Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis.
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.
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. bibi.bielekova@uc.edu
Bibiana
B
Bielekova
Marta
M
Catalfamo
Susan
S
Reichert-Scrivner
Amy
A
Packer
Magdalena
M
Cerna
Thomas A
TA
Waldmann
Henry
H
McFarland
Pierre A
PA
Henkart
Roland
R
Martin
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology; D019002:CD56 Antigen / Q000276:immunology*; D000077561:Daclizumab; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology; D007376:Interleukin-2 / Q000172:deficiency / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D019002:CD56 Antigen; C508017:IL2RA protein, human; C508018:Il2ra protein, mouse; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D000077561:Daclizumab