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

Dietlinde Wolf, Henry Barreras, Cameron S. Bader, Sabrina Copsel, Casey O. Lightbourn, Brent J. Pfeiffer, Norman H. Altman, Eckhard R. Podack, Krishna V. Komanduri, Robert B. Levy

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), 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 (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo–expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.

Original languageEnglish (US)
Pages (from-to)757-766
Number of pages10
JournalBiology of Blood and Marrow Transplantation
Volume23
Issue number5
DOIs
StatePublished - May 1 2017

Keywords

  • Graft-versus-host disease (GVHD)
  • Hematopoietic stem cell transplantation (HSCT)
  • Interleukin-2 (IL-2)
  • T regulatory cells (Treg)
  • Tumor necrosis factor receptor superfamily 25 (TNFRSF25)

ASJC Scopus subject areas

  • Hematology
  • Transplantation

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