title: Early and late extensive chronic graft-versus-host disease in children is characterized by different Th1/Th2 cytokine profiles: findings of the Children's Oncology Group Study ASCT0031.
abstract: Numerous mechanisms underlie chronic graft-versus-host disease (cGVHD), including skewing of Th1/Th2 cytokine expression. There are biological differences between early-onset and late-onset cGVHD. To test whether different Th1/Th2 cytokines are associated with early- or late-onset cGVHD, peripheral blood was collected from 63 children enrolled on the Children's Oncology Group Phase III trial ASCT0031 evaluating hydroxychloroquine therapy for newly diagnosed extensive cGVHD. mRNA expression of interferon (IFN)-γ and interleukin (IL)-2, -4, and -10 from stimulated peripheral blood mononuclear cells was evaluated by quantitative polymerase chain reaction. Early-onset cGVHD (n = 33) was characterized by decreased expression of IFN-γ and IL-2 mRNA after nonspecific phorbol 12-myristate 13-acetate-ionomycin stimulation. In contrast, late-onset cGVHD (n = 11) was characterized by decreased expression of IL-4 and IL-2 mRNA after anti-CD3 stimulation of T cells. Receiver-operating characteristic curve analysis revealed that IFN-γ expression was correlated with the absence of early cGVHD (area under the curve [AUC] = 0.77) and that IL-4 (AUC = 0.89) and IL-2 (AUC = 0.84) expression was correlated with the absence of late cGVHD. There was no correlation between cytokine expression and a specific immune cell subset. Increased expression of Foxp3 mRNA was seen in early-onset cGVHD and late controls. The different time-dependent cytokine profiles in patients with newly diagnosed cGVHD suggests that the mechanisms underlying cGVHD are temporally regulated. Although larger validation studies are needed, our data suggest that cytokine profiles have a potential use as biomarkers for the diagnosis of cGVHD.
authors.affiliation: Children's Oncology Group, Pediatric Hematology/Oncology/Bone Marrow Transplantation, British Columbia Children's Hospital/University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rozmus
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
authors.forename: Kristin
authors.initials: K
authors.lastname: Wynne
authors.forename: Amina
authors.initials: A
authors.lastname: Kariminia
authors.forename: Preeti
authors.initials: P
authors.lastname: Satyanarayana
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gilman
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Goldman
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D007223:Infant; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D007378:Interleukins; D012333:RNA, Messenger; D006886:Hydroxychloroquine; D007371:Interferon-gamma