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*
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215;
Department of Pathology, University of Florida College of Medicine, Gainesville, FL 32610; and
§
Department of Pathology, Thomas Jefferson Medical Center, Philadelphia, PA 19107
The Fas/Fas ligand (FasL) pathway is involved in a variety of
regulatory mechanisms that could be important for the development of
graft-vs-host disease (GVHD) after bone marrow transplantation (BMT),
such as cytolysis of target cells by cytotoxic T cells, regulation of
inflammatory responses, peripheral deletion of autoimmune cells,
costimulation of T cells, and activation-induced cell death. To further
evaluate the role of Fas/FasL in the complex pathophysiology of GVHD,
we used Fas-deficient B6.lpr mice as recipients in a
MHC-matched minor histocompatibility Ag-mismatched murine model for
GVHD after allogeneic BMT (C3H.SW
B6). We found a significantly
higher morbidity and mortality from GVHD compared with control B6
recipients. In contrast, B6.lpr recipients had very
little hepatic GVHD, although all other specific GVHD target organs
(skin, intestines, and thymus) were more severely affected than in the
control B6 recipients. B6.lpr recipients with GVHD
demonstrated intact donor lymphoid engraftment and an increase in
expansion of donor T cells and monocytes/macrophages compared with
control B6 recipients. Serum levels of IFN-
and TNF-
were higher
in B6.lpr recipients than in control B6 recipients, and
monocytes/macrophages in B6.lpr recipients appeared more
sensitized. B6.lpr recipients had more residual
peritoneal macrophages after BMT, and peritoneal macrophages from
B6.lpr mice could induce a greater proliferative
response from C3H.SW splenocytes. This study demonstrates that the
expression of Fas in the recipient is required for GVHD of the liver,
but shows unexpected consequences when host tissues lack the expression
of Fas for the development of GVHD in other organs and systemic
GVHD.
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