Immunoregulation in an experimental model of allergic asthma
Author
Summary, in English
In allergic asthma the immune response to antigen is inappropriate, leading to an inflammatory process in the respiratory mucosa. To further elucidate immunological mechanisms involved in the development of such inflammation, control mice and mice deficient in selected cell types or proteins, were used in experimental models of allergic asthma and anaphylaxis.
The present study demonstrates that allergic airway inflammation, characterized by eosinophilia, CD4+ T cell infiltration, and increased numbers of mucus cells, develops in mice that lack all immunoglobulins and B lymphocytes. However, immediate hypersensitivity reactions, such as acute phase plasma extravasation in airways and systemic anaphylaxis, are completely blunted in these animals. These findings support the possibility that important aspects of allergic airway inflammation may develop independent of IgE and without the involvement of B lymphocytes as antigen presenting cells. These data also show that immediate hypersensitivity responses and allergic late phase inflammation may be two independent processes.
In addition, the present study demonstrates that the immune response to antigen leading to allergic airway inflammation may be critically regulated by NK cells. Mice depleted of NK1.1+ cells (NK cells and NKT cells) prior to sensitization, but not mice lacking NKT cells (CD1d1 mutant mice), thus exhibit little pulmonary eosinophil and CD3+ T cell infiltration as well as low bronchoalveolar lavage fluid levels of IL-4, IL-5, and IL-12 at allergen aerosol exposure. Allergen-specific IgE and IgG2a levels and cytokine production in spleen are also diminished in these animals compared to control mice. Depletion of NK1.1+ cells during the allergen challenge period only does not influence eosinophilic inflammation. Mice deficient in gd T cells show relatively less attenuation of the lung tissue eosinophilia than mice depleted of NK1.1+ cells. A separate series of experiments show that macrophage migration inhibitory factor may not play a major role for the development of either allergic or endotoxin-induced airway inflammation in mice.
In conclusion, the main findings of this thesis indicate a novel critical role of NK cells in sensitization and subsequent development of allergen-induced airway inflammation, and suggest that this inflammation in part develops independent of IgE.
The present study demonstrates that allergic airway inflammation, characterized by eosinophilia, CD4+ T cell infiltration, and increased numbers of mucus cells, develops in mice that lack all immunoglobulins and B lymphocytes. However, immediate hypersensitivity reactions, such as acute phase plasma extravasation in airways and systemic anaphylaxis, are completely blunted in these animals. These findings support the possibility that important aspects of allergic airway inflammation may develop independent of IgE and without the involvement of B lymphocytes as antigen presenting cells. These data also show that immediate hypersensitivity responses and allergic late phase inflammation may be two independent processes.
In addition, the present study demonstrates that the immune response to antigen leading to allergic airway inflammation may be critically regulated by NK cells. Mice depleted of NK1.1+ cells (NK cells and NKT cells) prior to sensitization, but not mice lacking NKT cells (CD1d1 mutant mice), thus exhibit little pulmonary eosinophil and CD3+ T cell infiltration as well as low bronchoalveolar lavage fluid levels of IL-4, IL-5, and IL-12 at allergen aerosol exposure. Allergen-specific IgE and IgG2a levels and cytokine production in spleen are also diminished in these animals compared to control mice. Depletion of NK1.1+ cells during the allergen challenge period only does not influence eosinophilic inflammation. Mice deficient in gd T cells show relatively less attenuation of the lung tissue eosinophilia than mice depleted of NK1.1+ cells. A separate series of experiments show that macrophage migration inhibitory factor may not play a major role for the development of either allergic or endotoxin-induced airway inflammation in mice.
In conclusion, the main findings of this thesis indicate a novel critical role of NK cells in sensitization and subsequent development of allergen-induced airway inflammation, and suggest that this inflammation in part develops independent of IgE.
Department/s
Publishing year
2000
Language
English
Document type
Dissertation
Publisher
Department of Physiological Sciences, Lund University
Topic
- Medicinal Chemistry
- Pharmacology and Toxicology
Keywords
- allergic asthma
- macrophage migration inhibitory factor
- eosinophils
- gd T cells
- NK1.1+ T cells
- natural killer cells
- immunoglobulins
- B cells
- innate immunity
- allergic airway inflammation
- immediate hypersensitivity
- Physiology
- Fysiologi
- Immunology
- serology
- transplantation
- Immunologi
- serologi
Status
Published
Supervisor
- [unknown] [unknown]
ISBN/ISSN/Other
- ISBN: 91-628-4015-0
- ISRN: LUMEDW/MEFN--28--SE
Defence date
7 April 2000
Defence time
09:15
Defence place
Fernströmsalen, BMC, Sölvegatan 19, Lund
Opponent
- Jan Lötvall (Associate Professor)