RESUMO
The TAPR locus containing the TIM gene family is implicated in the development of atopic inflammation in mouse, and TIM-1 allelic variation has been associated with the incidence of atopy in human patient populations. In this study, we show that manipulation of the TIM-1 pathway influences airway inflammation and pathology. Anti-TIM-1 mAbs recognizing distinct epitopes differentially modulated OVA-induced lung inflammation in the mouse. The epitopes recognized by these Abs were mapped, revealing that mAbs to both the IgV and stalk domains of TIM-1 have therapeutic activity. Unexpectedly, mAbs recognizing unique epitopes spanning exon 4 of the mucin/stalk domains exacerbated immune responses. Using Ag recall response studies, we demonstrate that the TIM-1 pathway acts primarily by modulating the production of T(H)2 cytokines. Furthermore, ex vivo cellular experiments indicate that TIM-1 activity controls CD4(+) T cell activity. These studies validate the genetic hypothesis that the TIM-1 locus is linked to the development of atopic disease and suggest novel therapeutic strategies for targeting asthma and other atopic disorders.
Assuntos
Anticorpos Monoclonais/farmacologia , Epitopos/imunologia , Proteínas de Membrana/imunologia , Pneumonia/imunologia , Células Th2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Asma/tratamento farmacológico , Asma/genética , Asma/imunologia , Asma/patologia , Células Cultivadas , Citocinas/imunologia , Mapeamento de Epitopos , Epitopos/genética , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/toxicidade , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/patologia , Estrutura Terciária de Proteína/genética , Locos de Características Quantitativas/genética , Locos de Características Quantitativas/imunologia , Células Th2/patologiaRESUMO
The development of asthma and other atopic diseases is influenced by cytokines produced by Th2 effector T cells. How effector T cell responses are regulated once these cell populations are established remains unclear. The recently described T cell and airway phenotype regulator locus, containing the T cell, Ig domain, mucin domain (TIM) genes, is genetically associated with Th2 cytokine production and Th2-dependent immune responses. In this study, we report the phenotype of the TIM-2 gene-deficient mouse, and demonstrate exacerbated lung inflammation in an airway atopic response model. Immune responses in the TIM-2-deficient mouse reveal disregulated expression of Th2 cytokines, and adoptive transfer experiments show that the T cell compartment is responsible for the heightened inflammatory phenotype. These studies show that TIM-2 is a novel and critical regulator of effector T cell activity.