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

35 Citations (Scopus)

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

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T-cells
Adoptive Transfer
Graft vs Host Disease
Regulatory T-Lymphocytes
Grafts
Germinal Center
Interleukin-2
Monoclonal Antibodies
Therapeutics
T-Lymphocytes
Transplantation (surgical)
Antibodies
Hematopoietic Stem Cell Transplantation
Stem cells
B-Lymphocytes
Cells
Lung
Mortality
Wounds and Injuries

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

McDonald-Hyman, C., Flynn, R., Panoskaltsis-Mortari, A., Peterson, N., MacDonald, K. P. A., Hill, G. R., ... 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

Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. / McDonald-Hyman, Cameron; Flynn, Ryan; Panoskaltsis-Mortari, Angela; Peterson, Nicholas; MacDonald, Kelli P.A.; Hill, Geoffrey R.; Luznik, Leo; Serody, Jonathan S.; Murphy, William J.; Maillard, Ivan; Munn, David H; Turka, Laurence A.; Koreth, John; Cutler, Corey S.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Blazar, Bruce R.

In: Blood, Vol. 128, No. 7, 18.08.2016, p. 1013-1017.

Research output: Contribution to journalArticle

McDonald-Hyman, C, Flynn, R, Panoskaltsis-Mortari, A, Peterson, N, MacDonald, KPA, Hill, GR, Luznik, L, Serody, JS, Murphy, WJ, Maillard, I, Munn, DH, Turka, LA, Koreth, J, Cutler, CS, Soiffer, RJ, Antin, JH, Ritz, J & Blazar, BR 2016, 'Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner', Blood, vol. 128, no. 7, pp. 1013-1017. https://doi.org/10.1182/blood-2016-05-715896
McDonald-Hyman C, Flynn R, Panoskaltsis-Mortari A, Peterson N, MacDonald KPA, Hill GR et al. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. Blood. 2016 Aug 18;128(7):1013-1017. https://doi.org/10.1182/blood-2016-05-715896
McDonald-Hyman, Cameron ; Flynn, Ryan ; Panoskaltsis-Mortari, Angela ; Peterson, Nicholas ; MacDonald, Kelli P.A. ; Hill, Geoffrey R. ; Luznik, Leo ; Serody, Jonathan S. ; Murphy, William J. ; Maillard, Ivan ; Munn, David H ; Turka, Laurence A. ; Koreth, John ; Cutler, Corey S. ; Soiffer, Robert J. ; Antin, Joseph H. ; Ritz, Jerome ; Blazar, Bruce R. / Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. In: Blood. 2016 ; Vol. 128, No. 7. pp. 1013-1017.
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AU - Luznik, Leo

AU - Serody, Jonathan S.

AU - Murphy, William J.

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AU - Munn, David H

AU - Turka, Laurence A.

AU - Koreth, John

AU - Cutler, Corey S.

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