Induction and inhibition of the Th2 phenotype spread: implications for childhood asthma.
The interactions between genetic and environmental factors play a major role in the development of childhood asthma. We hypothesized that a pre-existing Th2/asthmatic response can promote Th2 responses to newly encountered Ags (i.e., phenotype spread). To test this hypothesis, we developed a mouse model in which the requirements for the induction and inhibition of phenotype spread to a clinically relevant neo-allergen (i.e., ragweed) were investigated. Our results indicate that 1) phenotype spread to the neo-allergen can be induced only within the first 8 h after a bronchial challenge with the first Ag (OVA); 2) Th2 differentiation of naive CD4(+) T cells occurs in bronchial lymph nodes; 3) trafficking of naive CD4(+) T cells to local lymph nodes and IL-4 produced by OVA-activated Th2 cells play essential roles in the differentiation of naive CD4(+) T cells to Th2 cells; and 4) suppression of the production of chemokines involved in the homing of naive CD4(+) T and Th2 cells to bronchial lymph nodes by a TLR9 agonist inhibited phenotype spread and abrogated the consequent development of experimental asthma. These findings provide a mechanistic insight into Th2 phenotype spread and offer an animal model for testing relevant immunomodulatory interventions.
Hayashi
Tomoko
T
Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Gong
Xing
X
Rossetto
Cyprian
C
Shen
Carol
C
Takabayashi
Kenji
K
Redecke
Vanessa
V
Spiegelberg
Hans
H
Broide
David
D
Raz
Eyal
E
D000276:Adjuvants, Immunologic / Q000502:physiology* / Q000627:therapeutic use; D019264:Adoptive Transfer; D031164:Ambrosia / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002648:Child; D006131:Growth Inhibitors / Q000502:physiology* / Q000627:therapeutic use; D006801:Humans; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D006131:Growth Inhibitors; D009838:Oligodeoxyribonucleotides; D015847:Interleukin-4; D010047:Ovalbumin