title: Epitope-dependent effect of anti-murine TIM-1 monoclonal antibodies on T cell activity and lung immune responses.
abstract: 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.
authors.affiliation: Biogen Idec Incorporated, Cambridge, MA 02142, USA.
authors.forename: Irene D
authors.initials: ID
authors.lastname: Sizing
authors.forename: Véronique
authors.initials: V
authors.lastname: Bailly
authors.forename: Patricia
authors.initials: P
authors.lastname: McCoon
authors.forename: Wenjie
authors.initials: W
authors.lastname: Chang
authors.forename: Sambasiva
authors.initials: S
authors.lastname: Rao
authors.forename: Lourdes
authors.initials: L
authors.lastname: Pablo
authors.forename: Rachel
authors.initials: R
authors.lastname: Rennard
authors.forename: Meghan
authors.initials: M
authors.lastname: Walsh
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Li
authors.forename: Mohammad
authors.initials: M
authors.lastname: Zafari
authors.forename: Max
authors.initials: M
authors.lastname: Dobles
authors.forename: Leticia
authors.initials: L
authors.lastname: Tarilonte
authors.forename: Steven
authors.initials: S
authors.lastname: Miklasz
authors.forename: Gerard
authors.initials: G
authors.lastname: Majeau
authors.forename: Kevin
authors.initials: K
authors.lastname: Godbout
authors.forename: Martin L
authors.initials: ML
authors.lastname: Scott
authors.forename: Paul D
authors.initials: PD
authors.lastname: Rennert
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D018604:Epitope Mapping; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D008168:Lung / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000633:toxicity; D011014:Pneumonia / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D000939:Epitopes; D008565:Membrane Proteins; C442242:Timd2 protein, mouse; D010047:Ovalbumin