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Epitope-Dependent Effect of Anti-Murine TIM-1 Monoclonal Antibodies on T Cell Activity and Lung Immune Responses

Biogen Idec Incorporated, Cambridge, MA 02142

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_H2 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Paul D. Rennert, Biogen Idec Incorporated, 12 Cambridge Center, Cambridge, MA 02142. E-mail address: paul.rennert{at}biogenidec.com

² Abbreviations used in this paper: TAPR, T cell and airway phenotype regulator; TIM, T cell Ig domain and mucin domain; HAV, hepatitis A virus; IHC, immunohistochemistry; SPR, surface plasmon resonance; CHO, Chinese hamster ovary; KLH, keyhole limpet hemocyanin; BAL, bronchial lavage; LN, lymph node.

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