Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells

Reconstitution of the peripheral T-cell compartment is a critical aspect fo r the success of bone marrow transplantation end is also dependent on the r eestablishment of normal thymic structure and function. Graft-versus-host d isease (GVHD), however, exacerbates posttransplant Immunodeficiency through a deleterious effect on thymic function. To Investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F-1 transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was assoc iated with changes in thymic architecture and a reduction in cellularity ma inly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymo cytes, to less than 15% of values found in mice without GVHD. Simultaneousl y, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was secondary to a decreased commitment of resident pro-T end pre-T cells to enter the cell cycle. Moreover, DP cells themselves showed altered proliferative capacities in the presence of acute GVHD. These findi ngs suggested that thymic atrophy in acute GVHD is effected by impaired cel lular proliferation of immature host thymocytes and that the failure of the se cells to enter the cell cycle is dependent on an interferon (IFN)-gamma- driven immune response. In contrast, interleukin-4-drive chronic GVHD was n ot accompanied by a sustained thymic infiltration of donor T cells. Consequ ently, there was a lack of apparent structural changes, a restricted in sit u transcription of inflammatory cytokines, and a virtually unchanged cell c ycle progression in vivo. (Blood. 2000;96: 347-354) (C) 2000 by The America n Society of Hematology.