Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease - PubMed (original) (raw)

Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease

Miriam Merad et al. Nat Med. 2004 May.

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Abstract

Skin is the most commonly affected organ in graft-versus-host disease (GVHD). To explore the role of Langerhans cells in GVHD, the principal dendritic cells of the skin, we studied the fate of these cells in mice transplanted with allogeneic bone marrow. In contrast to other dendritic cells, host Langerhans cells were replaced by donor Langerhans cells only when donor T cells were administered along with bone marrow, and the extent of Langerhans cell chimerism correlated with the dose of donor T cells injected. Donor T cells depleted host Langerhans cells through a Fas-dependent pathway and induced the production in skin of CCL20, which was required for the recruitment of donor Langerhans cells. Administration of donor T cells to bone marrow-chimeric mice with persistent host Langerhans cells, but not to mice whose Langerhans cells had been replaced, resulted in marked skin GVHD. These findings indicate a crucial role for donor T cells in host Langerhans cell replacement, and show that host dendritic cells can persist in nonlymphoid tissue for the duration of an animal's life and can trigger GVHD despite complete blood chimerism.

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Figures

Figure 1

Figure 1

Host Langerhans cells (LCs) persist in the skin after allogeneic stem cell transplantation. (a) BALB/c mice were reconstituted with low or high dose of TCD bone marrow (BM), purified HSCs, whole bone marrow or TCD bone marrow, together with peripheral blood (PB) T cells. Contour plots show percent of host and donor Langerhans cells in CD45+-gated epidermal cells after transplantation (Tx). (b) Percent of donor dendritic cells (DCs) and circulating monocytes (Mo) 4 weeks after transplantation. Mean of four separate experiments is shown. (c) Percent of host- and donor-derived Langerhans cells, 6–9 weeks after transplantation of TCD bone marrow alone or together with T cells purified from bone marrow, peripheral blood or spleen. (d,e) Epidermal cells were isolated 9 weeks after transplantation of 2 × 106 TCD bone marrow together with either 3 × 104 or 2 × 105 peripheral blood T cells. Contour plots (d) and bar graph (e) show percent of host- and donor-derived Langerhans cells. Results represent mean of two different experiments.

Figure 2

Figure 2

Allogeneic T cells deplete host Langerhans cells (LCs) through a Fas ligand–dependent pathway. BALB/c mice were injected with TCD bone marrow (BM), alone or with _gld, Prf1_−/− or wild-type (WT) peripheral blood T cells. (a) Proportion of donor and host Langerhans cells in epidermis 5 weeks after transplantation. (b,c) Percent host and donor Langerhans cells in epidermis (b), and donor T cells in skin (c) of recipient mice. Mean of three experiments is shown. (d–g) Histological examination 4 weeks after transplantation reveals normal skin in mice transplanted with TCD bone marrow alone (d) or together with gld T cells (e). Skin GVHD with necrotic keratinocytes and focal inflammatory infiltrate is seen in mice injected with _Prf1_−/− T cells (f), and severe GVHD with numerous necrotic keratinocytes and predominantly lymphoid inflammatory infiltrate is seen in mice injected with wild-type T cells (g). Magnification, ×200. (h) Dot plots show percentage of host dendritic cells (DCs) among gated CD11c+ cells in mesenteric lymph nodes (MLNs) and peripheral skin-draining (inguinal) lymph nodes (PLNs) at 4 and 8 months after transplantation. One of two experiments is shown.

Figure 3

Figure 3

Expression of CCR2 and CCR6 on donor bone marrow (BM) cells is required for Langerhans cell (LC) chimerism. (a) Fold increase of relative levels of chemokine transcripts in skin of treated mice compared with nontransplanted BALB/c control mice. Data represent mean of two different experiments. (b–d) Mice were injected with either _Ccr2_−/− or Ccr2+/+ (b), a 1:1 mixture of CD45.2+ _Ccr2_−/− and CD45.1+ Ccr2+/+ or CD45.2+ Ccr2+/+ and CD45.1+ Ccr2+/+ cells (c), or _Ccr6_−/− or Ccr6+/+ TCD bone marrow (d), alone or in addition to wild-type (WT) T cells. Results shown are mean of three separate experiments. (e,f) Mice were transplanted as described in c and d. Source of spleen dendritic cells (DCs), T cells and monocytes (Mo) was determined 5 weeks later.

Figure 4

Figure 4

Host Langerhans cells (LCs) that persist in chimeric mice induce severe skin GVHD. BALB/c mice were reconstituted with whole C57BL/6 bone marrow (BM) or TCD bone marrow, lethally irradiated 8 weeks later, and injected again with TCD bone marrow and T cells from C57BL/6 mice. Plots show percentage of infiltrating donor T cells in skin (a) and percentage of host and donor LCs in CD45+-gated epidermal cells (b), before and 3 and 5 weeks after second transplantation (Tx). (c,d) Histological examination 4 weeks after second transplant reveals severe (grade 4) GVHD, characterized by extensive apoptosis of basal keratinocytes, vacuolization and infiltration of inflammatory cells, in mice that had only host Langerhans cells at time of second transplantation (c). No skin GVHD was observed in mice that had full Langerhans cell chimerism at time of the second transplant (d). Results shown are representative of two separate mice. Magnification, ×200.

Figure 5

Figure 5

Depletion of host Langerhans cells (LCs) prevents skin GVHD. (a) BALB/c mice were reconstituted with C57BL/6 TCD bone marrow (BM) and either left untreated or exposed to ultraviolet (UV) light. Six weeks after ultraviolet exposure, all mice were reconstituted with TCD bone marrow and T cells from C57BL/6 mice. (b) Contour plots show percentage of host and donor Langerhans cells in gated PI− epidermal cells 3 weeks after exposure to ultraviolet light. (c–e) Skin sections obtained 3 weeks after second transplant and stained with H&E are shown at ×200 magnification. Mice not previously reconstituted with TCD bone marrow but exposed to ultraviolet light (c) and mice previously reconstituted with TCD bone marrow, but not exposed to ultraviolet light (d), show extensive mononuclear infiltrates in superficial dermis that focally infiltrate epidermis, associated with necrotic keratinocytes and vacuolization of basal keratinocytes (grade 2 GVHD). Mice previously reconstituted with TCD bone marrow and exposed to ultraviolet light (e) lack infiltrates in skin, and show only rare necrotic keratinocytes (grade 0.5 GVHD).

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