The role of interferon‐γ, nitric oxide and lipopolysaccharide in intestinal graft‐versus‐host disease developing in F₁‐hybrid mice

Abstract

SUMMARY(C57BL/6 Â DBA/2)F 1 -hybrid mice injected with lymphoid cells from wild-type, C57BL/6 donors develop acute, lethal graft-versus-host disease (GVHD) in which the intestine is a major target. In its destructive phase intestinal GVHD is characterized by apoptosis of intestinal crypt epithelial cells and the development of endotoxaemia. Injection of as little as 10 mg endotoxin is lethal in mice with acute GVHD, and associated with the release of large amounts of tumour necrosis factor-a (TNF-a) into the serum. To explore the role of interferon-g (IFN-g) in the pathogenesis of intestinal GVHD we used IFN-g gene knockout (gko) mice as donors. Recipients of grafts from these donors did not develop intestinal GVHD and, unlike recipients of wild-type grafts, did not die when injected with lipopolysaccharide (LPS). We also found that injection 10 mg LPS into recipients of wild-type grafts induced apoptosis of intestinal epithelial crypt cells and was associated with a burst of nitric oxide production in the intestine. Administration of N o nitro L-arginine methyl ester blocked this response. In contrast, LPS did not induce either intestinal epithelial cell apoptosis or increased nitric oxide production in recipients of IFN-g gko grafts. These ®ndings indicate that donor-derived IFN-g is instrumental for the development of intestinal GVHD. In a previous study we showed that recipients of IFN-g gko grafts develop high levels of LPS-induced TNF-a release. When our current data are viewed in the context of this observation, they suggest that intestinal epithelial cell apoptosis in the parent3F 1 -hybrid model of acute GVHD is mediated primarily by nitric oxide rather than TNF-a, and that this depends on donor-derived IFN-g.

An Increase in Epithelial Cell Apoptosis Is Associated with Chronic Intestinal Nematode Infection

“…As with T. muris infection, the development of both crypt hyperplasia and epithelial cell apoptosis has been reported in GVHD (24,37,47,48). Moreover, a role for both IFN-␥ and TNF-␣ in the development GVHD-related pathology is clear (12,14,48). Indeed, the neutralization of TNF-␣ inhibits the development of GVHDassociated epithelial cell apoptosis (12,47).…”

The CCL3/Macrophage Inflammatory Protein-1α–Binding Protein Evasin-1 Protects from Graft-versus-Host Disease but Does Not Modify Graft-versus-Leukemia in Mice

“…In agreement with the latter studies, the local production of IFN-g was decreased in the intestine and liver of evasin-1-treated mice subjected to GVHD. As IFN-g is shown to play a role in GVHD (37)(38)(39)(40), a decrease in the levels of this cytokine may also contribute to the overall inhibition of GVHDassociated disease and lethality. Moreover, studies have suggested a role for TNF-a in GVHD (1-3, 8-10).…”

Minor Antigen H60-Mediated Aplastic Anemia Is Ameliorated by Immunosuppression and the Infusion of Regulatory T Cells

“…combined LN and spleen cells, or combined BM and spleen cells were the usual sources of donor lymphocytes that produce severe inflammatory responses in multiple organs and tissues (12,23,24,26). In the current study, we adopted a similar approach but used only LN cells as the source of lymphocytes.…”

“…Transplanting cells from donors to recipients that differ at MHC generates MHC-mediated GVH responses in which reaction to thousands of novel MHC-presented peptides results in the activation and expansion of a large number of clonally diverse CD8 T cells, causing fatal injury to a broad range of tissues and organs (12,14,19). Previously we produced a transfusion-associated BM failure model by the infusion of lymph node (LN) cells from C57BL/6 mice (B6) into B6D2F 1 and CByB6F 1 recipients using donor-recipient MHC disparity (20,21).…”