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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 347-354
Thymic atrophy in murine acute graft-versus-host disease is
effected by impaired cell cycle progression of host
pro-T and pre-T cells
Werner Krenger,
Simona Rossi,
Luca Piali, and
Georg A. Holländer
From the Laboratory of Pediatric Immunology, The Children's
University Hospital, and the Department of Research, Kantonsspital
Basel, Basel University, Switzerland.
Reconstitution of the peripheral T-cell compartment is a critical
aspect for the success of bone marrow transplantation and is also
dependent on the reestablishment of normal thymic structure and
function. Graft-versus-host disease (GVHD), however,
exacerbates posttransplant immunodeficiency through a deleterious
effect on thymic function. To investigate the mechanisms of
GVHD-mediated thymic disease, 2 murine parent F1
transplantation models of acute and chronic GVHD, respectively,
were studied. Acute GVHD was associated with changes in thymic
architecture and a reduction in cellularity mainly because of the
decrease in CD4+CD8+, or double-positive
(DP) thymocytes, to less than 15% of values found in mice without
GVHD. Simultaneously, 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 and pre-T cells to enter
the cell cycle. Moreover, DP cells themselves showed altered
proliferative capacities in the presence of acute GVHD. These findings
suggested that thymic atrophy in acute GVHD is effected by
impaired cellular proliferation of immature host thymocytes and that
the failure of these cells to enter the cell cycle is dependent on an
interferon (IFN)- -driven immune response. In contrast,
interleukin-4-driven chronic GVHD was not accompanied by a sustained
thymic infiltration of donor T cells. Consequently, there was a lack of
apparent structural changes, a restricted in situ transcription of
inflammatory cytokines, and a virtually unchanged cell cycle
progression in vivo.
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