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Gene Knockout Donors1
Departments of
*
Pathology and
Immunology, University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba, Canada
These experiments were performed to determine whether the absence
of donor-derived IFN-
would influence the outcome of acute
graft-vs-host disease (GVHD). Graft-vs-host reactions were induced in
B6D2F1 hybrids using grafts from either IFN- gene
knockout (gko) or wild-type, C57BL/6J,
parental strain donors. GVHD was equally lethal in both groups, but
IFN- gko graft recipients developed a more protracted
form of the disease. These mice developed early wasting that persisted
until death. IFN- was present in spleen cell cultures from wild-type
graft recipients, but was absent in cultures from IFN-
gko graft recipients. Both recipient groups showed
macrophage priming for LPS-induced TNF-
release. Engraftment of
donor-derived CD4+ and CD8+ cells was greater
in IFN- gko graft recipients. Pathologic changes in
IFN- gko graft recipients were different from those
typically seen in acute GVHD. The syndrome developing in IFN-
gko recipients consisted of patchy alopecia, corneal
dryness and clouding, and lymphocytic infiltration of the liver,
pancreas, salivary gland, lung, and kidney. Lymphocytic infiltrates
were also present in the epidermis and the epithelium of both bile and
salivary gland ducts. Some of the lesions closely resembled those seen
in the "sicca"/Sjogren’s-like syndrome associated with chronic
GVHD; however, there was no evidence of immune complex deposition in
the kidney. These results indicate that GVHD in IFN- gko
graft recipients shares many features with acute GVHD, but both the
duration of the disease and its pathologic manifestations are
different. Our results suggest that IFN- plays a significant role in
the pathogenesis of acute GVHD by increasing the rate at which
mortality develops.
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