The allergen-induced airway hyperresponsiveness in a human-mouse chimera model of asthma is T cell and IL-4 and IL-5 dependent.
The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-gamma after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype.
Tournoy
K G
KG
Department of Respiratory Diseases (7 K12 I.E.), Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. kurt.tournoy@rug.ac.be
Kips
J C
JC
Pauwels
R A
RA
D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D039741:Antigens, Dermatophagoides; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D001835:Body Weight / Q000235:genetics / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002678:Chimera / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006023:Glycoproteins / Q000008:administration & dosage* / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000008:administration & dosage; D007073:Immunoglobulin E / Q000032:analysis; D007274:Injections, Intraperitoneal; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D007442:Intubation, Intratracheal; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008925:Mites / Q000276:immunology; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*
D000485:Allergens; D000911:Antibodies, Monoclonal; D039741:Antigens, Dermatophagoides; D016207:Cytokines; D006023:Glycoproteins; D007106:Immune Sera; D018793:Interleukin-13; D015848:Interleukin-5; D015847:Interleukin-4; D007073:Immunoglobulin E