Antigen presentation and antigen-presenting cells in graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 185

responses has been hampered by the absence of techniques to specifically
deplete macrophages without targeting other phagocytic cells or to more
selectively deplete specific macrophage subsets.

The injection of clodronate-loaded liposomes is a classical method of
depleting macrophages [148] , but it also targets some phagocytic DCs.
The injection of clodronate-loaded liposomes diminished liver GVHD,
coincident with a reduction in liver macrophages, though a cause-effect
relationship could not be established [149] .

CSF-1R −/− mice lack tissue macrophages, have fewer circulating monocytes,
and lack CD11c + CD11b + DCs in nonlymphoid tissues [52,150,151] . However,
these mice have other defects that render them inappropriate for in vivo
GVHD studies. Antibody-mediated blockade of CSF-R1 recapitulates the
hematopoietic defect in the CSF-1R −/− mice and two groups exploited this
approach to study the role of CSF-1R-dependent cells in GVHD. MacDonald
et al.[152] found that pretreatment with an anti-CSF-R antibody augmented
GVHD responses in a P → F1 model. Hashimoto et al. also found that anti-
CSF-R antibody treatment (or liposomal clodronate to deplete host macro-
phages) prior to allo-BMT exacerbated GVHD [52] . They attributed GVHD
augmentation to the absence of macrophage engulfment of donor T cells
in macrophage-depleted mice, which was observed in macrophage-intact
mice [52] . These results do not indicate that macrophages or subpopula-
tions of macrophages cannot or do not stimulate alloreactive T cells; rather
that broad monocyte and macrophage ablation when other potential APCs
are intact has the net effect of augmenting alloimmunity.

188

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