title: A novel soluble form of Tim-3 associated with severe graft-versus-host disease.
abstract: The T cell Ig and mucin domain 3 (Tim-3) receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasma from subjects with mid-gut and upper-gut GVHD compared with those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A follow-up validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut GVHD, compared with those with upper-gut GVHD (P = .005), patients without GVHD (P = .002), and normal controls (P < .0001). Surface expression of Tim-3 was increased on CD8(+) T cells from patients with grade 2 to 4 acute GVHD (P = .01). Mass spectrometry-based profiling of plasma from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. jhansen@fhcrc.org
authors.forename: John A
authors.initials: JA
authors.lastname: Hansen
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.forename: Laura
authors.initials: L
authors.lastname: Tabellini
authors.forename: Chris
authors.initials: C
authors.lastname: Baik
authors.forename: Richard L
authors.initials: RL
authors.lastname: Lawler
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Grogan
authors.forename: Barry
authors.initials: B
authors.lastname: Storer
authors.forename: Alice
authors.initials: A
authors.lastname: Chin
authors.forename: Melissa
authors.initials: M
authors.lastname: Johnson
authors.forename: Chee-Hong
authors.initials: CH
authors.lastname: Wong
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Martin
authors.forename: George B
authors.initials: GB
authors.lastname: McDonald
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D040901:Proteomics / Q000379:methods; D055815:Young Adult
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins
keywords: Graft-versus-host disease; Hematopoietic cell transplantation; Marrow transplantation; Proteomics; TIM-3