APCs in the Liver and Spleen Recruit Activated Allogeneic CD8+ T Cells to Elicit Hepatic Graft-Versus-Host Disease

Abstract

Host APCs are required for initiating T cell-dependent acute graft-vs-host disease (GVHD), but the role of APCs in the effector phase of acute GVHD is not known. To measure the effect of tissue-resident APCs on the local development of acute GVHD, we selectively depleted host macrophages and DCs from the livers and spleens, but not from the skin, peripheral lymph nodes (PLN), or mesenteric lymph nodes (MLN), of C57BL/6 (B6) mice by i.v. administration of liposomal clodronate before allogeneic bone marrow transplantation. Depletion of host hepatic and splenic macrophages and DCs significantly inhibited the proliferation of donor C3H.SW CD8+ T cells in the spleen, but not in the PLN or MLN, of B6 mice. Such organ-selective depletion of host tissue APCs also markedly reduced the trafficking of allogeneic CD8+ T cells into the livers and spleens, but not PLN and MLN, of B6 recipients compared with that of the control mice. Acute hepatic, but not cutaneous, GVHD was inhibited as well, resulting in improved survival of liposomal clodronate-treated B6 recipients. When C3H.SW CD8+ T cells were activated in normal B6 recipients, recovered, and adoptively transferred into secondary B6 recipients, activated donor CD8+ T cells rapidly migrated into the livers and spleens of control B6 recipients but were markedly decreased in B6 mice that were depleted of hepatic and splenic macrophages and DCs. Thus, tissue-resident APCs control the local recruitment of allo-reactive donor T cells and the subsequent development of acute GVHD.

Organ-derived dendritic cells have differential effects on alloreactive T cells

“…5 To mount an efficient alloresponse, antigens need to be presented by professional antigen presenting cells (APCs) with host APCs being crucial for the initiation of GVHD. [6][7][8][9][10] Depletion of APCs in the liver and the spleen significantly inhibits the recruitment and proliferation of donor T cells, 11 and the elimination of Langerhans cells seems to be efficient in preventing skin GVHD. 12 However, there is also increasing evidence implicating crosspresenting donor APCs in acute 13 and chronic 14 GVHD.…”

NF-κB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145

“…1 The initial event in GVHD pathophysiology derives from the conditioning regimen that results in host tissue damage, proinflammatory cytokine release, MHC and adhesion molecule up-regulation, and chemokine production. [2][3][4] Donor T-cell recognition of host alloantigens subsequently results in T-cell activation, 5,6 further cytokine secretion, 7 and acquisition of effector cell function, resulting in damage to host tissues through perforin/granzyme, fas/fas ligand, and other cytotoxic pathways. [8][9][10][11] Moreover, the release of cytokines leads to the recruitment of secondary effector cell populations (eg, macrophages, NK cells) that cause additional proinflammatory cytokine production.…”

In Vivo Imaging of Differences in Early Donor Cell Proliferation in Graft-Versus-Host Disease Hosts with Different Pre-Conditioning Doses

“…At this time, we are not aware of exactly what cell types go through early in situ proliferation, since we did not perform a subtyping analysis on the donor cells in this study. It is possible that macrophages and granulocytes are activated by irradiation-induced inflammation or T cells may be activated by recognition of allo-antigens presented by regional antigen presenting cells, such as myeloid and plasmacytoid dendritic cells (DC) in the liver (Shlomchik et al, 1999;Thomson and Knolle, 2010;Zhang et al, 2002). Whatever the subtype of cells that go through in situ proliferation, the degree of in situ early proliferation is closely related to the further expansion of donor cells after infiltration into the target organs and with the severity of GVHD.…”

“…For this reason, this technique has been used to track immune cells during GVHD, usually under MHC-mismatched conditions. After transplantation of luciferase-expressing bone marrow (BM) and leukocytes from FVB luc+ mice into irradiated BALB/c mice, which are a MHC-mismatched recipient strain (FVB → BALB/c), cells were detected in the secondary lymphoid organs within 1 day after transplantation and spread into the intestine, liver, and skin during GVHD development Zhang et al, 2002). Previously, we demonstrated the induction of acute GVHD by transplantation of BM and splenocytes from C57BL/6 (B6) mice into irradiated BALB.B mice (B6 → BALB.B), a mouse strain matched at the MHC locus, but disparate at other loci compared with the B6 strain (Choi et al, 2002a;2011).…”