Technical Advance: Function and efficacy of an {alpha}4-integrin antagonist using bioluminescence imaging to detect leukocyte trafficking in murine experimental colitis.
Leukocyte trafficking is a therapeutic target in IBD. The integrins α₄β 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.
Murphy
Carola T
CT
Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland.
Moloney
Gerard
G
Macsharry
John
J
Haynes
Andrea
A
Faivre
Emilie
E
Quinlan
Aoife
A
McLean
Peter G
PG
Lee
Kevin
K
O'Mahony
Liam
L
Shanahan
Fergus
F
Melgar
Silvia
S
Nally
Kenneth
K
D000818:Animals; D002465:Cell Movement; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D016264:Dextran Sulfate; D039441:Integrin alpha4 / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology*; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000032:analysis
D016207:Cytokines; D012333:RNA, Messenger; D039441:Integrin alpha4; D016264:Dextran Sulfate