Requirements for allergen-induced airway inflammation and hyperreactivity in CD4-deficient and CD4-sufficient HLA-DQ transgenic mice.
BACKGROUND
Airway inflammation is central to the pathogenesis of allergic asthma, and molecules that mediate this process obviously represent targets for therapy.


OBJECTIVE
To study the role of CD4(+) T cells and/or HLA-DQ molecules in allergic asthma, we have generated and characterized models of short ragweed allergen (SRW)-induced inflammation using transgenic mice with HLA-DQ (DQ6 or DQ8), human CD4 (hCD4), or both on a genetic background that lacks mouse MHC II and CD4 (Abeta(0)/mCD4(0)).


METHODS
Mice were actively sensitized and later challenged intranasally with SRW allergenic extract. Bronchoalveolar lavage fluid composition, airway inflammation and hyperresponsiveness, blood eosinophil levels, and cell proliferation were examined.


RESULTS
In response to SRW treatment, both DQ6 and DQ8 transgenic mice expressing hCD4 developed pulmonary eosinophilia and associated lung tissue damage with increase in eosinophil peroxidase and T(H)2 cytokines in bronchoalveolar lavage fluid, strong airway hyperreactivity, and persistent blood eosinophilia. The response was independent of mast cells/histamine pathway and was mediated by DQ-restricted hCD4(+) T cells. Interestingly, lungs of CD4-deficient DQ6 transgenic mice showed an eosinophilic inflammation without local increase in cytokines and eosinophil peroxidase. The allergic reaction was absent in double-knockout mice and mice expressing either DQ8 or hCD4 alone.


CONCLUSIONS
DQ6 molecules are critical to SRW-induced allergy and can operate in the presence or absence of CD4. However, both DQ antigens and CD4 molecules are critical for full manifestation of allergen-induced asthma in transgenic mice.
Chapoval
S P
SP
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Marietta
E V
EV
Smart
M K
MK
David
C S
CS
D000485:Allergens / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011058:Pollen / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000097:blood / Q000276:immunology* / Q000473:pathology
D000485:Allergens; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D006683:HLA-DQ Antigens; D007073:Immunoglobulin E