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Departments of
*
Internal Medicine and
Pediatrics, University of Michigan Cancer Center, Ann Arbor, MI 48109;
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
Department of Pathology, University of Florida College of Medicine, Gainesville, FL 32610; and
¶ Department of Hematology and Oncology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The relationships between T cell subsets (CD4+ or CD8+) and MHC alloantigenic targets are well described (10, 11). MHC class II differences between donors and recipients stimulate CD4+ T cells, while MHC class I differences stimulate CD8+ T cells. Therefore, MHC class II-deficient (II–/–) mice are resistant to CD4-dependent GVHD (12). When BM cells of II–/– mice are reconstituted with syngeneic II+/+ BM cells, these mice render to succumb to acute GVHD (12). These results demonstrate that recognition of MHC class II alloantigens on hemopoietically derived APCs alone is sufficient to activate donor CD4+ T cells and cause lethal acute GVHD. This is seen even in the absence of MHC class II alloantigen expression on GVHD target cells, such as epithelium, endothelium, and parenchyma. Thus, this GVHD model system using II–/– mice presents a stringent test of the allostimulatory functions of a subpopulation of APCs. Using this system, we demonstrated that host DCs, but not B cells, can induce acute GVHD.
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Materials and Methods |
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Female C57BL/6 (B6, KbDbI-AbI-Eb, CD45.2+), B6.Ly-5a (CD45.1+), B6.C-H2bm1 (bm1, Kbm1DbI-AbI-Eb, CD45.2+), and B6.C-H2bm12 (bm12, KbDbI-Abm12I-Eb, CD45.2+) were purchased from The Jackson Laboratory (Bar Harbor, ME). Bm1 and bm12 mice possess a mutant class I and class II allele, respectively, that differs from B6 mice. B6-background II–/– mice (II–/–: B6.129-Abbtm1N5, CD45.2+) (13) and B6.Ly-5a-background II–/– mice (II–/– B6.Ly-5a: B6.SJL-Ptprca/BoAiTac-Abbtm1N13, CD45.1+) were purchased from Taconic Farms (Germantown, NY). The age range of mice used as BMT donor and recipients was between 9 and 16 wk.
Isolation of DCs and B cells
To expand splenic DCs, mice were injected s.c. once daily with 10 µg of recombinant human flt3 ligand (kindly provided by Immunex, Seattle, WA) for 8 consecutive days, and splenic DCs were isolated, as described (14). Briefly, after digestion with collagenase D (1 mg/ml; Boehringer Mannheim, Indianapolis, IN), cells were resuspended in 1.035 g/ml Percoll (Pharmacia Biotech, Uppsala, Sweden), and underlaid with an equivalent volume of 1.075 g/ml Percoll. After centrifugation, the resulting band was harvested and washed twice, and DCs were isolated by using CD11c (N418) microbeads and the AutoMACS (Miltenyi Biotec, Bergisch Gladbach, Germany). B cells were isolated with B220 microbeads and the AutoMACS. In one experiment, isolated B cells were stimulated in vitro with 20 µg/ml LPS (Escherichia coli; Sigma-Aldrich, St. Louis, MO) for 48 h.
BM transplantation
BMT was performed according to a standard protocol, as described previously (15). Mice were irradiated with 11 Gy of total body irradiation (TBI: 137Cs source) on day –1 and were injected with 5 x 106 nylon wool-purified splenic T cells or 3 x 106 CD8+ T cells isolated with CD8+ microbeads and 5 x 106 BM cells or 5 x 106 CD4+ T cell-depleted BM cells on day 0. Mice were injected with 2–5 x 106 DCs or 2–30 x 106 B cells on day –1 following TBI. For some experiments, BM chimeras were used as recipients. To create BM chimeras, mice received 13 Gy of TBI split into two doses separated by 3 h to minimize gastrointestinal toxicity, and then were injected i.v. with 5 x 106 T cell-depleted BM cells with Thy-1.2 MicroBeads and the autoMACS (Miltenyi Biotec) separation. Five months later, BM chimeras were used as recipients. Mice were housed in sterilized microisolator cages and received autoclaved hyperchlorinated drinking water for the first 3 wk after BMT, and filtered water thereafter.
Systemic analysis of GVHD
Survival after BMT was monitored daily, and the degree of clinical GVHD was assessed weekly by a scoring system that sums changes in five clinical parameters: weight loss, posture, activity, fur texture, and skin integrity (maximum index = 10), as described (16). This score is a more sensitive index of GVHD severity than weight loss alone in multiple murine models (16). Acute GVHD was also assessed in the thymus, a sensitive target organ of acute GVHD (17, 18), by enumerating CD4 CD8 double-positive (DP) thymocytes. Acute GVHD was also assessed by detailed histopathological analysis of liver and intestine. Slides were coded without reference to mouse type or prior treatment status and examined systematically by a single pathologist (C.L.) using a semiquantitative scoring system (19, 20).
Flow cytometric analysis and ELISA
A flow cytometric analysis was performed using FITC-, PE-, or allophycocyanin-conjugated mAbs to mouse CD45.1, CD4, CD8
, CD11c (HL3), CD25, and I-Ab (BD PharMingen, San Diego, CA). Cells were preincubated with 2.4G2 mAbs to block Fc
R, and were then incubated with the relevant mAbs for 30 min at 4°C. Finally, cells were washed twice with 0.2% BSA in PBS, fixed with 1% paraformaldehyde in PBS, and analyzed by EPICS Elite ESP cell sorter (Beckman Coulter, Miami, FL). Irrelevant IgG2a/b mAbs were used as a negative control. Ten thousand live events were acquired for analysis. For intracellular cytokine staining, cells were incubated for 4 h with PMA-ionomycin (BD PharMingen) and brefeldin A at 37°C. Cells were then permeabilized with the Cytofix/Cytoperm kit from BD PharMingen and subsequently stained with PE-conjugated IFN- mAb. ELISA for IFN- (BD PharMingen) was performed, as described (21).
Statistical analysis
Survival curves were plotted using Kaplan-Meier estimates. The Mann-Whitney U test or Student’s t test was used for the statistical analysis of in vitro data and clinical scores, while the Mantel-Cox log rank test was used to analyze survival data. Value of p < 0.05 was considered statistically significant.
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Results |
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MHC class II-deficient (II–/–) mice are resistant to CD4-dependent GVHD (12). We first studied whether the add back of MHC class II-expressing, host-derived APCs could break this GVHD resistance. Wild-type (wt) B6.Ly-5.2 mice (CD45.1+) and II–/– B6.Ly-5a mice (CD45.1+) were irradiated with 11 Gy TBI on day –1 and were injected with 5 x 106 T cells from bm12 donors (CD45.2+) on day 0. Bm12 mice differ from B6 mice at a single MHC class II allele. Flow cytometric analysis of the spleen on day +5 demonstrated the expansion of donor CD4+ T cells (CD45.2+CD4+) in a wt B6.Ly-5a recipient, while donor CD4+ cells were almost undetectable in II–/– B6.Ly-5a mice (Fig. 1a). Expansion of bm12 CD4+ T cells in wt recipients was also associated with increased expression of CD25 on donor CD4+ T cells (Fig. 1b) and elevated serum levels of IFN- (Fig. 1c). Intracytoplasmic staining of IFN- confirmed that IFN- was primarily produced by donor CD4+ T cells (data not shown). These findings were not seen in II–/– recipients, confirming that II–/– mice are resistant to CD4-mediated GVHD, as described (12).
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also increased and were even significantly greater than those of wt B6.Ly-5a mice (Fig. 1c). By contrast, when II–/– mice were injected with 30 x 106 B cells isolated from wt B6 mice on day –1, donor CD4+ T cells showed minimal expansion and IFN- production, and modest CD25 expression, although 15 times more B cells than DCs were injected. To rule out high-zone tolerance (23), we did additional experiments with different numbers of B cells added back. Neither the add back of 30 x 106 B cells nor the add back of 2 x 106 B cells did induce donor CD4+ T cell proliferation in comparison with the negative control (Table I). We found that adoptively transferred naive B cells did show activation by up-regulation of B7-2 in MHC class II–/– hosts 48 h after injection into irradiated mice (data not shown). To further test the ability of activated B cells in stimulating donor T cells, B cells were stimulated in vitro with LPS for 48 h. These LPS-stimulated B cells did not stimulate donor CD4+ T cells in vivo (Table I). Therefore, we conclude that host-derived B cells alone are not sufficient to induce GVHD even though these cells are activated in irradiated mice or in the presence of LPS. We next tested whether host B cells could down-regulate acute GVHD, because B cells have been suggested to act tolerogenic (5, 24, 25). We performed these experiments by adding back host B cells to B6D2F1 recipients on day –1 of BMT from B6 donors on day 0. In this strain combination, GVHD was severe, and addition of host B cells had any impact on clinical GVHD scores (3.6 ± 0.4 vs 3.8 ± 0.3 on day 7). Second, numbers of CD4+25+ cells were enumerated in spleens of II–/– mice receiving various numbers of B cells, either resting or activated. Add back of B cells did not increase these cells. Taken together, these results suggest that host B cells were not tolerogenic.
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We then tested the hypothesis that the presence of host DCs alone is sufficient for the induction of GVHD mortality and target organ damage. Wt B6 and II–/– B6 were irradiated with 11 Gy of TBI on day –1 and were injected with 5 x 106 T cells and 5 x 106 BM cells from bm12 donors on day 0. Consistent with the striking differences in donor T cell responses between the groups, day 7 clinical GVHD scores of II–/– recipients preinjected with wt DCs (3.9 ± 0.4, p < 0.02) were significantly greater than those of II–/– recipients preinjected with wt B cells (2.3 ± 0.3) or II–/– recipients (2.3 ± 0.2), but equivalent to those of wt recipients (4.1 ± 0.1). This strain combination with intensified conditioning produced acute mortality in wt B6 recipients so that all died by day 20, as previously reported (12, 26). By contrast, 31% of II–/– recipients died from radiation toxicity and 69% of II–/– recipients survived (Fig. 2a, p < 0.01). The addition of wt DCs (5 x 106) to II–/– recipients significantly increased the mortality (75%, p < 0.03), while addition of wt B cell (30 x 106) did not alter mortality (37%).
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Presence of allogeneic DCs in syngeneic hosts stimulates donor CD8+ T cells following syngeneic BMT
We next examined whether the presence of allogeneic DCs in syngeneic hosts could stimulate donor CD8+ T cells after syngeneic BMT using a murine model of CD8-dependent GVHD across an MHC class I mismatch. Bm1 mice differ from B6 mice at a single MHC class I allele. B6 and bm1 mice (CD45.2+) were irradiated with 11 Gy of TBI on day –1, followed by the injection of DCs or B cells on day –1, and 3 x 106 T cells from B6.Ly-5a donors (CD45.1+) on day 0. Flow cytometric analysis of the spleen on day 5 demonstrated equally robust proliferation of donor CD8+ T cells in both allogeneic bm1 recipients and syngeneic B6 recipients preinjected with 5 x 106 DCs isolated from bm1 mice (Fig. 3a). Expansion of donor CD8+ T cells in allogeneic bm1 recipients and in B6 recipients preinjected with bm1 DCs was associated with increased expression of cytoplasmic IFN- in donor CD8+ T cells (Fig. 3b). These changes were not induced by the injection of 26 x 106 B cells from bm1 mice or B6 DCs, confirming the potent allostimulatory activity of DCs.
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Given that above experiments did not cause GVHD mortality, we hypothesized that the failure to induce clinical GVHD in these mice was due to the absence of alloantigens in these mice. Therefore, to test the hypothesis that host-derived DCs activate donor CD8+ T cells to cause clinical GVHD, we generated BM chimeras expressing alloantigens on target epithelial cells, but not on hemopoietically derived APCs by reconstituting lethally irradiated bm1 mice with T cell-depleted BM cells from B6 mice (B6
bm1 chimeras). Identically treated bm1bm1 chimeras were created as controls. After 5 mo, there is nearly complete replacement of DCs in the spleens by donor BM cells (1, 12, 27). These chimeras were reirradiated with 11 Gy of TBI on day –1, followed by the injection of DCs or B cells on day –1 and 2 x 106 CD8+ T cells together with 5 x 106 CD4+-depleted BM cells from B6 donors on day 0. B6 T cells did not induce GVHD in B6bm1 chimeric recipients that are resistant to CD8-dependent GVHD because their APCs are syngeneic to donors (1). Clinical scores were also equally high in both bm1bm1 chimeric recipients and B6bm1 chimeric recipients preinjected with DCs isolated from bm1 mice (Fig. 4a). Weight loss as a single parameter of acute GVHD was also equally severe in those chimeric recipients (Fig. 4b). Histopathologic examination of the liver and intestine on day 21 also showed equally significant GVHD pathology score in those chimeras (Fig. 4, c and d). Detailed comparison of each pathological finding between groups showed that host DCs alone could induce standard acute GVHD pathology (Table III). These results demonstrate that host-derived DCs alone are sufficient to activate CD8+ T cells to mediate GVHD.
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Discussion |
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MHC class II–/– mice were completely resistant to CD4-dependent GVHD. We previously showed that this GVHD resistance in II–/– mice was broken when host APCs were made to express MHC class II alloantigens by reconstituting II–/– mice with BM cells from wt mice (12). In the current study, II+/+ APCs were added back to II–/– mice, so that we were able to test the ability of each subpopulation of APCs in inducing GVHD. DCs were isolated from mice treated with flt3 ligand, which has been shown to increase the DC numbers in vivo without affecting function of each DC (14, 28). When II+/+ DCs isolated from wt mice were injected into II–/– recipients, these cells alone were sufficient to stimulate allogeneic CD4+ T cells in II–/– mice.
By contrast, II+/+ B cells alone were not sufficient to activate CD4+ T cells to cause acute GVHD. By adding back different doses of host B cells, we could rule out high-zone tolerance (23) as the cause for these results. We also observed no down-regulation of acute GVHD by adding back of host B cells. Although the contribution of B cells as APCs for CD4+ T cells is still controversial, with evidence of the ability of B cells to induce both anergy (5, 24, 25) and priming (6, 7, 8), in our model of experimental GVHD B cells failed to induce activation or tolerance of donor CD4+ T cells. Our results are consistent with a previous report demonstrating the reduced hepatic GVHD when both DCs and macrophages are depleted in recipients (29).
The potent allostimulatory capacity of DCs led to the induction of GVHD mortality and target organ injury. These results also confirm our recent observations that CD4-mediated GVHD can develop even in the absence of MHC class II alloantigen expressions on epithelial cells, the primary target cells of GVHD, and is primarily mediated by inflammatory cytokines, such as TNF- and IL-1 (12). It has been shown that both TNF- and IL-1 are involved in the development of GVHD-associated immunosuppression (30, 31), and neutralization of such inflammatory cytokines ameliorates thymic injury (12, 30). It should be noted, however, that mortality was less in II–/– mice preinjected with II+/+ DCs compared with wt recipients. Although a previous study demonstrated the presence of a small number of radioresistant host APCs in recipients 4 mo after allogeneic BMT (1), we could not detect residual DCs 3 days after add back (data not shown). Thus, reduced mortality in II–/– mice preinjected with II+/+ DCs compared with wt recipients may be due to shorter survival of injected II+/+ DCs compared with resident DCs. This may be due to the shorter survival of injected DCs compared with resident DCs in wt mice. Surprisingly, serum levels of IFN- in II–/– mice preinjected with II+/+ DCs were much greater than those in wt recipients despite equivalent donor CD4 expansion in spleens between these two groups, suggesting the donor CD4+ T cell activation in tissues other than spleen probably due to the unphysiologic distribution of i.v. injected DCs (22).
Host-derived DCs are also sufficient to activate donor CD8+ T cells. Consistent with recent studies (1), only host-derived DCs can prime CD8+ T cells, demonstrating a predominant role of direct presentation over cross-presentation of Ags in GVHD in vivo. However, priming of donor CD8+ T cells by the injection of host-derived DCs into syngeneic hosts was not sufficient to cause clinically significant GVHD. This is different from our previous observation that GVHD can be induced in syngeneic recipients when APCs are replaced by allogeneic BM-derived cells (12). Absence of clinically significant GVHD in the current study may be because primed CD8+ donor T cells cannot survive long enough to cause mortality and target organ damage in the absence of Ags (10, 11). This may be due to shorter survival and/or unphysiologic distribution of injected host-derived DCs compared with resident DCs. Alternately, double irradiation used in our previous study may lower the threshold of GVHD development. Zhang et al. (32) recently reported that when CD8+ donor T cells were primed ex vivo by host DCs, they were able to proliferate and differentiate into IFN--producing cells in 
2-microglobulin–/– mice. Our results confirm that activated CD8+ T cells with DCs can cause GVHD and further identify DCs as an important subset of APCs. Because host APCs appear to be also critical for graft-vs-leukemia effects (33), our results have important clinical implications for hemopoietic stem cell transplantation, especially in nonmalignant diseases in which selective targeting of host DCs may be a promising strategy to prevent GVHD.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Takanori Teshima, Department of Hematology and Oncology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail address: tteshima{at}md.okayama-u.ac.jp
3 Abbreviations used in this paper: GVHD, graft-vs-host disease; BM, bone marrow; BMT, BM transplantation; DC, dendritic cell; DP, double positive; TBI, total body irradiation; wt, wild type.
Received for publication October 27, 2003. Accepted for publication April 15, 2004.
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+ dendritic cells and reduces experimental acute graft-versus-host disease. Blood 99:1825. antibodies on acute graft-versus-host disease pathologies. Blood 91:4051.This article has been cited by other articles:
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, wt recipients; 
, II–/– recipients; 
, II–/– recipients injected with wt DCs; 
, II–/– recipients injected with wt B cells. Data represent one of two similar experiments, and mean ± SD is shown. ±, p < 0.05 compared with II–/– mice; UD, undetectable.
, B6 recipients injected with bm1 B cells; dotted bar, B6 recipients injected with bm1 DCs. Data represent mean ± SD. *, p < 0.05 compared with B6 recipients injected with bm1 B cells.