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

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

  • Immunology
  • Biochemistry
  • 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 - Hill, Geoffrey R.

AU - Luznik, Leo

AU - Serody, Jonathan S.

AU - Murphy, William J.

AU - Maillard, Ivan

AU - Munn, David H.

AU - Turka, Laurence A.

AU - Koreth, John

AU - Cutler, Corey S.

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