Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

The paucity of regulatory T cells (Tregs) limits clinical translation to control aberrant immune reactions including graft-versus-host disease (GVHD). Recent studies showed that theagonisticantibodytoDR3(alpha DR3) expanded CD4(+)FoxP3(+) Tregs in vivo. We investigated whether treating donor mice with a single dose of alpha DR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. alpha DR3 induced selective proliferation of functional Tregs. CD4(+) T cells isolated from alpha DR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from alpha DR3-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 alpha DR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFN gamma, IL-1 beta, and TNF alpha) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from alpha DR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of alpha DR3 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.