title: Donor CD4+ T-cell production of tumor necrosis factor alpha significantly contributes to the early proinflammatory events of graft-versus-host disease.
abstract: OBJECTIVE
  Tumor necrosis factor alpha (TNFalpha) is an old foe in allogeneic bone marrow transplantation (allo-BMT) promoting acute graft-versus-host disease (aGVHD). We investigated to what extent donor T cells contribute to TNFalpha production.
  
  
  METHODS
  Lethally irradiated B6D2F1 mice were transplanted with bone marrow (BM) and T cells from syngeneic B6D2F1 or allogeneic B6 donors and assessed for cytokine production, aGVHD, and survival.
  
  
  RESULTS
  Analysis of serum TNFalpha kinetics in recipients of allogeneic B6 wild-type BM and wild-type T cells revealed that TNFalpha levels peaked around day 7 after allo-BMT, whereas TNFalpha was undetectable in syngeneic controls. TNFalpha was produced by both host and donor cells. Further exploration showed that specifically donor CD4(+) but not CD8(+) T cells were the primary donor cell source of TNFalpha at this early time point; numbers of TNFalpha expressing splenic CD4(+) T cells were higher than CD8(+) T cells 7 days after allo-BMT, and maximal serum TNFalpha levels were detected following allo-BMT with only CD4(+) T cells compared to levels found in allogeneic recipients of only wild-type CD8(+) or to only CD4(+) TNFalpha(-/-) T cells. Concurrent with increased TNFalpha levels, early clinical aGVHD and mortality were more severe following allo-BMT with either wild-type CD4(+) and CD8(+) or CD4(+) T cells only.
  
  
  CONCLUSIONS
  Our data demonstrate that in addition to residual host cells donor CD4(+) T cells significantly contribute to the proinflammatory cytokine milieu engendered early after allo-BMT through the production of TNFalpha. These findings support strategies focusing on TNFalpha neutralization as primary treatment for aGVHD.
authors.affiliation: Department of Hematology and Oncology, University of Regensburg Medical School, Regensburg, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ewing
authors.forename: Sandra
authors.initials: S
authors.lastname: Miklos
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Olkiewicz
authors.forename: Gunnar
authors.initials: G
authors.lastname: Müller
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
authors.forename: Gerhard C
authors.initials: GC
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes; D006086:Graft vs Host Disease / Q000209:etiology* / Q000473:pathology; D007249:Inflammation / Q000209:etiology*; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D015996:Survival Rate; D013601:T-Lymphocytes / Q000637:transplantation; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha