Biology Reference
In-Depth Information
Host APCs
Donor APCs
177
FIGURE 9.1
Differential roles of donor and host APCs based on the kinetics of engraftment and direct or indirect presentation. Host APCs are the predominant APCs early
after transplantation. As a result of conditioning and the GVH response, in the days to weeks that follow, host APCs are replaced by donor APCs. This results in a period of
mixed chimerism, followed by complete or nearly complete donor chimerism
.
In MHC-mismatched or partially mismatched hosts, all host APCs express mismatched MHC
molecules for direct stimulation of donor T cells. In the context of MHC-matched transplants, miHAs are directly presented on host MHC or taken up exogenously, followed
by indirect or cross-presentation on MHCII or MHCI molecules, respectively. Donor-derived APCs indirectly present and/or cross-present exogenously acquired host miHAs
potentially derived from free host proteins or cell fragments or apoptotic or necrotic host cells. Either host or donor APCs may acquire and incorporate fully formed host
MHC/peptide complexes into their cell membranes (cross-dressing). This would be a method whereby donor APCs can present mismatched host MHCs, though the
in vivo
significance of this mode of presentation is not established.
compared to MHC-matched, miHA-mismatched transplants, both in ani-
mal models and in humans
[54-56]
. Given that donor T cells reacting to
mismatched host MHCs would be restricted by host MHCs, then donor
T-cell activation must be initiated either by a host cell or by a donor cell
that has acquired host MHCs. Further data supporting the ability of host
APCs to initiate the alloresponse in GVHD came from clever experiments
wherein the alloresponse was monitored by measuring donor T cells in
thoracic duct lymph of irradiated recipients of MHC-disparate T cells
injected intravenously (so-called blood → lymph filtering)
[57]
. In experi-
ments with MHCI and/or MHCII differences, donor T cells isolated from
thoracic duct lymph (TDL) 1-2 days post-transfer lost the ability to pro-
liferate in response to host stimulators
in vitro
and to cause GVHD in
newly transplanted identical hosts, but could cause GVHD in third-party
hosts. However, when donor T cells were isolated from TDL 3-5 days
post-transfer, they were activated blasts and had regained the ability to
cause GVHD upon transfer to newly irradiated identical hosts. This was
consistent with the hypothesis that infused allogeneic T cells were primed
on host APCs and that the “filtering” effect seen in the first 2 days after
transplant was mediated by APC “trapping” of T cells during priming in
secondary lymphoid organs.
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