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However, these experiments did not address whether the cells that mediated
trapping and priming in blood → lymph recirculation were bone marrow
(BM)-derived, parenchymal, or both. To ask if trapping and proliferation
depended on host BM-derived cells, Sprent and colleagues performed simi-
lar blood → lymph experiments in parent → F1 (P → F1) BM chimeras
[58,59]
.
Trapping and priming of parental CD4 cells was reduced but not absent in
P → F1 chimeras
[59]
. Overall these results suggested that host BM-derived
cells played a role in trapping and priming allogeneic CD4 cells, but did not
exclude a role for nonhematopoietic host cells.
CD8 cells filtered through P → F1 chimeras were blunted in their ability to
proliferate against or to kill F1 cells, but not third-party stimulators
[58]
.
Filtering in P → F1 chimeras also reduced cytotoxic T lymphocyte (CTL)
precursor frequency, but not as effectively as when filtered through F1 mice.
When TDL was collected between days 3 and 5, there was an increase in
CTL precursors in the P → F1 chimeras that was only somewhat delayed
compared to TDL harvested from F1 mice. Finally, the investigators asked if
P → F1 chimeras were resistant to GVHD induced by parental CD8 cells. Very
large doses of unfractionated T cells (nearly 10
8
) were able to cause GVHD
in reirradiated P → F1 mice; lower doses in the range of 5 × 10
6
, which are
capable of killing nonchimeric F1 mice, were not tested. In sum, these data
raised the possibility that nonhematopoietic cells could prime alloreactive
CD8 cells, with the limitation that effects of residual host hematopoietic
cells could not be excluded.
178
Hematopoietic APCs have been shown to be sufficient for GVHD induc-
tion. In an MHC-mismatched, miHA-matched model, host hemato-
poietic cells were sufficient for CD4-mediated GVHD and for a modest
CD8-mediated GVHD reaction
[60]
. A major conclusion of these models
was that hematopoietic antigen alone was sufficient for GVHD, which was
found not to be the case in an MHC-matched, miHA-mismatched model
[61]
. Another conclusion was that CD4 and CD8 cells could cause pathol-
ogy without TCR:MHC contact with nonhematopoietic host cells—this was
confirmed in MHC-matched, miHA-mismatched models of CD4- but not
CD8-mediated GVHD
[62]
. Nonetheless, these experimental designs were
elegant approaches for isolating APC function to host hematopoietic cells.
Although this chapter focuses on GVHD, residual host hematopoietic cells
were also shown to be key for donor leukocyte infusion (DLI)-induced
graft-versus-leukemia (GVL)
[63]
. A nonoverlapping role for host hema-
topoietic cells in allo-BMT was also suggested by experiments wherein
RelB
−/−
→ wild-type (WT) B6 hosts were relatively resistant to GVHD
induction by allogeneic B6 BM and T cells. The reduction in GVHD was
attributed to diminished Th1 polarization when host hematopoietic cells
were RelB
−/−
[64]
.
Another demonstration of the importance of host hematopoietic APCs in
initiating GVHD in MHC-mismatched transplants comes from studies by
Velardi and colleagues
[65]
. They analyzed the results of human haploiden-
tical transplants and found that when NK cell alloreactivity was predicted
(based on the HLA C and HLA B haplotypes of the donors and recipients),
the incidence of GVHD was reduced
[65]
. One possible explanation for this
finding was that alloreactive NK cells ameliorated GVHD via elimination of
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