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

Patricia Ewing, Sandra Miklos, Krystyna M. Olkiewicz, Gunnar Müller, Reinhard Andreesen, Ernst Holler, Kenneth R. Cooke, Gerhard C. Hildebrandt

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Objective: Tumor necrosis factor alpha (TNFα) 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 TNFα 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 TNFα kinetics in recipients of allogeneic B6 wild-type BM and wild-type T cells revealed that TNFα levels peaked around day 7 after allo-BMT, whereas TNFα was undetectable in syngeneic controls. TNFα 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 TNFα at this early time point; numbers of TNFα expressing splenic CD4+ T cells were higher than CD8+ T cells 7 days after allo-BMT, and maximal serum TNFα 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+ TNFα-/- T cells. Concurrent with increased TNFα 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 TNFα. These findings support strategies focusing on TNFα neutralization as primary treatment for aGVHD.

Original languageEnglish
Pages (from-to)155-163
Number of pages9
JournalExperimental Hematology
Issue number1
StatePublished - Jan 2007

Bibliographical note

Funding Information:
Dr. Cooke is an Amy Strelzer-Manasevit Scholar of the National Marrow Program, a Fellow of the Robert Wood Johnson, Harold Amos Medical Faculty Development Program, a Leukemia and Lymphoma Society Scholar in Clinical Research, and the recipient of a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund. Dr. Hildebrandt is a Max Eder Scholar of the Deutsche Krebshilfe e.V.

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research


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