IL-2 Receptor Blockade Inhibits Late, But Not Early, IFN-γ and CD40 Ligand Expression in Human T Cells: Disruption of Both IL-12-Dependent and -Independent Pathways of IFN-γ Production

Abstract

mAbs directed against the α-chain (Tac/CD25) of the IL-2R are an emerging therapy in both transplantation and autoimmune disease. However, the mechanisms underlying their therapeutic efficacy have not been fully elucidated. Therefore, we examined the affect of IL-2R blockade on Th1 and Th2 cytokine production from human PBMC. Addition of a humanized anti-Tac Ab (HAT) to activated PBMC cultures inhibited IFN-γ production from CD4 and CD8 T cells by 80–90%. HAT partially inhibited production of TNF-α and completely inhibited production of IL-4, IL-5, and IL-10. Furthermore, IL-12, a central regulatory cytokine that induces IFN-γ, was undetectable in treated cultures. As T cell-dependent induction of IL-12 is regulated via CD40/CD40 ligand (CD40L) interactions, we examined the affect of HAT on CD40L expression. We found CD40L expression to be biphasic with an early (6 h) peak that is CD28/IL-2-independent, but a later peak (48 h) being CD28/IL-2-dependent and inhibited by HAT. Similarly, IFN-γ production at 6 h was CD28/IL-2-independent but CD28/IL-2-dependent and inhibited by HAT at 48 h. Nonetheless, addition of rCD40L or exogenous IL-12 to HAT-treated cultures could not restore IFN-γ production. The IFN-γ deficit in such cultures appears to be due to a direct inhibition by HAT of IL-12-independent IFN-γ production from T cells rather than altered expression of either the IL-12Rβ1 or IL-12Rβ2 chains. These data demonstrate that IL-2 plays a critical role in the regulation of Th1 and Th2 responses and impacts both IL-12-dependent and -independent IFN-γ production.

Everolimus and Basiliximab Permit Suppression by Human CD4+CD25+ Cells in vitro

“…Returning to the drugs, blockade of CD25 has previously been shown to reduce IFN-c production in PBMCs at 48 h implying that IL-2 signaling can directly induce IFN-c production (45). We corroborate these findings and further show that RAD can also directly inhibit IFN-c production before its anti-proliferative effect; whether this effect of RAD is dependent on mTOR, has not been defined in this study.…”

Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial

“…30,31 Despite undetectable changes in T-cell number and cell surface markers, in vitro studies suggest that IL-2 receptor antibodies inhibit IL-12-independent interferon-␥ production. 32 The observed clinical effects could occur with daclizumab treatment if CD25 ϩ blockade crippled conventional T cells enough to interfere with graft-versus-tumor effects while inhibition of CD4 ϩ CD25 ϩ activity allowed residual conventional T cells to perpetuate GVHD. Some evidence from murine studies suggests that CD4 ϩ CD25 ϩ cells are involved in protection from GVHD but leave tumor immunity intact.…”

The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

“…This blockade results in the inhibition of several IL-2 dependent T-cell functions, including antigen-and mitogen-induced proliferation, cytokine secretion by activated Th1 and Th2 lymphocytes, and interference with CD28-dependent CD40 ligand expression [McDyer et al 2002]. Daclizumab also decreases CD25 expression on activated CD4+ T cells through a FC-receptor mechanism [Sheridan et al 2006].…”