Epitope-dependent effect of anti-murine TIM-1 monoclonal antibodies on T cell activity and lung immune responses.
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.
Sizing
Irene D
ID
Biogen Idec Incorporated, Cambridge, MA 02142, USA.
Bailly
Véronique
V
McCoon
Patricia
P
Chang
Wenjie
W
Rao
Sambasiva
S
Pablo
Lourdes
L
Rennard
Rachel
R
Walsh
Meghan
M
Li
Zhifang
Z
Zafari
Mohammad
M
Dobles
Max
M
Tarilonte
Leticia
L
Miklasz
Steven
S
Majeau
Gerard
G
Godbout
Kevin
K
Scott
Martin L
ML
Rennert
Paul D
PD
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
D000911:Antibodies, Monoclonal; D016207:Cytokines; D000939:Epitopes; D008565:Membrane Proteins; C442242:Timd2 protein, mouse; D010047:Ovalbumin