Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

Cameron McDonald-Hyman, Ryan Flynn, Angela Panoskaltsis-Mortari, Nicholas Peterson, Kelli P.A. MacDonald, Geoffrey R. Hill, Leo Luznik, Jonathan S. Serody, William J. Murphy, Ivan Maillard, David H. Munn, Laurence A. Turka, John Koreth, Corey S. Cutler, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibitGCreactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present.

Original languageEnglish (US)
Pages (from-to)1013-1017
Number of pages5
JournalBlood
Volume128
Issue number7
DOIs
StatePublished - Aug 18 2016

Bibliographical note

Funding Information:
This study was funded by the National Institutes of Health, National Cancer Institute grants P01 CA142106-08A1 (B.R.B.) and R01 CA183560 (J.R.); National Institute of Allergy and Infectious Diseases grants P01 AI056299-13 (B.R.B.) and T32 AI007313 (C.M.-H. and R.F.); National Heart, Lung, and Blood Institute F30 HL121873 (C.M.-H.); and Leukemia and Lymphoma Society Translational Research grants 6458-15 (B.R.B.) and 6462-15 (I.M. and B.R.B.).

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