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Acute graft-versus-host disease (GvHD) affects up to 50% of patients receiving allogeneic bone marrow transplant (BMT) and is the leading cause of morbidity and mortality from BMT. While animal models suggest that donor myeloid cells play a role in the enhancement of GvHD, technical limitations of in situ microscopy prevent the precise identification of which cells infiltrate GvHD lesions. Splenic T cells are used to induce GvHD in animal models, but human BMT recipients are depleted of T cells prior to transplant to decrease graft rejection, so these may not be the sole mediators of GvHD pathology.
A study published by Laura Jardine and colleagues in the Journal of Clinical Investigation1 examined acute GvHD skin lesions, to identify which cells were present in skin explants and whether these cells were donor or recipient in origin.
Table 1. Cell surface markers used to determine cell identities1
BMT, bone marrow transplant; CD, cluster of differentiation; FXIII, factor XIII |
|
Marker |
Cell type |
CD11c |
Myeloid cells |
CD3 |
T cells |
CD163 |
Macrophages (not monocytes) |
FXIII |
Tissue resident macrophages (BMT recipient macrophages) |
Table 2. Genes upregulated in GvHD macrophages1
CCL, C-C chemokine ligand; CD, cluster of differentiation; GvHD, graft-versus-host disease; HLA, human leukocyte antigen; IL, interleukin; RANTES, regulated upon activation, normal T cell expressed, and presumably secreted; SELPLG, selectin P ligand; SPP, secreted phosphoprotein; TAP, transporter associated with antigen processing; TNF, tumor necrosis factor |
|
Class of Genes |
Genes |
Antigen presentation |
HLA TAP1 |
Cell recruitment |
CCL24 |
Lymphocyte stimulation |
CD82 |
Pro-inflammatory cytokine stimulation |
SPP1 |
Leukocyte extravasation |
SELPLG |
Cytokines and chemokines |
CCL5/RANTES, CXCL10, IL-8, TNFβ, IL-10 |
Table 3. Gene expression in GvHD PBMCs1
CCR, C-C chemokine receptor; CIITA, Class II major histocompatibility complex transactivator; FCER, Fc epsilon receptor; FCGR, Fc gamma receptor; GBP, guanylate-binding proteins; GNLY, granulysin; GvHD, graft-versus-host disease; IFITM, interferon-induced transmembrane; IRF, interferon regulatory factor; MRC, macrophage mannose receptor; PBMC, peripheral blood mononuclear cell; ZBTB, zinc finger and BTB domain |
|
|
Genes |
Upregulated |
CCR5, MRC1, FCGR3A/B, GNLY, IFITM1, GBP1 |
Downregulated |
FCER1A, IRF4, ZBTB46, CIITA |
Table 4. Genes expressed in GvHD macrophages and MLR macrophages1
CCR, C-C chemokine receptor; GNLY, granulysin; GvHD, graft-versus-host disease; MLR, mixed leukocyte reaction; MRC, macrophage mannose receptor; PPBP, pro-platelet basic protein; TRAIL, TNF-related apoptosis-inducing ligand |
|
|
Genes |
Upregulated in GvHD and MLR macrophages |
CCR5 MRC1 PPBP |
Upregulated in MLR macrophages |
Perforin Granzyme A GNLY TRAIL |
The authors found that skin biopsies from GvHD patients contain donor derived CD11c+CD14+ macrophages that potently activate T cells, and highlight that this interaction between donor macrophages and T cells has the potential to mediate pathology in the GvHD skin lesion. The authors conclude that understanding the function of these macrophages may enhance GvHD treatment and prevention options.
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