Oligonucleotide therapy of allergic asthma

doi:10.1016/S0091-6749(99)70361-1

Journal of Allergy and Clinical Immunology

Volume 104, Issue 2, August 1999, Pages 260-266

https://doi.org/10.1016/S0091-6749(99)70361-1 Get rights and content

Abstract

The recent increase in the prevalence of and mortality from asthma has inspired several new molecular techniques to improve treatment. Because asthma is a disease of gene polymorphism, gene therapy is unlikely to be effective. Alternative methods use oligonucleotides (ODNs) in the form of (1) DNA vaccination expressing CpG motifs that mimic bacterial DNA or (2) antisense ODNs inhaled and locally deposited into pulmonary airways to specifically modulate receptors for inflammatory mediators. DNA vaccination, a form of “molecular immune surveillance,” attenuates a TH2 predominance. Antisense directed against the adenosine A₁ receptor abrogates A₁ sensitivity, improves allergen-induced immediate airway obstruction, and inhibits the expected increase in histamine responsiveness in allergic rabbits. Adenosine receptor inhibition lasts for an average of 7 days and the majority of the antisense remains in the lung. ODN therapy for asthma seem unlimited, but confirmation awaits the extension from animal models to human studies. (J Allergy Clin Immunol 1999;104:260-6.)

Section snippets

GENE OR EPIGENE THERAPY

Many attempts at gene therapy have been made to correct mutations by inserting normal genetic material where mutated genetic material is functionally defective, such as in cystic fibrosis.¹⁰ Epigenetic therapy refers to modulation of gene expression rather than manipulation of the gene itself to “arrest” translation of the gene into its product(s). Antisense therapy, an example of epigenetic therapy, has been described in the context of inflammatory models for asthma.¹¹ Although gene therapy

TARGETS FOR OLIGONUCLEOTIDE THERAPY IN ASTHMA

Modern concepts of allergic rhinitis and asthma originate from the use of the fiberoptic bronchoscope to analyze bronchoalveolar lavage fluid23, 24 and biopsy specimen tissue²⁵ after late-phase allergic reactions. These are inflammatory and lead to previously observed increases in persistent bronchial hyperresponsiveness (BHR). A switch from the normal balance between TH1- and TH2-biased immunity leads to predominance of TH2 cytokines in the face of allergen exposure. Even in mild or

DNA vaccination

Krieg³⁸ and others³⁹ have reviewed the use of CpG DNA as a vaccine adjuvant to promote TH1 cells by increasing secretion of INF-γ from B cells or NK cells. It has been known for some time that bacterial DNA contains numerous unmethylated CpG motifs (70%-90%, unmethylated), whereas vertebrate DNA has fewer CpG motifs and is mostly methylated (5% unmethylated). These differences in human DNA, methylation, and lack of CpG motifs permit modification of human DNA to mimic bacterial DNA. When the

Antisense oligonucleotides

Antisense oligonucleotides (ASONs) are single-stranded nucleic acids, generally 15 to 24 bases long, chemically modified to prevent rapid nuclease digestion, which can impede the template properties of messenger RNA (mRNA). The end result is the loss of the ability to synthesize the target protein. Cellular quantitities of the target protein then diminish over time with kinetics that depend on the half-life of the protein and DNA strand, the half-life and total amount of the mRNA, and other

Acknowledgements

We thank Cindy Kukoly, Sherry Leonard, and Dr Shahid Ali for their expertise and technical assistance and Theresa Phillips for her administrative assistance in processing the manuscript.

References (58)

TB Casale et al.
Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis
J Allergy Clin Immunol
(1997)
Y Nakamura et al.
Gene expression of the GATA-3 transcription factor is increased in atopic asthma
J Allergy Clin Immunol
(1999)
WJ Metzger et al.
DNA antisense therapy for asthma
BJ O’Connor et al.
Selective airway responsiveness in asthma
TIPS
(1999)
D Cockcroft et al.
Asthma control verses asthma severity
J Allergy Clin Immunol
(1996)
WJ Metzger et al.
Local antigen challenge and bronchoalveolar lavage of allergic asthmatic lungs
Chest
(1985)
BL Bradley et al.
Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness
J Allergy Clin Immunol
(1991)
WR Roche et al.
Subepithelial fibrosis in the bronchi of asthmatics
Lancet
(1989)
J Linden
Cloned adenosine A3 receptors: pharmacological properties, species differences and receptor functions
Trends Pharmacol Sci
(1994)
S Huang
Molecular modulation of allergic responses
J Allergy Clin Immunol
(1998)

J Bousquet et al.

Allergen immunotherapy: therapeutic vaccines for allergic diseases

J Allergy Clin Immunol

(1998)

T Zeiler et al.

Recombinant allergen fragments as candidate preparations for allergen immunotherapy

J Allergy Clin Immunol

(1997)

JJ Kim et al.

Engineering DNA vaccines via co-delivery of co-stimulatory molecule genes

Vaccine

(1998)

SM Stepkowski

Application of antisense oligodeoxynucleotides for organ transplantation

Transplantation Proc

(1998)

RM Sly

Changing prevalence of allergic rhinitis and asthma

Ann Allergy Asthma Immunol

(1999)

A Frew

Effects of anti-IgE in asthmatic subjects

Thorax

(1998)

JM Drazen

Pharmacology of leukotriene receptor antagonists and 5-lipoxygenase inhibitors in the management of asthma

Pharmacotherapy

(1997)

WJ Metzger

Therapeutic approaches to asthma based on VLA-4 integrin and its counter receptors

Springer Semin Immunopathol

(1995)

J Fahy et al.

The effect of an anti-IgE monoclonal antibody on the early and late phase responses to allergen inhalation in asthmatic subjects

Am J Respir Crit Care Med

(1997)

L Boulet et al.

Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response

Am J Respir Crit Care Med

(1997)

J Nyce

Insight into adenosine receptor function using antisense gene-knockout approaches

Trends Pharmacol Sci

(1999)

KK Jain

Textbook of gene therapy

(1998)

JW Nyce et al.

DNA antisense therapy in an animal model

Nature

(1997)

SP Galant

Therapeutic targets in bronchial asthma pathophysiology

Pediatr Asthma Allergy Immunol

(1998)

MO Turner et al.

Risk factors for near-fatal asthma: a case control study in hospitalized patients with asthma

Am J Respir Crit Care Med

(1998)

D Spina

B₂ -agonists

D Rosenstreich et al.

The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma

N Engl J Med

(1999)

J Gennuso et al.

The relationship between asthma and obesity in urban minority children and adolescents

Arch Pediatr Adolesc Med

(1998)

G Vogel

New clues to asthma therapies

Science

(1997)

Cited by (37)

Future Therapies
2009, Asthma and COPD
This chapter explores the various new drugs now in development for asthma and chronic obstructive pulmonary disease (COPD). Current asthma therapy is highly effective and majority of patients can be well controlled with inhaled corticosteroids and short- and longacting β₂-agonists. These treatments are not only effective, but also safe and relatively inexpensive. This poses a challenge for the development of new treatments, since they will need to be safer or more effective than existing treatments, or offer some other advantage in long-term disease management. In sharp contrast to asthma there are few effective therapies in COPD, despite the fact that it is a common disease that is increasing worldwide. None of the treatments currently available prevents the progression of the disease, and yet the disease is associated with an active inflammatory process that results in progressive obstruction of small airways and destruction of lung parenchyma. Blocking the receptors or synthesis of inflammatory mediators is a logical approach to the development of new treatments for asthma and COPD. Several mediator antagonists have now been tested in asthma and COPD. Proteases are involved in the pathophysiology of asthma and COPD and are therefore a logical target for inhibition. However, it has proved very difficult to find drugs that effectively block specific proteases without side effects. New drugs for the treatment of severe asthma and COPD are greatly needed and there has been an enormous effort now invested by the pharmaceutical industry to find such treatments.
CpG Motifs of Bacterial DNA Exert Protective Effects in Mouse Models of IBD by Antigen-Independent Tolerance Induction
2009, Gastroenterology
Prophylactic treatment of mice with CpG motifs of bacterial DNA protects from experimental inflammatory bowel disease, at least partly via induction of inhibitory T-cells. The aim of this study was to elucidate whether these CpG-dependent protective effects require presence of bacterial flora suggesting antigen-specific regulatory activity.
Germ-free BALB/c and IL-10^−/− mice were treated with CpG-oligodeoxynucleotides (ODN), control-ODN, or PBS. CD4⁺CD62L⁺ cells of these mice were transferred into SCID recipients. CpG-ODN–treated germ-free IL-10^−/− mice were transferred into colitogenic environment. Monoclonal antibodies were used to neutralize TGF-β and IFN-α/β during CpG-ODN treatment. CD4⁺CD62L⁺ cells of donors were evaluated for cytokine secretion and FOXP3, PD-1, and CD25 expression.
Compared to PBS or control-ODN treatment, CpG-ODN application to germ-free donors led to decreased intestinal inflammation as indicated by histology, decreased proinflammatory cytokines, and increased IL-10 secretion. Protection was also observed after cotransfer of cells from PBS and CpG-ODN treated donors. Anti-TGF-β and anti-INF-α/β partly reversed the protective CpG-ODN effect. CpG-ODN–treated germ-free IL-10^−/− mice transferred into colitogenic environment developed significantly less colitis than controls but not recipients of IL-10^−/− CD4⁺CD62L⁺ cells. CD4⁺CD62L⁺ cells of CpG-treated germ-free animals displayed increased expression of regulatory markers.
Even without pre-existence of bacterial flora CpG-ODN exposition induces tolerance, indicating that CpG-ODN–induced regulatory T-cells are not bacterial antigen specific. TGF-β and IFN-α/β play major roles in induction of regulatory cells, and although IL10–independent mechanisms play a role in CpG-ODN protection, this cytokine likely is important for the effector mechanism of CpG-ODN–induced regulatory T-cells.
Future therapies
2008, Asthma and COPD: Basic Mechanisms and Clinical Management
This chapter explores the various new drugs now in development for asthma and chronic obstructive pulmonary disease (COPD). Current asthma therapy is highly effective and majority of patients can be well controlled with inhaled corticosteroids and short- and longacting β₂-agonists. These treatments are not only effective, but also safe and relatively inexpensive. This poses a challenge for the development of new treatments, since they will need to be safer or more effective than existing treatments, or offer some other advantage in long-term disease management. In sharp contrast to asthma there are few effective therapies in COPD, despite the fact that it is a common disease that is increasing worldwide. None of the treatments currently available prevents the progression of the disease, and yet the disease is associated with an active inflammatory process that results in progressive obstruction of small airways and destruction of lung parenchyma. Blocking the receptors or synthesis of inflammatory mediators is a logical approach to the development of new treatments for asthma and COPD. Several mediator antagonists have now been tested in asthma and COPD. Proteases are involved in the pathophysiology of asthma and COPD and are therefore a logical target for inhibition. However, it has proved very difficult to find drugs that effectively block specific proteases without side effects. New drugs for the treatment of severe asthma and COPD are greatly needed and there has been an enormous effort now invested by the pharmaceutical industry to find such treatments.
25. Immunotherapy of allergic disease
2003, Journal of Allergy and Clinical Immunology
Specific immunotherapy involves the administration of allergen extracts to achieve clinical tolerance of the allergens which cause symptoms in patients with allergic conditions. Immunotherapy has been shown to be effective in patients with mild forms of allergic disease, and also in those who do not respond well to standard drug therapy. Recent studies suggest that specific immunotherapy may also modify the course of allergic disease, by reducing the risk of developing new allergic sensitizations, and also inhibiting the development of clinical asthma in children treated for allergic rhinitis. Specific immunotherapy remains the treatment of choice for patients with systemic allergic reactions to wasp and bee stings. The precise mechanisms responsible for the beneficial effects of SIT remain a matter of research and debate. An effect on regulatory T cells seems most probable, associated with switching of allergen-specific B cells towards IgG4 production. Few direct comparisons of specific immunotherapy and drug therapy have been made. Existing data suggest that the effects of specific immunotherapy take longer to come on, but once established, specific immunotherapy will give long-lasting relief of allergic symptoms, whereas the benefits of drugs only last as long as they are continued. (J Allergy Clin Immunol 2003;111:S712-9.)
Lessons from allergic rhinitis versus asthma pathogenesis and treatment
2002, Immunology and Allergy Clinics of North America
Interleukins-4, -5, and -13: Emerging therapeutic targets in allergic disease
2002, Pharmacology and Therapeutics
For the first time, allergic diseases have emerged as major public health concerns. Highly effective therapies for allergic disease now exist, but are plagued by serious side effects and the fact that a significant minority of patients remains unresponsive. Studies from many laboratories have established that T helper type 2 (T_H2) cytokines contribute importantly to diseases such as asthma, and therapeutic strategies that target the key T_H2 cytokines are of potential benefit in allergic disease. In this article, we will review the biology of the T_H2 cytokines interleukin (IL)-4, IL-5, and IL-13 and their receptors, and will consider several novel strategies to neutralize these molecules in human and experimental asthma. While promising, newer therapies face a gauntlet of developmental challenges, but offer the hope of reducing allergic diseases once again to minor public health concerns.

View all citing articles on Scopus

^☆: Reprint requests: W. James Metzger, MD, East Carolina University School of Medicine, Section of Allergy, Asthma, and Immunology, Greenville, NC 27858.

^☆☆: 0091-6749/99 $8.00 + 0 1/1/100385

View full text

Oligonucleotide therapy of allergic asthma☆,☆☆

Abstract

Section snippets

GENE OR EPIGENE THERAPY

TARGETS FOR OLIGONUCLEOTIDE THERAPY IN ASTHMA

DNA vaccination

Antisense oligonucleotides

Acknowledgements

J Allergy Clin Immunol

J Allergy Clin Immunol

TIPS

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Lancet

Trends Pharmacol Sci

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Vaccine

Transplantation Proc

Changing prevalence of allergic rhinitis and asthma

Ann Allergy Asthma Immunol

Effects of anti-IgE in asthmatic subjects

Thorax

Pharmacology of leukotriene receptor antagonists and 5-lipoxygenase inhibitors in the management of asthma

Pharmacotherapy

Therapeutic approaches to asthma based on VLA-4 integrin and its counter receptors

Springer Semin Immunopathol

The effect of an anti-IgE monoclonal antibody on the early and late phase responses to allergen inhalation in asthmatic subjects

Am J Respir Crit Care Med

Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response

Am J Respir Crit Care Med

Insight into adenosine receptor function using antisense gene-knockout approaches

Trends Pharmacol Sci

Textbook of gene therapy

DNA antisense therapy in an animal model

Nature

Therapeutic targets in bronchial asthma pathophysiology

Pediatr Asthma Allergy Immunol

Risk factors for near-fatal asthma: a case control study in hospitalized patients with asthma

Am J Respir Crit Care Med

B2 -agonists

The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma

N Engl J Med

The relationship between asthma and obesity in urban minority children and adolescents

Arch Pediatr Adolesc Med

New clues to asthma therapies

Science

B₂ -agonists