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 journalArticle

45 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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    McDonald-Hyman, C., Flynn, R., Panoskaltsis-Mortari, A., Peterson, N., MacDonald, K. P. A., Hill, G. R., Luznik, L., Serody, J. S., Murphy, W. J., Maillard, I., Munn, D. H., Turka, L. A., Koreth, J., Cutler, C. S., Soiffer, R. J., Antin, J. H., Ritz, J., & Blazar, B. R. (2016). Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. Blood, 128(7), 1013-1017. https://doi.org/10.1182/blood-2016-05-715896