title: Donor Requirements for Regulatory T Cell Suppression of Murine Graft-versus-Host Disease.
abstract: Adoptive transfer of freshly isolated natural occurring CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) prevents graft-versus-host disease (GVHD) in several animal models and following hematopoietic cell transplantation (HCT) in clinical trials. Donor-derived Treg have been mainly used, as they share the same MHC with CD4(+) and CD8(+) conventional T cells (Tcon) that are primarily responsible for GVHD. Third party-derived Treg are a promising alternative for cellular therapy, as they can be prepared in advance, screened for pathogens and activity, and banked. We explored MHC disparities between Treg and Tcon in HCT to evaluate the impact of different Treg populations in GVHD prevention and survival. Third-party Treg and donor Treg are equally suppressive in ex vivo assays, whereas both donor and third-party but not host Treg protect from GVHD in allogeneic HCT, with donor Treg being the most effective. In an MHC minor mismatched transplantation model (C57BL/6 → BALB/b), donor and third-party Treg were equally effective in controlling GVHD. Furthermore, using an in vivo Treg depletion mouse model, we found that Treg exert their main suppressive activity in the first 2 d after transplantation. Third-party Treg survive for a shorter period of time after adoptive transfer, but despite the shorter survival, they control Tcon proliferation in the early phases of HCT. These studies provide relevant insights on the mechanisms of Treg-mediated protection from GVHD and support for the use of third-party Treg in clinical trials.
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pierini
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98109.
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Colonna
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Maite
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schneidawind
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nishikii
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Mareike
authors.initials: M
authors.lastname: Florek
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Byung-Su
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; and negrs@stanford.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000097:blood; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D015415:Biomarkers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit