title: Reconstitution of FOXP3+ regulatory T cells (Tregs) after CD25-depleted allotransplantation in elderly patients and association with acute graft-versus-host disease.
abstract: Selective depletion (SD) of host-reactive donor T cells from allogeneic stem-cell transplants (SCTs) using an anti-CD25 immunotoxin (IT) is a strategy to prevent acute graft-versus-host disease (aGvHD). There is concern that concurrent removal of regulatory T cells (T(regs)) with incomplete removal of alloactivated CD25(+) T cells could increase the risk of aGvHD. We therefore measured T(regs) in the blood of 16 patients receiving a T-cell-depleted allograft together with anti-CD25-IT-treated SD lymphocytes, in 13 of their HLA-identical donors, and in 10 SD products. T(regs) were characterized by intracellular staining for forkhead box protein 3 (FOXP3) and by quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) for FOXP3 gene in CD4(+) cells. Patients received a median of 1.0 x 10(8)/kg SD T cells and a stem cell product containing a median of 0.25 x 10(4)/kg residual T cells. T(regs) reconstituted promptly after SCT and underwent further expansion. Of the CD4(+) T cells in SD products, 1.5% to 4.8% were CD25(-) T(regs). Acute GvHD (>or= grade II) was restricted to 5 patients whose donors had significantly (P = .019) fewer T(regs) compared with those without clinically significant aGvHD. These results suggest that rapid T(reg) reconstitution can occur following SD allografts, either from CD25(-) T(regs) escaping depletion, or from residual CD25(-) and CD25(+) T(regs) contained in the stem-cell product that expand after transplantation and may confer additional protection against GvHD.
authors.affiliation: Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892-1202, USA. mielkes@nhlbi.nih.gov
authors.forename: Stephan
authors.initials: S
authors.lastname: Mielke
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.forename: Raquel
authors.initials: R
authors.lastname: Nunes
authors.forename: Agnes S M
authors.initials: AS
authors.lastname: Yong
authors.forename: John
authors.initials: J
authors.lastname: Schindler
authors.forename: Roger
authors.initials: R
authors.lastname: Kurlander
authors.forename: Victor
authors.initials: V
authors.lastname: Ghetie
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Read
authors.forename: Scott R
authors.initials: SR
authors.lastname: Solomon
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Vitetta
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D000208:Acute Disease; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology*; D006086:Graft vs Host Disease / Q000097:blood / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D019520:Living Donors; D008212:Lymphocyte Depletion / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D020127:Recovery of Function / Q000276:immunology*; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000922:Immunotoxins; D053645:Interleukin-2 Receptor alpha Subunit