Daclizumab Therapy for Multiple Sclerosis
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Daclizumab Therapy for Multiple Sclerosis Bibiana Bielekova
Published online: 5 October 2012 # The American Society for Experimental NeuroTherapeutics, Inc. (outside the U.S.) 2012
Abstract Daclizumab is a humanized monoclonal antibody of IgG1 subtype that binds to the Tac epitope on the interleukin-2 (IL-2) receptor α-chain (CD25), thus, effectively blocking the formation of the high-affinity IL-2 receptor. Because the high-affinity IL-2 receptor signaling promotes expansion of activated T cells in vitro, daclizumab was designed as a therapy that selectively inhibits T-cell activation. Assuming the previous statement, daclizumab received regulatory approval as add-on therapy to standard immunosuppressive regimen for the prevention of acute allograft rejection in renal transplantation. Based on its putative mechanism of action (MOA), daclizumab represented an ideal therapy for T-cell-mediated autoimmune diseases and was subsequently tested in inflammatory uveitis and multiple sclerosis (MS). In both of these diseases, daclizumab therapy significantly inhibited target organ inflammation. Mechanistic studies in MS demonstrated that the MOA of daclizumab is surprisingly broad and that the drug exerts unexpected effects on multiple components of the innate immune system. Specifically, daclizumab dramatically expands and activates immunoregulatory CD56bright NK cells, which gain access to the intrathecal compartment in MS and can kill autologous activated T cells. Daclizumab also blocks trans-presentation of IL-2 by mature dendritic cells to primed T cells, resulting in profound inhibition of Electronic supplementary material The online version of this article (doi:10.1007/s13311-012-0147-4) contains supplementary material, which is available to authorized users. B. Bielekova (*) Neuroimmunological Diseases Unit (NDU), Neuroimmunology Branch (NIB), National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD 20892, USA e-mail: [email protected] B. Bielekova National Institutes of Health (NIH), Bethesda, MD 20892, USA
antigen-specific T cells. Finally, daclizumab modulates the development of innate lymphoid cells. In conclusion, daclizumab therapy, which is currently in phase III testing for inflammatory MS, has a unique MOA that does not limit migration of immune cells into the intrathecal compartment, but rather provides multifactorial immunomodulatory effects with resultant inhibition of MS-related inflammation. Keywords Multiple sclerosis . Autoimmunity . Biological therapy . IL-2 . CD25
Introduction Interleukin (IL)-2 has been called “T cell growth factor” [1, 2], because since its discovery it has been used for in vitro expansion of T cells. Indeed, upon activation by the T-cell receptor (TCR), T cells start expressing on their surface high levels of heterotrimeric “high affinity” IL-2 receptor (IL-2R) (Fig. 1). At approximately the same time when the surface expression of IL-2R peaks (i.e., ~48-72 h post-stimulation), naïve T cells that have received an antigen-specific signal also start pr
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