Technical Advance: Function and efficacy of an α4-integrin antagonist using bioluminescence imaging to detect leukocyte trafficking in murine experimental colitis

Journal of Leukocyte Biology

Gerard Moloney²  Peter G. McLean¹  Kevin Lee¹  John MacSharry³  Carola T. Murphy³  Silvia Melgar  and²  Kenneth Nally³  Aoife Quinlan³  Fergus Shanahan³  Andrea Haynes¹  Emilie Faivre³  Liam O'Mahony³ 

[1]  Immuno-Inflammation, CEDD, GlaxoSmithKline, Stevenage, United Kingdom Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland;;Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland; and  Immuno-Inflammation, CEDD, GlaxoSmithKline, Stevenage, United KingdomAlimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland;

关键词: DSS colitis;    small molecule inhibitors;   

DOI  :  10.1189/jlb.0909627

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Leukocyte trafficking is a therapeutic target in IBD. The integrins α4β7 and α4β1 regulate leukocyte migration into tissues and lymphoid organs. Current strategies rely on biologics, such as mAb, to inhibit leukocyte recruitment. Here we show the in vivo therapeutic effects of a small molecule α4-integrin antagonist (GSK223618A) in a leukocyte-trafficking model and a murine model of colitis. Leukocytes isolated from MLNs of transgenic β-actin-luc+ mice were injected i.v. into recipients with DSS-induced colitis. Recipient mice were orally gavaged with vehicle or an α4-integrin antagonist 1 h pre-adoptive transfer, followed by bioluminescence whole body and ex vivo organ imaging 4 h post-transfer. To confirm its therapeutic effect, the α4-integrin antagonist was given orally twice daily for 6 days to mice with DSS-induced colitis, starting on Day 3. Clinical, macroscopic, and histological signs of inflammation were assessed and gene-expression profiles analyzed. Using bioluminescence imaging, we tracked and quantified leukocyte migration to the inflamed gut and demonstrated its inhibition by a small molecule α4-integrin antagonist. Additionally, the therapeutic effect of the antagonist was confirmed in DSS-induced colitis in terms of clinical, macroscopic, and histological signs of inflammation. Gene expression analysis suggested enhancement of tissue healing in compound-treated animals. Inhibition of leukocyte trafficking using small molecule integrin antagonists is a promising alternative to large molecule biologics. Furthermore, in vivo bioluminescence imaging is a valuable strategy for preclinical evaluation of potential therapeutics that target leukocyte trafficking in inflammatory diseases.

【 授权许可】

Unknown