APOPTOSIS OF THYMOCYTES DURING ACUTE GRAFT-VERSUS-HOST DISEASE IS INDEPENDENT OF GLUCOCORTICOIDS1

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Abstract
Background. Elimination of immature thymocytes resulting in thymic atrophy is characteristic of acute graft-versus-host disease (aGVHD).Because aGVHD has been associated with elevated glucocorticoid (GC) production, and CD4,CD8 double-positive thymocytes undergo rapid apoptosis in response to GCs, we hypothesized that administration of the GC receptor antagonist RU486 (mifepristone) should alter aGVHD-mediated thymocyte apoptosis. Methods. Thymic development in the presence of aGVHD was studied in a haploidentical nonirradiated murine transplantation model (C57BL/6→B6D2F1). Recipients were treated with RU486 or vehicle alone. Thymic development was analyzed by flow cytometry at different times post transplant. Results. Acute thymic GVHD was characterized (1) by infiltration of mature donor-derived T cells and (2) by increased apoptosis of immature CD4+CD8+ thymocytes between 1 and 2 weeks after allogeneic transplantation. Contrary to expectations, administration of RU486 had no effect on these two parameters. Conclusions. Our data suggest that thymic pathology during aGVHD is mediated via a glucocorticoid-independent mechanism of apoptosis as blockade of glucocorticoid receptors did not alter the GVHD-induced thymic phenotype.

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