Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-04, Vol.103 (15), p.5941
• Main Authors: Bielekova, Bibiana, Catalfamo, Marta, Reichert-Scrivner, Susan, Packer, Amy, Cerna, Magdalena, Waldmann, Thomas A, McFarland, Henry, Henkart, Pierre A, Martin, Roland
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antigens, CD - immunology; CD56 Antigen - immunology; Daclizumab; Disease Models, Animal; Humans; Immunoglobulin G - therapeutic use; Immunosuppressive Agents - therapeutic use; Inflammation - immunology; Interleukin-2 - deficiency; Interleukin-2 - immunology; Interleukin-2 Receptor alpha Subunit; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lymphocyte Activation; Lymphocyte Subsets; Mice; Mice, Knockout; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Receptors, Interleukin-2 - immunology; T-Lymphocytes - immunology
• ISSN: 0027-8424
• DOI: 10.1073/PNAS.0601335103

Administration of daclizumab, a humanized mAb directed against the IL-2Ralpha chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4(+) T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4(+) and CD8(+) T cells and significant expansion of CD56(bright) natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56(bright) NK cells and contraction of CD4(+) and CD8(+) T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56(bright) NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.