title: Clinical "cytokine storm" as revealed by monocyte intracellular flow cytometry: correlation of tumor necrosis factor alpha with severe gut graft-versus-host disease.
abstract: OBJECTIVE
  Gut graft-versus-host disease (GVHD) contributes significantly to lethality after allogeneic hematopoietic stem-cell transplantation (HSCT). In murine models, macrophage secretion of interleukin 1alpha (IL-1alpha) and tumor necrosis factor alpha (TNF-alpha) contributes to gut GVHD pathogenesis. To help characterize whether human gut GVHD has similar biological characteristics, monocyte IL-1alpha and TNF-alpha production were evaluated after HSCT.
  
  
  METHODS
  Patients with refractory hematologic malignancy (n = 17) underwent reduced-intensity conditioning, HLA-matched sibling HSCT, and cyclosporine A GVHD prophylaxis. After HSCT, monocyte IL-1alpha and TNF-alpha levels were measured using intracellular flow cytometry (IC-FCM), and results were correlated with clinical GVHD.
  
  
  RESULTS
  Incidences of acute GVHD were none (n = 3), grades I-II (n = 9), or grades III-IV (n = 5; each case with stage 2-3 gut GVHD). Posttransplantation monocyte IL-1alpha production (percentage of CD14(+)IL-1(+) cells) increased significantly from 8.7% +/- 3.7% (week 2) to 40.3% +/- 7.3% (week 4; P = 0.0065) and was not associated with GVHD severity (P = 1.00). Conversely, increases in monocyte TNF-alpha were quantitatively reduced and temporally delayed, from 0.6% +/- 0.2% (week 2) to 3.6% +/- 1.4% (week 6; P = 0.076). Most importantly, elevation of monocyte TNF-alpha level correlated with increased gut GVHD severity (P = 0.0041); increases in monocyte TNF-alpha levels typically preceded the onset of gut GVHD symptoms.
  
  
  CONCLUSIONS
  Human gut GVHD after reduced-intensity allogeneic HSCT is associated with monocyte cytokine secretion initially involving IL-1alpha, followed by TNF-alpha. Serial measurement of monocyte cytokines, in particular, TNF-alpha, by IC-FCM may represent a noninvasive method for GVHD monitoring, potentially allowing the identification of patients appropriate for early-intervention strategies.
authors.affiliation: Department of Experimental Transplantation and Immunology, National Cancer Institute, Center for Cancer Research, Bethesda, Maryland 20892, USA. hfowler@helix.nih.gov
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
authors.forename: Jason
authors.initials: J
authors.lastname: Foley
authors.forename: Jeannie
authors.initials: J
authors.lastname: Whit-Shan Hou
authors.forename: Jeanne
authors.initials: J
authors.lastname: Odom
authors.forename: Kate
authors.initials: K
authors.lastname: Castro
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Juan
authors.initials: J
authors.lastname: Gea-Banacloche
authors.forename: Claude
authors.initials: C
authors.lastname: Kasten-Sportes
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bishop
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D002465:Cell Movement; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000401:mortality / Q000503:physiopathology; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D016019:Survival Analysis; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha