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TRANSPLANTATION
From the Etablissement Français du Sang Bourgogne
Franche-Comté, UPRES EA2284-Université de
Franche-Comté, INSERM EO119 Besançon, France; Service
d'Anatomie Pathologique, CHU Besançon, France; Service de
Radiothérapie, CHU Besançon, France; and UPRES EA2085,
IETG, Université de Franche-Comté, Besançon, France.
Cross-tolerization of T lymphocytes after apoptotic cell uptake by
dendritic cells may be involved in self-tolerance maintenance. Furthermore, immunosuppressive properties are attributed to apoptotic cells. This study evaluated the consequences of apoptotic leukocyte administration in a restrictive engraftment model of murine bone marrow
(BM) transplantation. Sublethally irradiated recipients received a
limited number of allogeneic BM, with or without irradiated apoptotic
leukocytes of different origins. No graft-versus-host disease was
observed. Whereas only a low proportion of mice receiving BM cells
alone engrafted, addition of apoptotic irradiated leukocytes, independently of the origin (donor, recipient, third-party mice, as
well as xenogeneic peripheral blood mononuclear cells), significantly enhanced engraftment. Similar results were obtained after infusion of
leukocytes rendered apoptotic by UVB irradiation or by anti-Fas monoclonal antibody stimulation, thus confirming the role of apoptotic cells in engraftment facilitation. Overall, these results suggest that
apoptotic leukocytes can nonspecifically facilitate allogeneic BM
engraftment. Such a simple approach could be of interest in BM
transplantation settings involving an important HLA donor/recipient disparity, a T-cell-depleted graft, or reduced conditioning regimen intensity.
(Blood. 2001;98:224-230) Allogeneic hematopoietic stem cell (HSC)
transplantation is a major therapeutic option to treat malignant and
hereditary hematologic diseases. However, the high curative potential
as well as the expansion of such a treatment modality are limited by
the high rate of immunologic complications. Such side effects are
mainly due to the presence of immunocompetent cells of both host and donor origins and the consequent alloreactive conflict. Graft rejection
is mainly mediated by recipient T lymphocytes that resist the
conditioning regimen. The main factors influencing the engraftment are
the type and intensity of the myeloablative treatment, graft characteristics (number of stem cells and donor T cells) as well as the
magnitude of the major histocompatibility complex (MHC) disparity
between the donor and the recipient.1 Prevention of graft
rejection by the use of T-cell-containing grafts is unfortunately associated with a higher incidence of graft-versus-host disease (GvHD).
This complication occurs after the recognition of host alloantigens by
mature donor T lymphocytes present in the graft, in the context of
inflammatory cytokine release.2 An effective way to
prevent GvHD is to deplete the donor T-cell population present in the
graft, which is, however, associated with increased malignancy relapse
and graft rejection.3 Therefore, the development of new
strategies to modulate alloreactivity in the setting of allogeneic HSC
transplantation is necessary.
An alternative approach to T-cell depletion is to selectively eliminate
alloreactive T cells while retaining T-lymphocyte subsets with other
specificities (eg, antiviral).4 Recently, this interesting
approach has been used to anergize allogeneic T lymphocytes by blocking
the CD28 interaction with B7 molecules.5 In that study,
all recipients engrafted and experienced a lower than expected
incidence of GvHD after haploidentical HSC. In addition to anergic
donor T lymphocytes, a high number of apoptotic (or committed to
apoptosis) cells were injected, as indicated by the increase of the
absolute number of CD3+ cells infused.5 These
apoptotic cells are not immunologically inert.6
Immunosuppressive cytokine production by phagocytes having engulfed
apoptotic cells have been described.7-10 Furthermore, it
has been recently suggested that the permanent uptake of apoptotic cells in the periphery allows dendritic cells (DCs) to induce and
maintain tolerance to self after migration to draining lymph nodes.11
Using a restrictive engraftment model of murine bone marrow
transplantation (BMT), we therefore decided to evaluate the
consequences of apoptotic leukocyte administration on the engraftment
of an allogeneic BM graft. We found that apoptotic leukocytes
co-infused with BM cells have a graft-facilitating effect without
causing GvHD. This effect was not restricted to the donor origin of the apoptotic cells, because recipient, third-party, as well as xenogeneic apoptotic leukocytes facilitated engraftment. The graft-facilitating effect observed after the injection of apoptotic cells suggested a
hyporeactivity against allogeneic donor BM cells but not apoptotic cells. The use of irradiated apoptotic cells could be a relatively simple way to modulate alloreactivity in HSC transplantation settings such as an important HLA donor/recipient disparity, a T-cell-depleted graft, or reduced conditioning regimen intensity (eg, older patients, nonmalignant disorders, or tolerance induction for organ transplantation).
Mice
Bone marrow transplantation
Apoptosis induction Apoptosis was induced either by - or UVB-irradiation or by
exposure of activated SCs to a lytic anti-Fas monoclonal antibody (mAb). SCs and PBMCs were adjusted to 2 × 106 cells/mL
(in PBS) and submitted to -irradiation (40 Gy) 6 hours before
injection of the mice to allow apoptotic changes to occur. Alternatively, SCs were dispersed into Petri dishes (100-mm diameter) and exposed to 200 J/m2 UVB radiation (Sankyo Denki, Tokyo,
Japan). For Fas-induced apoptosis, SCs were adjusted to
2 × 106 cells/mL and activated by the addition of 2.5 µg/mL concanavalin A (Con-A, Seromed, Berlin, Germany) and
recombinant human interleukin-2 (IL-2; 500 IU/mL; Cetus,
Rueil-Malmaison, France) in Dulbecco modified Eagle medium
(BioWhittaker) culture medium supplemented with 10% heat-inactivated
fetal calf serum (Boehringer Mannheim, Meylan, France),
5 × 10 5 M 2-mercaptoethanol, 2 mM L-glutamine, 100 IU/mL penicillin, and 100 µg/mL streptomycin (Sigma) (complete
medium) and incubated at 37°C in a humidified atmosphere with 5%
CO2. After 3 days of activation, apoptosis was induced by
the addition of a lytic anti-Fas mAb (1 µg/mL, clone Jo2; Pharmingen,
San Diego, CA) during an additional culture period of 6 or 24 hours in
the absence of IL-2. The cells were then washed in PBS and adjusted to
the desired concentration before injection. At the time of injection,
only a small proportion of the leukocytes were in an advanced death stage as determined by trypan blue exclusion ( 10%). No aggregation was observed.
Flow cytometry analysis for the detection of engraftment Detection of the engraftment was performed between day 45 and day 50 post-BMT. H-2 phenotypes of SCs from recipient mice were determined by flow cytometry using fluorescein isothiocyanate (FITC)-labeled anti-H-2q (KH114, mouse immunoglobulin G2a [IgG2a]) and phycoerythrin (PE)-labeled anti-H-2d (SF1-1.1, mouse IgG2a) antibodies (Pharmingen). Analysis was performed on a FACSCalibur (Becton Dickinson, Mountain View, CA) using CellQuest software (Becton Dickinson). Engraftment was routinely evaluated in spleen cells and circulating leukocytes. In one experiment, engraftment was determined in additional immunologic sites: thymus, BM, and cervical lymph node. Engraftment was considered as positive if at least 15% of recipient cells had the BM donor H-2 phenotype.12 Engraftment in different lineage (lymphoid or myeloid) was determined using forward light scatter and side light scatter gating.GvHD evaluation In each experiment, GvHD was assessed by body weight loss (weekly) and skin lesions (daily). In killed animals, GvHD was also evaluated at day 45 to day 50 histologically as described.13 The following organs were systematically examined: stomach, small and large intestines, rectum, and skin (neck and abdominal wall) as targets for GvHD. Liver, heart, lungs, spleen, kidney, testis, and brain were evaluated for tissue injuries due to irradiation.Apoptosis detection by Annexin-V staining Following induction of apoptosis, SCs were resuspended at 2 × 106 cells/mL in complete medium and dispensed into 24-well plates. After different periods of culture at 37°C and 5% CO2, 5 × 105 cells were harvested, washed twice in cold PBS, and resuspended in cold Annexin-V buffer (Immunotech, Marseille, France). The cells were then stained with FITC-conjugated Annexin-V (Immunotech) for 10 minutes and analyzed using a FACSCalibur flow cytometer. In some experiments, detection of secondary necrotic cells was assessed using propidium iodide (Sigma) staining.Ex vivo splenocyte interferon- -irradiated (20 Gy) mature DCs generated from BM
(×105/well). Mature DCs were derived from naive C57BL/6
mice as described.14 Mixed T lymphocyte/DC cultures were
maintained in complete medium at 37°C in 5% CO2.
Supernatants were collected from 48-hour cultures. Mouse interferon
(IFN)- production was measured using an enzyme-linked immunosorbent
assay kit (R&D Systems, Abingdon, United Kingdom) according to
manufacturer's instructions.
Statistical analysis Statistical analysis was performed using SigmaStat and SigmaPlot software version 4.0 (Jandel Scientific, Erkrath, Germany). Chi-square and Fisher exact tests were used when indicated. P values < .05 were considered as statistically significant.
Splenocytes irradiated at 40 Gy are apoptotic Gamma-irradiation of murine SCs or human PBMCs leads to apoptotic death of such cells.10,15-17 Using FITC-Annexin-V staining and FACS analysis, we evaluated the kinetics of apoptosis induction by 40 Gy-irradiation in murine SCs. As soon as 2 hours
after irradiation, 40% of irradiated cells were labeled by
FITC-Annexin-V (Figure 1E), and by 6 hours after irradiation (when irradiated cells were injected in
recipient mice), as much as 80% of cells were apoptotic (Figure 1F),
indicating that a majority of irradiated SCs in our model were
apoptotic at the time of injection.
Donor-irradiated apoptotic SCs enhance the engraftment of an allogeneic HSC graft To study the host-versus-graft reactivity and modulation, we designed a restrictive murine BMT model. BALB/c mice (H-2d) were exposed to a 6-Gy TBI before receiving a limited number of 106 BM cells from FVB mice (H-2q). In this model, the low dose of irradiation allows the recipient immune system to reject the low number of allogeneic BM cells injected. An autologous hematopoietic recovery was observed, as only 11% of recipient mice engrafted under such conditions (Table 1). To evaluate the graft-facilitating potential of donor apoptotic SCs, 5 × 106 irradiated SCs from FVB mice were added to the BM cell suspension. This addition of apoptotic cells resulted in a significant increase in the percentage of engrafted mice (49% versus 11%, P < .001; Table 1). Furthermore, a higher percentage of donor-type cells was found in the engrafted mice that received apoptotic SCs in both lymphoid and myeloid lineage (Figure 2 and Table 2). This favorable effect of donor apoptotic SCs was also observed when the number of BM cells was reduced (3 × 105 instead of 10,6 P < .001; Table 1).
Donor apoptotic SCs were also capable of increasing the engraftment
rate in another donor/recipient pair, in which only 3% of C57BL/6
(H-2b) mice irradiated at 7 Gy and injected with
3 × 105 BM cells from FVB mice engrafted. This finding
was in contrast with engraftment in 57% of mice that received
3 × 105 BM cells plus 5 × 106 irradiated
FVB SCs (P < .001; Table 1). Administration of irradiated FVB SCs alone (with no BM cells) to BALB/c mice did not result in donor
hematopoietic reconstitution, therefore excluding the possibility that
our results were due to the presence in the splenic cell suspension of
HSCs resistant to Graft-facilitating effect of irradiated SCs is not mediated by residual antirecipient cytotoxic activity retained by such cells A recent report also described that engraftment of allogeneic BM cells is facilitated by the infusion of-irradiated donor SCs.18 In that report, the investigators suggested that
the graft-promoting effect was mediated by the irradiated T cells, due
to an enhancement of the donor T-cell antirecipient allospecific cytotoxicity after 7.5 Gy -irradiation.18 In our
experiments, some cells were not stained by FITC-Annexin-V at the time
of infusion (Figure 1F). We therefore decided to determine whether the
facilitating effect we observed with irradiated donor SCs was linked to
their residual antirecipient cytotoxic activity by using irradiated host SCs (ie, syngeneic and devoid of antirecipient cytotoxic activity). We found that irradiated SCs from recipient BALB/c mice
co-injected with FVB BM cells were also able to favor FVB donor-type
engraftment (P < .05; Tables 2 and
3).
We confirmed the potential of recipient-irradiated SCs to facilitate donor hematopoietic reconstitution in a different donor/recipient combination by using a more restrictive model. Recipient BALB/c mice were exposed to lethal 8-Gy TBI and then grafted with a limited dose of 106 BM cells from C57BL/6 mice. Under these conditions, all recipient mice were dead by day 11 after transplantation. In contrast, only 20% of recipient BALB/c mice died after infusion of C57BL/6 BM cells plus irradiated BALB/c SCs. All remaining recipient mice engrafted (P < .05), with a complete donor reconstitution (100% of cells with donor [H-2b] phenotype). These results suggest that the graft-promoting effects of irradiated SCs are not due to increased antirecipient alloreactivity of such cells. SCs rendered apoptotic by other stimuli also have graft-facilitating effects To confirm that the apoptotic status of the administered SCs was indeed responsible for the observed graft-facilitating activity, alternative stimuli (lytic anti-Fas mAb Jo2 treatment and UVB-irradiation) were used to induce apoptosis. As shown in Figure 3, 80% and 100% of recipient mice that received BM cells plus donor SCs exposed to Jo2 mAb engrafted (6 and 24 hours exposure to Jo2, respectively). In contrast, only 10% of recipient mice engrafted after administration of BM cells alone (P < .001; Figure 3). Furthermore, the addition of UVB-irradiated apoptotic SCs to BM cells also resulted in graft facilitation (40% engraftment versus 14% in the absence of apoptotic cells, P = .10). These results further support the demonstration that apoptotic cells have graft-promoting effects.
Apoptotic third-party SCs or xenogeneic human PBMCs retain graft-facilitating effects We then tested whether apoptotic SCs needed to be MHC-matched to BM cells or recipient mice to exert their graft-facilitating effect. We found that the addition of irradiated SCs from third-party C57BL/6 (H-2b) mice to FVB (H-2q) BM cells also increased the proportion of recipient BALB/C (H-2d) mice with FVB donor-type phenotype (Tables 2 and 3). To confirm that this effect was independent of MHC matching between BM cells and co-injected irradiated cells, a pool of-irradiated human PBMCs was infused with
the BM cell suspension. The lack of influence of MHC specificity in
this model was supported by the findings that co-injection of FVB BM
cells plus a pool of 40 Gy irradiated human PBMCs similarly increased
the proportion of recipient BALB/c mice with a FVB phenotype (Figure
4A). The graft-facilitating effect of
irradiated human PBMCs was also observed in another donor/recipient
combination by using C57BL/6 mice as the donors of BM cells and BALB/c
as recipients: 6% of mice receiving BM cells alone engrafted versus
25% after addition of 5 × 106 irradiated PBMCs and
100% after addition of 107 irradiated PBMCs
(P < .005; Figure 4B).
Injection of apoptotic leukocytes simultaneously to BM cells favors a full-donor chimerism To better characterize the graft-facilitating effect induced by apoptotic leukocyte infusion, the presence of cells with a donor phenotype was assessed in thymus, BM, and cervical lymph node at day 45 to day 50 post-BMT. None of the 5 mice that received BM cells alone engrafted (Table 4). In contrast, in 14 recipient mice that received apoptotic cells plus BM cells, 9 presented a full-donor phenotype in each evaluated organ (Table 4). Furthermore, in 5 previous experiments, the majority of the engrafted mice that received apoptotic cells in addition to BM cells had a full-donor phenotype in myeloid lineage (Table 2), suggesting that the reconstitution of the hematopoietic system was derived from the donor BM cells infused. In addition, the disappearance of recipient T lymphocytes in the immunologic organs (particularly in lymph node and thymus) in such mice (Table 4) also sustained this hypothesis. All these findings support persistent donor-derived engraftment.
Injection of third-party (C57BL/6) apoptotic cells does not modify
the alloreactivity of T lymphocytes from engrafted production was measured. This
cytokine has been shown to be necessary to initiate acute rejection of
MHC incompatible allografts.19 The capacity of IFN-
production by T lymphocytes from these engrafted mice was compared with
the IFN production capacity of T lymphocytes from naive BALB/c and FVB
mice. IFN- production by T lymphocytes in response to C57BL/6 DC was
similar for the 3 different groups of mice (Figure
5). These results suggest that T
lymphocytes from engrafted mice that have received apoptotic
third-party cells were fully responsive to these same third-party
cells, at least in vitro. In addition, mice that did not engraft
produced cytotoxic antibodies against BM cells but never against
apoptotic cells. Indeed, no antibodies against third-party SCs were
found in the sera of mice that had received apoptotic third-party
irradiated SCs (n = 21), whereas cytotoxic anti-BM donor antibodies
were identified in such mice that did not engraft (data not
shown).
Increased use of allogeneic HSC transplantation is limited by the
high toxicity of this approach. The complex immunologic setting of
allogeneic HSC transplantation is due to the possibility of direct
and/or indirect presentation of allogeneic peptides by
antigen-presenting cells (APCs) of donor and host origins to T cells of
both origins. Interrelated consequences of this immunologic reactivity,
such as graft rejection, GvHD, and leukemic relapse, significantly
affect survival after HSC transplantation. The intensity of the
pretransplant conditioning regimen has an important influence on the
outcome of HSC transplantation, because of its toxicity and immunologic
consequences. Reduction of the conditioning regimen is associated with
increased graft rejection.20 In contrast, increased
intensity of conditioning regimen can favor the GvHD occurrence, in
part by the release of pro-inflammatory cytokines.21 Here
we demonstrate that, in the context of suboptimal TBI regimen, simultaneous intravenous administration of apoptotic leukocytes with
the BM graft has graft-facilitating effects. Using a restrictive model
and 2 donor/recipient combinations, we found that SCs rendered apoptotic by different stimuli ( Several mechanisms may explain the graft-promoting effect induced by apoptotic cell infusion. One possibility is that irradiated SCs contained sufficient radioresistant hematopoietic progenitor cells capable of engraftment. This was not the case, as evidenced by the absence of a donor hematopoietic reconstitution after infusion of donor-irradiated SCs alone. Furthermore, a donor-type hematopoietic reconstitution was also observed when irradiated cells of recipient, third-party, or xenogeneic origins were injected. Another possibility involves the deletion of recipient antidonor cytotoxic T-lymphocyte precursors and T-helper cells by "veto cells."22 Indeed, such veto cells have been reported to facilitate engraftment.23 Several distinct cell populations can mediate such an effect, including BM cells24 and low-dose irradiated SCs.18 A "veto effect" directly mediated by the irradiated cells appears improbable, because the graft-promoting effect was also observed with apoptotic cells syngeneic to the recipient. However, the possibility that apoptotic cells could indirectly provide a microenvironment favoring putative veto cells present in the BM inoculum remains. Alternatively, Fas-mediated death of bystander leukocytes by macrophages phagocytizing apoptotic cells25 may contribute to the depletion of recipient antidonor T lymphocytes. The nonspecificity of the graft-promoting effect (ie, independent of
the MHC disparity between BM and apoptotic cells) suggests that
immunosuppressive cytokines such as transforming growth factor Cells rendered apoptotic by different stimuli also had a graft-facilitating effect, implying that the apoptotic status of cells co-injected with BM cells plays a significant role in our findings. Therefore, an additional (and possibly synergistic) mechanism is the cross-tolerization of host antidonor T cells by APCs after a massive infusion of apoptotic cells. This process mimics the successive physiologic events limiting inflammation during the elimination of unwanted cells in tissue homeostasis.28 It has been shown that DCs can engulf, process apoptotic cells,29 and, under certain conditions, tolerize T cells,30,31 and, more specifically, induce alloantigen-specific hyporesponsiveness in vitro and in vivo.32 An immature DC subset trafficking through diverse tissues can continuously phagocytose cells undergoing normal turnover by apoptosis and then induce tolerance of autoreactive naive T cells in draining lymph nodes.11,33 One can therefore hypothesize that massive infusion of apoptotic leukocytes can overcome a DC stimulatory signal (inflammation induced by TBI21,34) with a tolerogenic signal favoring recipient antidonor T cells cross-tolerization. Whether this DC-mediated donor hyporeactivity would be mediated directly by donor DCs present in the BM or indirectly by recipient DCs is a question that remains to be answered. A further explanation for these results is the potential immunosuppressive properties of MHC-derived peptides. Apoptotic cells co-injected with BM cells are a potential source of relative high quantities of MHC peptides. Peptides derived from the polymorphic or nonpolymorphic regions of MHC class I and II molecules have been described to possess immunomodulatory capacities both in vitro and in vivo.35 Human HLA-DQ1-derived peptide can indeed inhibit CD4+ lymphocyte rat alloimmune responses, supporting the immunomodulatory potential of xenogeneic MHC peptides.36 In conclusion, our findings show that it is possible to overcome the MHC barriers and to easily facilitate allogeneic HSC engraftment by the addition of apoptotic cells to the BM inoculum. Such an approach could be used to reduce the conditioning regimen intensity and its associated toxicity in some settings in which it is not desirable (ie, older patients, nonmalignant disorders). This approach would also permit the expansion of HSC transplantation to tolerance induction protocols for solid organ transplantation.37 Further studies are necessary to evaluate other important issues such as possible impairment of the graft-versus-leukemia response38 or triggering of autoimmunity39 after the infusion of high quantities of apoptotic cells in the setting of HSC transplantation.
We thank Dany Trestchenkoff for help in preparing the manuscript, Eric Robinet and David E. Chalmers for critical reading of the manuscript, and Dominique Paris for his expertise in animal care and management.
Submitted September 7, 2000; accepted March 8, 2001.
Supported by grants from Fondation pour la Recherche Médicale (FRM) to M.C.B., from Association pour la Recherche sur le Cancer (No. 5567) to P.S., and from Comité Départemental de la Ligue contre le Cancer du Doubs to S.P. (Comité de Montbéliard), P.T., and P.S.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Philippe Saas, Laboratoire Thérapeutique Immuno-Moléculaire, Etablissement Français du Sang Bourgogne Franche-Comté, 1 boulevard A Fleming, BP 1937, F-25020 Besançon, France; e-mail: philippe.saas{at}efs.sante.fr.
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© 2001 by The American Society of Hematology.
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  P. Gurung, T. A. Kucaba, T. A. Ferguson, and T. S. Griffith Activation-Induced CD154 Expression Abrogates Tolerance Induced by Apoptotic Cells J. Immunol., November 15, 2009; 183(10): 6114 - 6123. [Abstract] [Full Text] [PDF]
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 C.-Q. Xia, R. Peng, Y. Qiu, M. Annamalai, D. Gordon, and M. J. Clare-Salzler Transfusion of Apoptotic {beta}-Cells Induces Immune Tolerance to {beta}-Cell Antigens and Prevents Type 1 Diabetes in NOD Mice Diabetes, August 1, 2007; 56(8): 2116 - 2123. [Abstract] [Full Text] [PDF]
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A. Maeda, A. Schwarz, K. Kernebeck, N. Gross, Y. Aragane, D. Peritt, and T. Schwarz Intravenous Infusion of Syngeneic Apoptotic Cells by Photopheresis Induces Antigen-Specific Regulatory T Cells J. Immunol., May 15, 2005; 174(10): 5968 - 5976. [Abstract] [Full Text] [PDF]
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P. R. Hoffmann, J. A. Kench, A. Vondracek, E. Kruk, D. L. Daleke, M. Jordan, P. Marrack, P. M. Henson, and V. A. Fadok Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo J. Immunol., February 1, 2005; 174(3): 1393 - 1404. [Abstract] [Full Text] [PDF]
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 F. Garnache-Ottou, L. Chaperot, S. Biichle, C. Ferrand, J.-P. Remy-Martin, E. Deconinck, P. D. de Tailly, B. Bulabois, J. Poulet, E. Kuhlein, et al. Expression of the myeloid-associated marker CD33 is not an exclusive factor for leukemic plasmacytoid dendritic cells Blood, February 1, 2005; 105(3): 1256 - 1264. [Abstract] [Full Text] [PDF]
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A. E. Morelli, A. T. Larregina, W. J. Shufesky, A. F. Zahorchak, A. J. Logar, G. D. Papworth, Z. Wang, S. C. Watkins, L. D. Falo Jr, and A. W. Thomson Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production Blood, January 15, 2003; 101(2): 611 - 620. [Abstract] [Full Text] [PDF]
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P. Ducoroy, O. Micheau, S. Perruche, L. Dubrez-Daloz, D. de Fornel, P. Dutartre, P. Saas, and E. Solary LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level Blood, January 1, 2003; 101(1): 194 - 201. [Abstract] [Full Text] [PDF]
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W. H. Peranteau, S. Hayashi, M. Hsieh, A. F. Shaaban, and A. W. Flake High-level allogeneic chimerism achieved by prenatal tolerance induction and postnatal nonmyeloablative bone marrow transplantation Blood, August 28, 2002; 100(6): 2225 - 2234. [Abstract] [Full Text] [PDF]
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J. Wilpshaar, M. Bhatia, H. H. H. Kanhai, R. Breese, D. K. Heilman, C. S. Johnson, J. H. F. Falkenburg, and E. F. Srour Engraftment potential of human fetal hematopoietic cells in NOD/SCID mice is not restricted to mitotically quiescent cells Blood, June 17, 2002; 100(1): 120 - 127. [Abstract] [Full Text] [PDF]
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L. M. Stuart, M. Lucas, C. Simpson, J. Lamb, J. Savill, and A. Lacy-Hulbert Inhibitory Effects of Apoptotic Cell Ingestion upon Endotoxin-Driven Myeloid Dendritic Cell Maturation J. Immunol., February 15, 2002; 168(4): 1627 - 1635. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
1 of bone marrow
transplantation (BMT) to reduce the risk of infection.
(TGF-