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residual recipient hematopoietic APCs. Murine experiments supported this
hypothesis
[65]
. Infused alloreactive NK cells augmented the eradication of
host hematopoietic cells, including APCs. Importantly, recipients of allore-
active NK cells given as part of the transplant conditioning regimen did not
develop GVHD even when given a dose of donor T cells 100-fold greater
than the number necessary to kill mice that did not receive alloreactive NK
cells. When BM chimeric animals were made such that the NK cells could
not act against hematopoietic cells, but could against parenchymal cells, all
GVHD protection was lost. These data suggest that hematopoietic APCs are
required and sufficient for GVHD.
While alloreactivity against peptides restricted by the mismatched MHC
has been presumed to dominate in MHC-mismatched, miHA-mismatched
transplantation, host miHAs restricted by the donor MHC may still be
targeted. This would be consistent with the persistence of GVHD long after
host hematopoietic cells have been eliminated, leaving only donor APCs
to stimulate T cells (unless nonhematopoietic host cells are sufficient—
see below). Supporting a role for donor APCs in MHC-mismatched trans-
plants, MacDonald et al.
[64]
found, in the B6 (H-2
b
) → (B6×DBA/2; (H-2
d/b
))
MHC-partially matched and miHA-mismatched model, that when donor
BM was RelB-deficient, GVHD was reduced. Consistent with these data,
when donor DCs were deleted beginning at day +14 (in the same strain pair-
ing), clinical GVHD was modestly decreased during the time of donor DC
depletion
[64]
. In a second MHC-mismatched model, TEa TCR transgenic
CD4 cells were used to monitor indirect presentation of a host-derived
antigen by donor-derived APCs. TEa TCR transgenic T cells recognize a
fragment from MHCII I-E
d
presented by MHCII I-A
b
APCs. I-E
d
I-A
−
hosts
were irradiated and reconstituted with donor I-A
b
I-E
−
BM and TEa T cells.
The transferred TEa T cells expanded in an I-E
d
-dependent fashion post-
transplant. Deletion of donor DCs diminished but did not completely block
this expansion
[53]
.
179
MHC matched, miHA mismatched
In contrast to MHC-incompatible allo-BMT, in which MHC itself acts
as foreign antigen, wherein it was fairly straightforward to predict that
recipient APCs would be critical, the relative importance of host and donor
APCs in MHC-compatible transplants, in which both donor and host APCs
can present host peptide antigens, was less clear. Superimposed on pre-
dictions based on the biology of antigen processing and presentation are
kinetic issues. That is, if early T-cell activation is important, then recipient
APCs might be critical as large numbers of donor-derived APCs would not
be available shortly after T-cell transfer. In contrast, if later T-cell activation
is important, donor APCs might be more important, as residual recipient
APCs would be rare.
Blood → lymph filtering experiments were also used to study donor T priming
when donors and hosts differ only by miHAs. Donor T cells from CBA mice
(H-2
k
), “filtered” through syngeneic recipients, caused lethal GVHD in B10.
BR mice (H-2
k
). However, when CBA T cells were filtered in B10.BR mice,
they could not induce GVHD in newly transplanted B10.BR mice. Nonethe-
less, CBA T cells filtered through B10 background mice congenic for other
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