Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

Abstract

CD4 + CD25 + Foxp3 + Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT.

Transient antibody targeting of CD45RC inhibits the development of graft-versus-host disease

“…[34][35][36][37][38] An alternative strategy is to increase endogenous CD8 1 and CD4 1 Treg function and numbers through the administration of low doses of IL-2 acting through the high-affinity IL-2R, [39][40][41] although this treatment can also activate Teff cells. 39 Low-dose IL-2 has been used in both aGVHD rodent models and patients receiving HLA-matched BMT as prophylactic as well as therapeutic treatments with beneficial effects on some, 42,43 but not all, clinical studies. 44 Although increasing Treg global activity has shown preliminary positive results in animal models and small clinical studies, it remains to be confirmed in large series and has the potential disadvantage that effector T cells are not depleted; because Tregs are plastic in inflammatory conditions, they may convert in potentially pathogenic cells.…”

Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models

“…However, native frequencies of Tregs in donor grafts are insufficient to facilitate transplantation across mismatched barriers; consequently, it has become clear that therapeutic application of these cells will require significant enrichment of Tregs from their basal frequencies. Several clinical investigations have shown promise in the use of ex vivo-expanded Tregs for GVHD amelioration (11)(12)(13), and experimental studies continue to evaluate how to expand and enhance Treg function to maximize their capacity to induce immune transplant tolerance and ameliorate GVHD (14)(15)(16). We have recently described a novel strategy that markedly expands Tregs in vivo following signaling by TNFRSF25 and CD25 receptors (10).…”

Sensitive Photodynamic Detection of Adult T-cell Leukemia/Lymphoma and Specific Leukemic Cell Death Induced by Photodynamic Therapy: Current Status in Hematopoietic Malignancies

“…Although it crucially affects the mortality and morbidity of long-term survivors after transplant, there is no established secondary treatment for steroid-refractory cases. Various treatments such as UV-ECP, iburutinib, ruxolitinib, and low-dose IL-2 have been studied for chronic GVHD [100,101]. Previous studies reported that UV-ECP can induce tolerance by modulating immune cells [102].…”