Advertisement

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

Byung-Su Kim, Hidekazu Nishikii, Jeanette Baker, Antonio Pierini, Dominik Schneidawind, Yuqiong Pan, Andreas Beilhack, Chung-Gyu Park and Robert S. Negrin

Key Points

  • Donor treatment with agonistic DR3 antibody induces selective expansion of Tregs and reduced activation of conventional T cells.

  • T cells from DR3 antibody–treated donors result in reduced acute GVHD and preserved GVT effects.

Abstract

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 the agonistic antibody to DR3 (αDR3) expanded CD4+FoxP3+ Tregs in vivo. We investigated whether treating donor mice with a single dose of αDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. αDR3 induced selective proliferation of functional Tregs. CD4+ T cells isolated from αDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from αDR3-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 αDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNγ, IL-1β, and TNFα) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from αDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of αDR3 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.

  • Submitted April 3, 2015.
  • Accepted May 28, 2015.
View Full Text