Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Abstract

Administration of daclizumab, a humanized mAb directed against the IL-2R␣ 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.CD25 ͉ IL-2 ͉ immunoregulatory natural killer cells M ultiple sclerosis (MS) is an inflammatory͞demyelinating disease of the CNS that is one of the leading causes of neurological disability in young adults (1). It is believed that MS is a T cell-mediated autoimmune disease, and therefore the search for new therapies focuses on agents that affect lymphocyte function. Daclizumab (Zenapax), a humanized mAb that blocks the IL-2 binding site on the IL-2R␣ chain, CD25 (i.e., Tac epitope), is among these novel agents (2). The IL-2R complex is comprised of three subunits: IL-2R␣ (CD25), IL-2R␤ (CD122), and IL-2R␥ (CD132). CD122 and CD132 have intracellular signaling motifs and together form the intermediate-affinity (K dis Ϸ 0.1-1 nM) IL-2R. CD25 binds IL-2 with low (K dis Ϸ 10 nM) affinity, but when it associates with CD122͞CD132 it stabilizes the complex to form the highaffinity (K dis Ϸ 10 pM) receptor (3). CD25 is present at low levels in resting human T cells (with the exception of T regulatory cells) but is significantly up-regulated on activated T cells, enabling them to receive a high-affinity IL-2 signal (4). Therefore, it is believed that the blockade of CD25 will result in selective functional inhibition of activated T cells (5). Although it has been demonstrated that daclizumab (or the original murine anti-Tac mAb) inhibits early IL-2R signal transduction events (6, 7) and blocks T cell activation and expansion in vitro (8), a comprehensive characterization of its in vivo effects is still lacking.We recently concluded a phase II, open-label, baseline-versustreatment crossover trial of daclizumab in 10 MS patients with incomplete therapeutic response to IFN-␤. Daclizumab showed a profound inhibitory effect on brain inflammatory activity (78% reduction) and subsequent stabilization o...

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

“…This observation is in line with previous reports of increased expression of NK activation receptors during preeclampsia typically present on effector NK cells 24. These data are especially important in light of the observations in human autoimmune disorders (uveitis and multiple sclerosis) treated with either combinations of IFN‐β and declizumab (monoclonal antibody against the human IL‐2 receptor α chain) or declizumab alone 25, 26. The authors found the CD56hi CD16− NK cell population expanding and a reduction of disease symptoms.…”

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

“…S2). This is consistent with previous reports showing daclizumabinduced regulatory NK-cell expansion in patients suffering from autoimmune disease (37,38).…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…48, 100 However, both CD56 bright NK cells51 and CD161++ CD8+ T‐cells (including the MAIT cells)90 can upregulate GrB and perforin, and become efficient killer cells, after activation. For example, the CD56 bright NK cell population can kill activated autologous CD4+ T‐cells in MS 101, 102. Furthermore, immature DCs are killed by CD56 bright NK cells in lymph nodes in a TRAIL‐dependent manner,103, 104 and IL‐2‐activated peripheral blood CD56 bright NK cells can become efficient killers 50, 51, 52.…”