Responses of regulatory and effector T-cells to low-dose interleukin-2 differ depending on the immune environment after allogeneic stem cell transplantation

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs promptly respond to low concentrations of IL-2 through the constitutive expression of high-affinity IL-2 receptors. It has been reported that low-dose IL-2 therapy increased circulating Tregs and improved clinical symptoms of chronic GVHD. Clinical studies of IL-2 therapy so far have mainly targeted patients in the chronic phase of transplantation when acute immune responses has subsided. However, the biological and clinical effects of exogenous IL-2 in an acute immune environment have not been well investigated. In the current study, we investigated the impact of exogenous IL-2 therapy on the post-transplant homeostasis of T cell subsets which influence the balance between GVHD and GVL in the acute phase, by setting the various immune environments early after HSCT in murine model. We initially found that 5,000 IU of IL-2 was enough to induce the active proliferation of Treg without influencing other conventional T cells (Tcons) when administered to normal mice. However, activated Tcons showed the response to the same dose of IL-2 in recipients after allogeneic HSCT. In a mild inflammatory environment within a threshold, exogenous IL-2 could effectively modulate Treg homeostasis with just limited influence to activated T cells, which resulted in an efficient GVHD suppression. In contrast, in a severely inflammatory environment, exogenous IL-2 enhanced activated T cells rather than Tregs, which resulted in the exacerbation of GVHD. Of interest, in an immune-tolerant state after transplant, exogenous IL-2 triggered effector T-cells to exert an anti-tumor effect with maintaining GVHD suppression. These data suggested that the responses of Tregs and effector T cells to exogenous IL-2 differ depending on the immune environment in the host, and the mutual balance of the response to IL-2 between T-cell subsets modulates GVHD and GVL after HSCT. Our findings may provide useful information in the optimization of IL-2 therapy, which may be personalized for each patient having different immune status.

The impact of regulatory T cells on the graft-versus-leukemia effect

“…Using a mouse model, Meguri et al. ( 54 ) have shown that IL-2 therapy affects Treg and effector T cells (Teff) responses differently depending on the immune environment in the host. In mild inflammatory conditions, the IL-2 therapy controlled GVHD without affecting GVL.…”

“…In mild inflammatory conditions, the IL-2 therapy controlled GVHD without affecting GVL. Moreover, their results indicate that in an immune-tolerant state after HSCT, IL-2 therapy may even enhance the GVL effect without exacerbating GVHD ( 54 ). More recently, adaptations to the previous approaches using IL-2 therapy have been performed aiming to specifically promote Treg expansion and not alloreactive effector T cells.…”

Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy

“…In a clinical trial assessing the efficacy of low IL-2 to suppress allospecific immune responses and allow the complete discontinuation of maintenance immunosuppression in liver transplant recipients, rejection episodes were reported for four of five participants who initiated immunosuppression withdrawal [214]. Interestingly, exogenous IL-2, even at low doses, has been shown to induce conflicting effects on Tregs in the allo-HCT setting depending on the immune environment of the host; in a mild inflammatory state, low IL-2 regulated Treg homeostasis and suppressed GvHD, whereas in an intense inflammatory environment, the same IL-2 doses enhanced activated T cells rather than Tregs and exacerbated GvHD in a mouse model [217].…”

“…Tregs, as discussed earlier. In fact, when IL-2 was combined with donor-specific Tregs, but not with polyclonal Tregs, it preferentially enhanced the proliferation of the allospecific Tregs and a synergistic effect in prolonging skin allograft survival was observed [217]. Nevertheless, IL-2 receptor complexes are also expressed on immune cells other than CD4+ T cells, making them responsive to IL-2.…”

A Stable Micellar Formulation of RAD001 for Intracerebroventricular Delivery and the Treatment of Alzheimer’s Disease and Other Neurological Disorders

“…This type of micelle is well known for its capacity to entrap and deliver a broad range of hydrophobic drugs [31,32]. A large body of literature addressing DSPE-PEG2000 micelle use in drug delivery exists [33][34][35][36][37]. Properties like a low critical micellar concentration and aggregation number, good stability, a lean preparation process and affordability make DSPE-PEG2000 micelles a potentially good delivery platform even for RAD001.…”