Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation

Abstract

Regulatory T cells (Tregs) are critical for self-tolerance. While adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen and colon (a GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy (GVM) responses. Adoptive transfer of in vivo expanded Tregs in the setting of MHC-mismatched or MHC-matched allo-HSCT significantly ameliorated GVHD. Critically, transplant of Treg expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of GVM. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.

Death receptor 3 signaling enhances proliferation of human regulatory T cells

“…Mouse studies reported an increase in Treg frequency in vivo upon activation of DR3 using agonistic antibodies [9,[11][12][13][14] or a TL1A-Ig fusion protein [25,26]. Our findings regarding DR3 expression and signaling in human Tregs prompted us to evaluate whether DR3 activation also enhanced proliferation of human Tregs.…”

Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy

“…Novel targets include kinase inhibitors that block the protein serine/threonine kinase ROCK1 111 , Aurora kinase A 112 , MEK 113 , and others (Supplemental appendix and Figure 3B). Strategies being investigated to improve Treg efficacy by in vivo Treg expansion in mouse models include TNFRSF25 (DR3) stimulation using a fusion protein to ligate the receptor 114 , agonistic DR3 antibody 115 and agonistic TNFR2 antibody 116 .…”

Multifaceted death receptor 3 signaling—promoting survival and triggering death

“…A DR3-specific agonistic antibody triggered Treg proliferation and attenuated cardiac allograft rejection in fully major histocompatibility complex (MHC)-mismatched ectopic heart transplants [62]. In line with this, a number of studies recently demonstrated that DR3-mediated proliferation of Tregs attenuated GVHD in mice after allogeneic hematopoietic stem cell transplantation (HSCT) or autologous bone marrow transplantation [60,61,63,64]. Treatment of donor mice with an agonistic anti-DR3 antibody induced Treg proliferation and transfer of DR3-expanded Tregs together with hematopoietic stem cells (HSC) attenuated disease activity in a MHC major mismatch GVHD model [63].…”