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VLA-4 blockade by natalizumab inhibits sickle reticulocyte and leucocyte adhesion during simulated blood flow.
Br J Haematol. 2016 09; 174(6):970-82.BJ

Abstract

Very Late Antigen-4 (VLA-4, α4β1-integrin, ITGA4) orchestrates cell-cell and cell-endothelium adhesion. Given the proposed role of VLA-4 in sickle cell disease (SCD) pathophysiology, we evaluated the ability of the VLA-4 blocking antibody natalizumab to inhibit SCD blood cell adhesion. Natalizumab recognized surface VLA-4 on leucocytes and reticulocytes in whole blood from SCD subjects. SCD reticulocytes were positive for VLA-4, while VLA-4 staining of non-SCD reticulocytes was undetectable. Titrations with natalizumab revealed the presence of saturable levels of VLA-4 on both SCD reticulocytes and leucocytes similar to healthy subject leucocytes. Under physiological flow conditions, the adhesion of SCD whole blood cells and isolated SCD leucocytes to immobilized vascular cell adhesion molecule 1 (VCAM-1) was blocked by natalizumab in a dose-dependent manner, which correlated with cell surface receptor binding. Natalizumab also inhibited >50% of whole blood cell binding to TNF-α activated human umbilical vein endothelial cell monolayers under physiological flow at clinically relevant concentrations (10 to 100 μg/ml). This indicates that VLA-4 is the dominant receptor that drives SCD reticulocyte and mononuclear cell adhesion to VCAM-1 and that the VLA-4 adhesion to VCAM-1 is a significant contributor to SCD blood cell adhesion to endothelium. Thus, VLA-4 blockade may be beneficial in sickle cell disease.

Authors+Show Affiliations

Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.Biogen, Cambridge, MA, USA.Biogen, Cambridge, MA, USA.Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.Biogen, Cambridge, MA, USA.Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.Biogen, Cambridge, MA, USA.Biogen, Cambridge, MA, USA.Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA. Division of Critical Care Medicine, Children's Hospital of Michigan, Detroit, MI, USA. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27291690

Citation

White, Jennell, et al. "VLA-4 Blockade By Natalizumab Inhibits Sickle Reticulocyte and Leucocyte Adhesion During Simulated Blood Flow." British Journal of Haematology, vol. 174, no. 6, 2016, pp. 970-82.
White J, Krishnamoorthy S, Gupta D, et al. VLA-4 blockade by natalizumab inhibits sickle reticulocyte and leucocyte adhesion during simulated blood flow. Br J Haematol. 2016;174(6):970-82.
White, J., Krishnamoorthy, S., Gupta, D., Lancelot, M., Moore, N., Sarnaik, S., Hobbs, W. E., Light, D. R., & Hines, P. (2016). VLA-4 blockade by natalizumab inhibits sickle reticulocyte and leucocyte adhesion during simulated blood flow. British Journal of Haematology, 174(6), 970-82. https://doi.org/10.1111/bjh.14158
White J, et al. VLA-4 Blockade By Natalizumab Inhibits Sickle Reticulocyte and Leucocyte Adhesion During Simulated Blood Flow. Br J Haematol. 2016;174(6):970-82. PubMed PMID: 27291690.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - VLA-4 blockade by natalizumab inhibits sickle reticulocyte and leucocyte adhesion during simulated blood flow. AU - White,Jennell, AU - Krishnamoorthy,Sriram, AU - Gupta,Dipti, AU - Lancelot,Moira, AU - Moore,Nancy, AU - Sarnaik,Sharada, AU - Hobbs,William E,2nd AU - Light,David R, AU - Hines,Patrick, Y1 - 2016/06/12/ PY - 2015/12/15/received PY - 2016/03/14/accepted PY - 2016/6/14/entrez PY - 2016/6/14/pubmed PY - 2017/5/16/medline KW - adhesion KW - microfluidics KW - natalizumab KW - sickle cell KW - very late antigen-4 SP - 970 EP - 82 JF - British journal of haematology JO - Br J Haematol VL - 174 IS - 6 N2 - Very Late Antigen-4 (VLA-4, α4β1-integrin, ITGA4) orchestrates cell-cell and cell-endothelium adhesion. Given the proposed role of VLA-4 in sickle cell disease (SCD) pathophysiology, we evaluated the ability of the VLA-4 blocking antibody natalizumab to inhibit SCD blood cell adhesion. Natalizumab recognized surface VLA-4 on leucocytes and reticulocytes in whole blood from SCD subjects. SCD reticulocytes were positive for VLA-4, while VLA-4 staining of non-SCD reticulocytes was undetectable. Titrations with natalizumab revealed the presence of saturable levels of VLA-4 on both SCD reticulocytes and leucocytes similar to healthy subject leucocytes. Under physiological flow conditions, the adhesion of SCD whole blood cells and isolated SCD leucocytes to immobilized vascular cell adhesion molecule 1 (VCAM-1) was blocked by natalizumab in a dose-dependent manner, which correlated with cell surface receptor binding. Natalizumab also inhibited >50% of whole blood cell binding to TNF-α activated human umbilical vein endothelial cell monolayers under physiological flow at clinically relevant concentrations (10 to 100 μg/ml). This indicates that VLA-4 is the dominant receptor that drives SCD reticulocyte and mononuclear cell adhesion to VCAM-1 and that the VLA-4 adhesion to VCAM-1 is a significant contributor to SCD blood cell adhesion to endothelium. Thus, VLA-4 blockade may be beneficial in sickle cell disease. SN - 1365-2141 UR - https://www.unboundmedicine.com/medline/citation/27291690/VLA_4_blockade_by_natalizumab_inhibits_sickle_reticulocyte_and_leucocyte_adhesion_during_simulated_blood_flow_ L2 - https://doi.org/10.1111/bjh.14158 DB - PRIME DP - Unbound Medicine ER -