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using bacterial artificial chromosome (BAC) transgenic mice that express
the diphtheria toxin A chain under control of the human langerin promoter
(hLangerin-DTA)
[119,129]
. These mice constitutively lack epidermal LCs
but retain dermal langerin
+
DCs, as the human BAC does not target the lat-
ter
[116]
. No difference in GVHD was found compared to controls when
hLangerin-DTA mice were recipients in the C3H.SW → B6, CD8-dependent
model or in the MHCII-mismatched B6
bm12
→ B6 model. Nor was GVHD
affected when hLangerin-DTA mice were used as BM donors in the C3H.
SW → B6 and B6.C → BALB/c models. Finally, no difference in GVHD was
observed in the C3H.SW → B6 model when both donor and host were hLan-
gerin-DTA transgenic. That a decrease in neither systemic nor cutaneous
GVHD was observed suggests that if LCs do participate in GVHD, other
APCs can compensate in their absence.
The role of host LCs was addressed in a DLI model of cutaneous GVHD
wherein donor T cells are infused into stable donor + host → host BM chime-
ras with topical imiquimod treatment. Imiquimod is a TLR7 agonist shown
to promote local GVHD in this model
[130]
. Ablation of residual recipi-
ent LCs in these chimeras reduced DLI/imiquimod-induced skin GVHD
pathology scores by a small amount without affecting the number of CD4
or CD8 cells infiltrating the epidermis. However, the number of transcripts
for genes associated with cytolytic effector function was reduced in CD8
cells extracted from the epidermis in LC-ablated hosts
[108]
.
186
Plasmacytoid DCs
Plasmacytoid DCs (pDCs) are distinct from “conventional” DCs (cDCs)
by lineage, phenotype and function. A detailed discussion of pDC biol-
ogy is, however, beyond the scope of this chapter (see
[131-133]
). In steady
state, pDCs are found predominantly in lymphoid tissues; however, they
can also migrate to inflamed nonlymphoid tissues and solid-organ grafts
[30,134,135]
. pDCs are less notable for their role in priming T cells than for
their ability to produce inflammatory cytokines in response to infection
and PAMPR stimulation, which was the property that drove their discovery.
Mouse pDCs are incapable of cross-presentation, though human pDCs may
have this ability
[132, 136]
.
Koyama et al.
[137]
performed add-back experiments to determine whether
host pDCs are sufficient to induce GVHD. Using a parallel design for add-
back experiments with cDCs, pDCs were also able to restore GVHD in
MHCII-deficient recipients
[137]
. pDCs were suggested to require activa-
tion in the environment created by total body irradiation. The relevance of
host pDCs has been questioned based on the rapidity with which they are
eliminated by TBI
[138,139]
. The requirement for host pDCs when other
APC subsets are functional has been studied by antibody-mediated deple-
tion. Pretransplant antibody-mediated depletion of pDCs in a P → F1 model
had no effect on GVHD
[139]
. When antibody-mediated pDC depletion
was added to cDC depletion, there was no effect in either a CD4-mediated
MHCII-mismatched model or an MHC-matched, miHA-mismatched CD8
model. When mature pDCs were depleted from donor marrow prior to
transplantation, GVHD was accelerated, suggesting that mature pDCs in
donor marrow downregulate GVHD
[138]
. If so, then anti-pDC antibodies
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