +/- 0.08 to 0.98 +/- 0.16 ng; P < .01). CONCLUSIONS: A relative absence of IL-10 characterizes the asthmatic airways and may contribute to the development and severity of allergic inflammation. Induction of IL-10 production by theophylline may therefore mitigate inflammation and contribute to the clinical efficacy of this class of medications.

Adjuvants, Immunologic↗