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Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis.
- Source :
-
Multiple sclerosis (Houndmills, Basingstoke, England) [Mult Scler] 2014 Feb; Vol. 20 (2), pp. 156-64. Date of Electronic Publication: 2013 Jul 11. - Publication Year :
- 2014
-
Abstract
- Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR(+)-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4(+) T cells and FoxP3(+) Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling.
- Subjects :
- Daclizumab
Double-Blind Method
Flow Cytometry
Humans
Interleukin-2 Receptor alpha Subunit biosynthesis
Lymphocyte Activation drug effects
Multiple Sclerosis immunology
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
T-Lymphocytes drug effects
T-Lymphocytes immunology
T-Lymphocytes metabolism
Antibodies, Monoclonal, Humanized therapeutic use
Immunoglobulin G therapeutic use
Immunosuppressive Agents therapeutic use
Interleukin-2 Receptor alpha Subunit drug effects
Monocytes immunology
Multiple Sclerosis drug therapy
T-Lymphocyte Subsets drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1477-0970
- Volume :
- 20
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Multiple sclerosis (Houndmills, Basingstoke, England)
- Publication Type :
- Academic Journal
- Accession number :
- 23846354
- Full Text :
- https://doi.org/10.1177/1352458513494488