Abstract

The paucity of regulatory T cells limits clinical translation to control aberrant immune reactions including graft-versus-host disease. Recent studies showed that the agonistic antibody to DR3 (aDR3) expanded CD4(+)FoxP3(+) Tregs in vivo. We investigated whether treating donor mice with a single dose of aDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. aDR3 induced selective proliferation of functional Tregs. CD4(+) T cells isolated from aDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from aDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4(+) T cells were maintained, resulting in improved survival. Conventional T cells derived from aDR3-treated donors showed reduced activation and proliferation. Serum levels of pro-inflammatory cytokines (IFN?, IL-1ß and TNFa) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from aDR3-treated donors retained graft-versus-tumor effects. In conclusion, a single dose of aDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg based therapies.

View details for DOI 10.1182/blood-2015-04-637587

View details for PubMedID 26063163