Donor CD4+ T-cell production of tumor necrosis factor alpha significantly contributes to the early proinflammatory events of graft-versus-host disease

Exp Hematol. 2007 Jan;35(1):155-63. doi: 10.1016/j.exphem.2006.09.012.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation / adverse effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes
  • Graft vs Host Disease / etiology*
  • Graft vs Host Disease / pathology
  • Inflammation / etiology*
  • Kinetics
  • Mice
  • Mice, Inbred Strains
  • Survival Rate
  • T-Lymphocytes / transplantation
  • Tissue Donors
  • Transplantation, Homologous
  • Transplantation, Isogeneic
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / physiology*


  • Tumor Necrosis Factor-alpha