Document Detail


Daclizumab therapy for multiple sclerosis.
MedLine Citation:
PMID:  23055048     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 CD56(bright) 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 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.
Authors:
Bibiana Bielekova
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Review    
Journal Detail:
Title:  Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics     Volume:  10     ISSN:  1878-7479     ISO Abbreviation:  Neurotherapeutics     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-29     Completed Date:  2013-07-29     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  101290381     Medline TA:  Neurotherapeutics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  55-67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal, Humanized / therapeutic use*
Clinical Trials as Topic
Humans
Immunoglobulin G / therapeutic use*
Immunosuppressive Agents / therapeutic use*
Lymphocyte Activation / drug effects,  immunology
Multiple Sclerosis / drug therapy*
T-Lymphocytes / drug effects,  immunology
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal, Humanized; 0/Immunoglobulin G; 0/Immunosuppressive Agents; CUJ2MVI71Y/daclizumab
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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