title: Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression.
abstract: Acute graft-versus-host disease (GVHD) occurs in 40% to 60% of recipients of partially matched umbilical cord blood transplantation (UCBT). In a phase I study, adoptive transfer of expanded CD4(+)CD25(+)Foxp3(+) natural regulatory T cells (nTregs) resulted in a reduced incidence of grade II-IV acute GVHD. To investigate potential mechanisms responsible for the reduced GVHD risk, we analyzed peripheral blood mononuclear cell mRNA expression of a tolerance gene set previously identified in operation- tolerant kidney transplant recipients, comparing healthy controls and patients who received nTregs and those who did not receive nTregs with and without experiencing GVHD. Samples from patients receiving nTregs regardless of GVHD status showed increased expression of Foxp3 expression, as well as B cell-related tolerance marker. This was correlated with early B cell recovery, predominately of naïve B cells, and nearly normal T cell reconstitution. CD8(+) T cells showed reduced signs of activation (HLA-DR(+) expression) compared with conventionally treated patients developing GVHD. In contrast, patients with GVHD had significantly increased TLR5 mRNA expression, whereas nTreg-treated patients without GVHD had reduced TLR5 mRNA expression. We identified Lin(-)HLADR(-)CD33(+)CD16(+) cells and CD14(++)CD16(-) monocytes as the main TLR5 producers, especially in samples of conventionally treated patients developing GVHD. Taken together, these data reveal interesting similarities and differences between tolerant organ and nTreg-treated hematopoietic stem cell transplantation recipients.
authors.affiliation: Institute of Medical Immunology, Charite Universitätsmedizin, Berlin, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charite Universitätsmedizin, Berlin, Germany. Electronic address: birgit.sawitzki@charite.de.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: Department of Internal Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brunstein
authors.affiliation: Institute of Medical Immunology, Charite Universitätsmedizin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.affiliation: Institute of Medical Immunology, Charite Universitätsmedizin, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schumann
authors.affiliation: Institute of Medical Immunology, Charite Universitätsmedizin, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Vogt
authors.affiliation: Institute of Medical Immunology, Charite Universitätsmedizin, Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Appelt
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Curtsinger
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: John E
authors.initials: JE
authors.lastname: Wagner
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D051198:Toll-Like Receptor 5
keywords: Graft-versus-host disease; Hematopoetic stem cell transplantation; Monocytes; Regulatory T cells; Tolerance; Toll-like receptor