scholarly journals Daclizumab: Mechanisms of Action, Therapeutic Efficacy, Adverse Events and Its Uncovering the Potential Role of Innate Immune System Recruitment as a Treatment Strategy for Relapsing Multiple Sclerosis

Biomedicines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 18 ◽  
Author(s):  
Stanley Cohan ◽  
Elisabeth Lucassen ◽  
Meghan Romba ◽  
Stefanie Linch
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
T Cell Activation ◽  
Therapeutic Efficacy ◽  
Cell Expansion ◽  
Interleukin 2 ◽  
Phase Iii ◽  
Critical Element ◽  
Increased Risk

Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease.

scholarly journals Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1600-1610 ◽  
Author(s):  
Steve Huang ◽  
Sergey Apasov ◽  
Masahiro Koshiba ◽  
Michail Sitkovsky
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Adenosine Receptors ◽  
Purinergic Receptors ◽  
Interleukin 2 ◽  
Strong Inhibition ◽  
Extracellular Adenosine ◽  
A2a Receptor ◽  
Adenosine Deaminase Activity

Abstract Accumulation of adenosine and of deoxyadenosine in the absence of adenosine deaminase activity (ADA) activity results in lymphocyte depletion and in severe combined immunodeficiency (ADA SCID), which is currently explained by direct cell death-causing effects of intracellular products of adenosine metabolism. We explored the alternative mechanisms of peripheral T-cell depletion as due to inhibition of T-cell expansion by extracellular adenosine-mediated signaling through purinergic receptors. The strong inhibition of the T-cell receptor (TCR)-triggered proliferation and of upregulation of interleukin-2 receptor α chain (CD25) molecules, but not the direct lymphotoxicity, were observed at low concentrations of extracellular adenosine. These effects of extracellular adenosine (Ado) are likely to be mediated by A2a receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites, because (1) poorly metabolized adenosine analogs cause the accumulation of cAMP and strong inhibition of TCR-triggered CD25 upregulation; (2) the A2a, but not the A1 or A3, receptors are the major expressed and functionally coupled adenosine receptors in mouse peripheral T and B lymphocytes, and the adenosine-induced cAMP accumulation in lymphocytes correlates with the expression of A2a receptors; (3) the specific agonist of A2a receptor, CGS21680, induces increases in [cAMP]i in lymphocytes, whereas the specific antagonist of A2a receptor, CSC, inhibits the effects of Ado and CGS21680; and (4) the increases in [cAMP]i mimic the adenosine-induced inhibition of TCR-triggered CD25 upregulation and splenocyte proliferation. These studies suggest the possible role of adenosine receptors in the regulation of lymphocyte expansion and point to the downregulation of A2a purinergic receptors on T cells as a potentially attractive pharmacologic target.

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Graziella Curtale ◽  
Franca Citarella ◽  
Claudia Carissimi ◽  
Marina Goldoni ◽  
Nicoletta Carucci ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Activation Induced Cell Death

Abstract Activation of the T cell–mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte–mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.

scholarly journals Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1600-1610 ◽  
Author(s):  
Steve Huang ◽  
Sergey Apasov ◽  
Masahiro Koshiba ◽  
Michail Sitkovsky
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Adenosine Receptors ◽  
Purinergic Receptors ◽  
Interleukin 2 ◽  
Strong Inhibition ◽  
Extracellular Adenosine ◽  
A2a Receptor ◽  
Adenosine Deaminase Activity

Accumulation of adenosine and of deoxyadenosine in the absence of adenosine deaminase activity (ADA) activity results in lymphocyte depletion and in severe combined immunodeficiency (ADA SCID), which is currently explained by direct cell death-causing effects of intracellular products of adenosine metabolism. We explored the alternative mechanisms of peripheral T-cell depletion as due to inhibition of T-cell expansion by extracellular adenosine-mediated signaling through purinergic receptors. The strong inhibition of the T-cell receptor (TCR)-triggered proliferation and of upregulation of interleukin-2 receptor α chain (CD25) molecules, but not the direct lymphotoxicity, were observed at low concentrations of extracellular adenosine. These effects of extracellular adenosine (Ado) are likely to be mediated by A2a receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites, because (1) poorly metabolized adenosine analogs cause the accumulation of cAMP and strong inhibition of TCR-triggered CD25 upregulation; (2) the A2a, but not the A1 or A3, receptors are the major expressed and functionally coupled adenosine receptors in mouse peripheral T and B lymphocytes, and the adenosine-induced cAMP accumulation in lymphocytes correlates with the expression of A2a receptors; (3) the specific agonist of A2a receptor, CGS21680, induces increases in [cAMP]i in lymphocytes, whereas the specific antagonist of A2a receptor, CSC, inhibits the effects of Ado and CGS21680; and (4) the increases in [cAMP]i mimic the adenosine-induced inhibition of TCR-triggered CD25 upregulation and splenocyte proliferation. These studies suggest the possible role of adenosine receptors in the regulation of lymphocyte expansion and point to the downregulation of A2a purinergic receptors on T cells as a potentially attractive pharmacologic target.

Anti-Thy-1-mediated T cell activation. Role of soluble factors and expression of interleukin 2 receptors on T cells

1981 ◽  
Vol 11 (6) ◽  
pp. 445-450 ◽  
Author(s):  
Yoshiteru Konaka ◽  
Michael A. Norcross ◽  
Vernon C. Maino ◽  
Richard T. Smith
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Soluble Factors

scholarly journals Cowpox virus encodes a protein that binds B7.1 and B7.2 and subverts T cell costimulation

2019 ◽  
Vol 116 (42) ◽  
pp. 21113-21119 ◽  
Author(s):  
Xiaoli Wang ◽  
Sytse J. Piersma ◽  
Jabari I. Elliott ◽  
John M. Errico ◽  
Maria D. Gainey ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cowpox Virus ◽  
Cell Responses ◽  
Cd28 Costimulation ◽  
Infected Cells ◽  
Culture Supernatants

Costimulation is required for optimal T cell activation, yet it is unclear whether poxviruses dedicatedly subvert costimulation during infection. Here, we report that the secreted M2 protein encoded by cowpox virus (CPXV) specifically interacts with human and murine B7.1 (CD80) and B7.2 (CD86). We also show that M2 competes with CD28 and CTLA4 for binding to cell surface B7 ligands, with stronger efficacy against CD28. Functionally, recombinant M2 and culture supernatants from wild-type (WT) but not M2-deficient (∆M2) CPXV-infected cells can potently suppress B7 ligand-mediated T cell proliferation and interleukin-2 (IL-2) production. Furthermore, we observed increased antiviral CD4 and CD8 T cell responses in C57BL/6 mice challenged by ∆M2 CPXV compared with WT virus. These differences in immune responses to ∆M2 and WT CPXV were not observed in CD28-deficient mice. Taken together, our findings define a mechanism of viral sabotage of T cell activation that highlights the role of CD28 costimulation in host defense against poxvirus infections.

The role of interleukin-6 in mitogenic T-cell activation: Detection of interleukin-2 heteronuclear RNA by polymerase chain reaction

1991 ◽  
Vol 134 (2) ◽  
pp. 511-519 ◽  
Author(s):  
Gerd Walz ◽  
Christopher Stevens ◽  
Bernd Zanker ◽  
Larry B. Melton ◽  
Steven C. Clark ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
T Cell ◽  
T Cell Activation ◽  
Interleukin 6 ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Activation Detection

scholarly journals Interleukin 2 induces the expression of CD45RO and the memory phenotype by CD45RA+ peripheral blood lymphocytes.

1994 ◽  
Vol 179 (3) ◽  
pp. 857-864 ◽  
Author(s):  
M D Roth
Keyword(s):  
T Cell ◽  
Cyclosporin A ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Peripheral Blood Lymphocytes ◽  
T Cell Subsets ◽  
Memory Phenotype ◽  
Blood Lymphocytes

The CD45RA and CD45RO isoforms of the leukocyte common antigen identify functionally distinct "naive" and "memory" T cell subsets. While antigenic and mitogenic stimuli are known to initiate transition from the naive to memory state, little is known about the role of cytokines in this process. This report demonstrates that in vitro exposure of purified CD45RA+/CD45RO- peripheral blood lymphocytes (PBL) to interleukin 2 (IL-2) promotes their conversion to the CD45RA-/CD45RO+ phenotype. Conversion to CD45RO occurs for both the CD3+ and CD3-/CD56+ lymphocyte subsets, but occurs more rapidly, and at lower IL-2 concentrations, in the CD3-/CD56+ population. Expression of CD45RO was observed only in response to IL-2 and was not observed during long-term culture in IL-4, IL-6, or IL-7. We also examined the effect of IL-2 on the expression of adhesion molecules by T cells. The expression of CD2, CD11a, and CDw29 increased, and expression of Leu-8 (LAM-1) decreased, on cultured CD45RA+/CD45RO- cells after they converted to expression of CD45RO. In contrast, lymphocytes that remained CD45RA+/CD45RO- after 10 d in culture exhibited no change from their baseline adhesion molecule profile. Finally, to test the role of endogenous IL-2 during T cell activation we stimulated CD45RA+/CD45RO- PBL with immobilized anti-CD3 in the presence of neutralizing anti-IL-2 antibody and/or cyclosporin A. Both agents significantly reduced the expression of CD45RO and the effect of cyclosporin A was reversed by exogenous IL-2. We conclude that IL-2 promotes CD45RA+ cells to express the memory phenotype and is a mediator of CD45RO expression after stimulation of the T cell receptor/CD3 complex.

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