The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Abstract

CD4 + FoxP3 + regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeostasis promoted the hypothesis that in vivo IL-2 treatment could provide a strategy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activation and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune diseases and graft- versus -host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft- versus -host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes. To date, promising pre-clinical and clinical studies have directly targeted Tregs and clearly established the ability to increase their levels and augment their function in vivo . Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.

CD4+ T-cell reconstitution predicts survival outcomes after acute graft-versus-host-disease: a dual-center validation

“…[21][22][23][24][25] These associations with aGVHD have not been studied in the setting of TCD or haploidentical HCT, where the mechanisms governing expansion of alloreactive T cells and recovery of Tregs may differ. 26 There is a poor understanding of aGVHD development after TCD transplantation, [27][28][29][30] but expansion of both polyclonal and oligoclonal alloreactive T cells has been demonstrated. Although CD4 1 IR did not seem to protect against aGVHD itself in our cohorts, it may translate to lower mortality after severe aGVHD.…”

Exosomes Secreted by Mesenchymal Stem Cells Induce Immune Tolerance to Kidney Transplantation via Transporting lncRNA DANCR

“…Treg cells play an important role in the resistance to immune rejection in kidney transplantation. Treg cells can speci cally inhibit autoreactive T cells and are important cells involved in peripheral immune tolerance [29]. It has been reported that injection of MSCs can improve kidney transplant rejection and induce immune tolerance by increasing the proportion of Treg cells [5,30].…”

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

“…Other strategies to induce tolerance were the subject of a CIRM Workshop and Perspective in 2015, and are discussed further there . A third general approach to address complications of tissue mismatch involves development of targeted therapies for the treatment of chronic GVHD including the in vivo expansion of endogenous regulatory T lymphocytes (Treg) with low‐dose interleukin‐2 or ex vivo expansion of Treg subsets followed by their in vivo administration …”

“…44 with low-dose interleukin-2 or ex vivo expansion of Treg subsets followed by their in vivo administration. 47…”