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.
Bielekova
Bibiana
B
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. bibi.bielekova@uc.edu
Catalfamo
Marta
M
Reichert-Scrivner
Susan
S
Packer
Amy
A
Cerna
Magdalena
M
Waldmann
Thomas A
TA
McFarland
Henry
H
Henkart
Pierre A
PA
Martin
Roland
R
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