title: Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner.
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 inhibit GC reactions, 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.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Cameron
authors.identifier: 0000-0002-9998-5123
authors.initials: C
authors.lastname: McDonald-Hyman
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Peterson
authors.affiliation: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, The Johns Hopkins University, Baltimore, MD;
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Lineberger Comprehensive Cancer Center, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC;
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.affiliation: Department of Dermatology, University of California, Davis, Sacramento, CA;
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Life Sciences Institute and Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Department of Pediatrics, Georgia Health Sciences University, Augusta, GA;
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: Center for Transplantation Science, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002908:Chronic Disease; D018450:Disease Progression; D006086:Graft vs Host Disease / Q000276:immunology* / Q000628:therapy*; D007376:Interleukin-2 / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D054380:Receptors, CXCR5 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C513179:CXCR5 protein, mouse; D007376:Interleukin-2; D054380:Receptors, CXCR5