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Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53326
In murine models of allogeneic bone marrow transplantation (BMT),
MHC-mismatched recipients given a delayed infusion of donor leukocytes
(DLI) at 21 days posttransplant develop significant GVHD whereas
MHC-matched recipients do not. The current study was initially designed
to test the hypothesis that small numbers of T cells in the
MHC-mismatched donor bone marrow (BM) graft exacerbated graft-vs-host
disease (GVHD) when DLI was administered at 21 days after BMT. Ex vivo
depletion of Thy1+ cells from the donor BM had no impact on
the severity of GVHD after DLI. However, depletion of donor T cells in
vivo with a Thy1 allele-specific mAb given after BMT resulted in
significantly more severe GVHD after DLI. Similar results were obtained
in a MHC-matched model of allogeneic BMT, indicating that this was a
general phenomenon and not model dependent. These results indicated
that a population of donor-derived Thy1+ cells suppressed
graft-vs-host reactivity after DLI. Results of experiments with
thymectomized recipients demonstrated that an intact thymus was
required for generation of the immunoregulatory donor cells.
Experiments using TCR ß-chain knockout mice as BM donors indicated
that the immunosuppressive Thy1+ cells coexpressed
ßTCR heterodimers. Similar experiments with CD4 and CD8 knockout
donor BM suggested that the immunoregulatory
Thy1+ßTCR+ cells consisted of two
subpopulations: a CD4+CD8- subpopulation and a
CD4-CD8- subpopulation. Together, these
results show that thymus-derived,
Thy1+ßTCR+ donor cells generated early
after allogeneic BMT suppress the graft-vs-host reactivity of T cells
given as DLI. These cells may mediate dominant peripheral tolerance
after allogeneic BMT.
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