Tumor necrosis factor-α production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease

Kenneth R. Cooke, Geoffrey R. Hill, James M. Crawford, David Bungard, Yani S. Brinson, John Delmonte, James L.M. Ferrara

Research output: Contribution to journalArticlepeer-review

Abstract

Donor T cell responses to host alloantigen are known predictors for graft-versus-host disease (GVHD); however, the effect of donor responsiveness to an inflammatory stimulus such as lipopolysaccharide (LPS) on GVHD severity has not been investigated. To examine this, we used mouse strains that differ in their sensitivity to LPS as donors in an experimental bone marrow transplant (BMT) system. Lethally irradiated (C3FeB6)F1 hosts received BMT from either LPS-sensitive (LPS-s) C3Heb/Fej, or LPS-resistant (LPS-r) C3H/Hej donors. Mice receiving LPS-r BMT developed significantly less GVHD as measured by mortality and clinical score compared with recipients of LPS-s BMT, a finding that was associated with significant decreases in intestinal histopathology and serum LPS and TNF-α levels. When donor T cell responses to host antigens were measured, no differences in proliferation, serum IFN- γ levels, splenic T cell expansion, or CTL activity were observed after LPS- r or LPS-s BMT. Systemic neutralization of TNF-α from day -2 to +6 resulted in decreased intestinal pathology, and serum LPS levels and increased survival after BMT compared with control mice receiving Ig. We conclude that donor resistance to endotoxin reduces the development of acute GVHD by attenuating early intestinal damage mediated by TNFα. These data suggest that the responsiveness of donor accessory cells to LPS may be an important risk factor for acute GVHD severity independent oft cell responses to host antigens.

Original languageEnglish (US)
Pages (from-to)1882-1891
Number of pages10
JournalJournal of Clinical Investigation
Volume102
Issue number10
DOIs
StatePublished - Nov 15 1998
Externally publishedYes

Keywords

  • Bone marrow transplantation
  • Cytokines
  • Gastrointestinal damage
  • Murine
  • T cells

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Tumor necrosis factor-α production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease'. Together they form a unique fingerprint.

Cite this