Integrin-directed antibody-based immunotherapy: focus on VLA-4

Abstract

One major finding of chronic inflammatory diseases of various origins is the establishment of inflammatory infiltrates, bearing different leukocyte subpopulations, including activated T lymphocytes. Integrins are among the large series of molecular interactions that have been implicated as players in both triggering and maintenance of leukocyte influx from the blood into a given organ parenchyme. Accordingly, blocking the interaction between VLA-6 integrin and laminin, experimentally abrogates heart graft rejection. Many reports have shown that VLA-4 is used by T cells to cross endothelial barriers, as well as to migrate within target tissues. In this respect, a humanized IgG4 anti-VLA-4 monoclonal antibody (specific to the α4-integrin chain of VLA-4) has been successfully applied to treat multiple sclerosis as well as inflammatory bowel disease. Anti-VLA-4 monoclonal antibody has also been applied to block transendothelial passage in other autoimmune diseases, such as rheumatoid arthritis. On this same vein is the action of such a reagent in impairing in vitro transendothial and fibronectin-driven migration of CD4⁺ and CD8⁺ T cells expressing high densities of VLA-4 from Duchenne muscular dystrophy patients, thus potentially enlarging the use of this strategy to other diseases. Yet, in a small number of patients, the use of Natalizumab has been correlated with the progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus. This issue restricted the use of the reagent. In this respect, the development of smaller and more specific antibody reagents should be envisioned as a next-generation promising strategy.

Keywords: T cells; cell trafficking; immunotherapy; neuroimmunology.

Figure 1

Anti-VLA-4 antibodies can potentially abrogate transendothelial and intra-tissular T cell migration and adhesion. 1. Extravasation of lymphocytes can be impaired by blocking VLA-4/VCAM-1 interaction at the endothelial of blood vessels; 2. Intratissular migration of lymphocytes in the inflammatory sites can be significantly diminished by blocking VLA-4/fibronectin interaction; 3. Adhesion of the activated lymphocyte to a potential organ specific cell type can be abolished by blocking fibronectin/VCAM-1/VLA-4 mediated cell–cell interaction. EC: endothelial cells; fibronectin is represented by the double waves in the extracellular space.

Figure 2

Role of VLA-4 in migration and adhesion of T-cells from Duchenne Muscular Dystrophy patients: blockade by anti-VLA-4 monoclonal antibody. Panel A reveals that transendothelial migration of CD4⁺ and CD8⁺ T cells expressing high densities of CD49d from DMD patients and unable to walk migrate more than the patients able to walk (upper graphics). Importantly, migration of CD49d^hi T cells is largely impaired in the presence of anti-VLA-4 antibody (bottom graphics). Similar enhancement of fibronectin-driven T cell migration is seen in panel B, which also shows that migration of CD49d^hi T cell subsets is largely impaired in the presence of anti-VLA-4 antibody. Finally, panel C provides evidence showing that both CD4⁺CD49d^hi and CD8⁺CD49d^hi T cells subsets adhere more to cultured human myoblasts, and that such an increase is abrogated by anti-VLA-4 antibody, as compared to unrelated Immunoglobulin. Groups were statistically compared using the Kruskal–Wallis test followed by Dunn’s multiple comparison test. *P < 0.05; **P < 0.01; ***P < 0.001. Modified from Pinto Mariz et al. 2015.