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The therapeutic impact of conventional extracorporeal photopheresis (ECP) on GvHD severity in the C57BL/6→BALB/c mouse model was assessed. Animals of the ECP group (---▪) were injected with 8-Methoxypsoralen and UV-A treated splenocytes from another cohort of C57BL/6→BALB/c transplanted GvHD animals with identical genetic chimerism. Animals received 3 ECP treatments in weekly intervals, started at day 1 after BMT. Control animals (—♦) received PBS injections at the same time points. Kaplan-Meier plot showing survival rates of the ECP treated vs. PBS control group (A). The ECP group consisted of 13 and the control group of 19 animals (*p<0.05, log rank test). Clinical GvHD score (B) and weight loss (C) were assessed daily.
Source publication
Background
Graft-versus-host disease (GvHD) is a major challenge after hematopoietic stem cell transplantation but treatment options for patients are still limited. In many cases first-line treatment with glucocorticoids is not successful. Among second-line therapies the extracorporeal photopheresis (ECP) is frequently performed, due to induction o...
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Introduction:
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Key Clinical Message
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Citations
... In a MHC minor mismatch mouse model of aGvHD the transfer of cells treated ex vivo with ECP significantly reduced established severe aGvHD, suppressed allogeneic responses of donor effector T cells that had never been exposed to psoralen and UVA radiation and increased the number of Treg cells derived from both the donor T-cell and bone marrow (BM) grafts [52]. Murine models showed that alloreactive apoptotic T cells are essential for the induction of ECP-mediated tolerance since ECP-treated cells from healthy mice with BM donor's genetic background were not effective in ameliorating aGvHD in a MHC I and II mismatched mouse model [53]. ...
Patients with steroid-refractory graft-versus-host disease (GvHD) are known to have a poor prognosis and for decades no approved drug has been available to treat this serious condition. Although ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor demonstrated significantly higher response rates in randomized trials compared to the best available therapy, and thus, is of benefit in both acute as well as chronic GvHD, there is an urgent medical need to improve results, such as durability of responses, response in eye, liver and lung manifestations and reduction of infectious complications. In this “Review” article we would like to offer strategies for improving treatment results in patients with steroid-refractory GvHD by combining ruxolitinib with extracorporeal photopheresis (ECP), a leukapheresis-based immunomodulatory treatment frequently applied in T-cell mediated immune disease including GvHD. Our article explores key published evidence supporting the clinical efficacy of both ruxolitinib and ECP in the treatment of GvHD and highlights their potentially complementary mechanisms of action.
... Mice were housed in a 12-h light/12-h dark cycle, under controlled temperature and humidity conditions, and were fed food and water ad libitum. Allogeneic hematopoietic cell transplantation was performed as previously described (Baake et al., 2018;Budde et al., 2014;Lasagni Vitar et al., 2021). Briefly, BALB/c mice were preconditioned by myeloablative total body irradiation and transplanted with C57BL/6N-derived bone marrow cells (BM n = 8). ...
The aim of this work was to assess corneal endothelial morphology in a well-established acute graft-versus-host disease (GVHD) murine model and to quantify the expression of neurokinin-1 receptor (NK1R) in the corneal endothelium during ocular GVHD (oGVHD). Pre-conditioning was performed in BALB/c using myeloablative total body irradiation. Subsequently, allogeneic bone marrow transplantation was performed without (BM) or with mature T cells (BM + T). Corneal transparency was monitored with in vivo biomicroscopy. After sacrifice, corneal thickness and endothelial cell number were measured, and the expression of NK1R was investigated in the corneal endothelium through immunofluorescence and quantified by immunohistochemistry. Mice presenting oGVHD showed a significant reduction in endothelial cell number compared to control animals (p < 0.0001). NK1R expression was significantly increased in oGVHD mice endothelium (p < 0.05). Corneal transparency and thickness were unchanged in all groups. Our results suggest that oGVHD affects the corneal endothelium, inducing a reduction of the cell number, and that this is associated with increased expression of the pro-inflammatory marker NK1R.
... However, it remained unknown whether NK1R can contribute to ocular GVHD and whether it might represent a new therapeutic target. Therefore, we adopted a well-established (Baake et al., 2018;Budde et al., 2014Budde et al., , 2016Budde et al., , 2018Theiss-Suennemann et al., 2015;Tischner et al., 2011) pre-clinical model of ocular GVHD, to (i) quantify ocular GVHD signs over time, and (ii) evaluate the expression ofNK1R and efficacy of its topical blockade in ocular GVHD. ...
... Although the development of ocular GVHD was previously studied in the preclinical animal model we used (Budde et al., 2014;Martínez-Carrasco et al., 2017;Pérez et al., 2011;Poe et al. n.d.;Sánchez-Abarca et al., 2015), the representation of the leukocytes infiltrating the ocular surface, and the role of NK1R, were not investigated before. ...
Purpose
to assess the effect of topical administration of the Neurokin-1 receptor (NK1R) antagonist Fosaprepitant in a pre-clinical model of ocular Graft-versus-Host disease (GVHD).
Methods
BALB/c mice were pre-conditioned by myeloablative total body irradiation and subjected to allogeneic bone marrow transplantation and mature T cell infusion (BM + T). BM-transplanted mice (BM) were used as controls. Ocular GVHD was specifically assessed by quantifying corneal epithelial damage, tear secretion, blepharitis and phimosis, 3 times/week for 28 days post-transplantation. A group of BM + T mice received Fosaprepitant 10 mg/mL, 6 times/day, topically, from day 7–29 after transplantation. After sacrifice, the expression of NK1R, CD45, CD3, and CXCL10 was quantified in the cornea, conjunctiva, and lacrimal gland by immunohistochemistry.
Results
BM + T mice developed corneal epithelial damage (day 0–29, p < 0.001), blepharitis (day 0–29, p < 0.001), and phimosis (day 0–29, p < 0.01), and experienced decreased tear secretion (day 21, p < 0.01) compared to controls. NK1R was found upregulated in corneal epithelium (p < 0.01) and lacrimal gland (p < 0.01) of BM + T mice. Fosaprepitant administration significantly reduced corneal epithelial damage (p < 0.05), CD45⁺ (p < 0.05) and CD3⁺ (p < 0.01) immune cell infiltration in the cornea and conjunctiva (p < 0.001 and p < 0.001, respectively). In addition, Fosaprepitant reduced the expression of CXCL10 in the cornea (p < 0.05) and in the lacrimal gland (p < 0.05).
Conclusions
Our results suggest that NK1R represents a novel druggable pathway for the therapy of ocular GVHD.
... allograft rejection [28][29][30], GVHD [31][32][33][34][35], CHS [19,20,22,23,36], experimental allergic encephalomyelitis [37,38], pathology in lupus-prone mice [39,40], type 1 diabetes in non-obese mice [41] and collagen-induced arthritis (CIA) [42]. The experimental design of these studies involved a donor of ECP-treated cells, incubation of donor cells with 8-MOP (range = 100-250 ng/ml), UVA irradiation (range = 1-5 J/cm 2 ) of donor cells and i.v. ...
... minor or major histocompatibility antigen of the graft donor) is not present in the ECPtreated inoculum and immunosuppressive effects are not donor-specific. The same holds true in experimental ECP treatment of GVHD if a naive ECP cell donor is syngeneic to the bone marrow donor [32,34,35], as pathological T cell responses in the setting of active GVHD are directed to the recipient but not donor, minor or major histocompatibility antigens. In these protocols, even third-party ECP cell donors [32,35] mediated immunosuppressive effects in the recipient. ...
... In other experimental ECP protocols, the ECP cell donor is antigen-experienced; that is, skin-transplanted [25,26], bone marrow-transplanted [31,34], sensitized to The therapeutic effect of extracorporeal photopheresis (ECP) mediated by dendritic cells is antigen-specific. The spleen and lymph node cells were obtained from the mice that were sensitized with 2-chloro-1,3,5-trinitrobenzene (TNCB) or oxazolone (OXA). ...
Extracorporeal photopheresis (ECP) represents one of the most widespread and effective cell therapies for graft-versus-host disease and other T cell-mediated disorders. However, the key factors affecting the therapeutic efficacy of ECP remain unclear. We hypothesized that therapeutic effects are mediated by ECP-treated antigen-presenting dendritic cells (DC). To test this hypothesis, we used the experimental model of contact hypersensitivity (CHS). The ECP's therapeutic activity improved when the total cell dose of the ECP-treated cells was increased. We used different haptens during sensitization to demonstrate that the anti-inflammatory activity of ECP is antigen-specific. This confirmed the hypothesis that professional antigen-presenting cells are involved in the mode of action. Also, the ECP's therapeutic activity was abrogated by the depletion of CD11c+ DC, which represents fewer than 1% of all the ECP-exposed cells. Finally, we confirm the critical importance of CD11c+ DC for ECP activity by showing that only a few purified CD11c+ DC are sufficient to mediate its therapeutic effect. The finding that ECP-treated, physiological antigen-presenting DC alone mediate antigen-specific modulation of a pathological immune response may result in better-targeted interventions when treating patients.
... Such observations in patients do not readily fit a model of ECP being primarily mediated through the induction of T-regs and other experimental data challenge this paradigm in the understanding of autologous ECP-treatment of ongoing inflammatory disease. A more recent in vivo model has shown that infusion of ECP/PUVA-treated cells from an allogeneic healthy donor failed to provide protection or reverse acute GVHD development, whereas splenocytes from an allogeneic donor of the same genetic background with acute GVHD provided significant protection (119). Further, in an in vivo model of ECP-modulation of rheumatoid arthritis, only ECP-treated splenocytes from arthritogenic donors could suppress inflammation, whereas those from healthy donors had no significant effect (120). ...
As the use of hematopoietic stem cell transplantation (HSCT) has become a more widespread and effective treatment for hematological malignant and non-malignant conditions, the need to minimize the harmful effects of graft- vs.-host disease (GvHD) has become more important in achieving good outcomes. With diagnosis of GvHD reliant on its clinical manifestations, research into biomarkers for the diagnosis, progression, and even for the prediction of disease, is imperative to combating the high levels of morbidity and mortality post-HSCT. Despite the development of novel treatment approaches to GvHD, corticosteroids remain the standard first-line treatment, with immunosuppressant therapies as second-line options. These strategies however have significant limitations and associated complications. Extracorporeal Photopheresis (ECP) has shown to be effective and safe in treating patients with symptomatic GvHD. ECP has been shown to have varied effects on multiple parts of the immune system and does not appear to increase the risk of relapse or infection in the post HSCT setting. Even so, ECP can be logistically more complex to organize and requires patients to be sufficiently stable. This review aims to summarize the potential role of biomarkers to help guide individualized treatment decisions in patients with acute and chronic GvHD. In relation to ECP, robust biomarkers of GvHD will be highly useful in informing patient selection, intensity and duration of the ECP schedule, monitoring of response and other treatment decisions alongside the concurrent administration of other GvHD therapies. Further research is warranted to establish how GvHD biomarkers are best incorporated into ECP treatment pathways with the goal of tailoring ECP to the needs of individual patients and maximizing benefit.
... Ces Lymphocytes T « pathogènes » sont impliqués dans l'induction, le développement et le maintien de ces pathologies. La présence de lymphocytes T « pathogènes » dans l'échantillon traité semble être essentielle pour le bon fonctionnement et l'efficacité du traitement (10,20). Lors d'un traitement PCE, seule une fraction de lymphocytes T « pathogènes » du patient sont traités et non l'ensemble. ...
... Il montre également dans cette étude que la réinjection de cellules « saines » traitées PUVA ne provoque pas d'amélioration du taux de survie ou du score clinique des souris traitées. C'est la réinjection répétée de cellules alloréactives traitées PUVA qui induit une amélioration de la GvHD (20). Ce modèle confirme que la présence de lymphocytes T « pathogènes » dans l'échantillon traité est nécessaire au bon fonctionnement de la PCE. ...
... Des données observées en clinique et dans un modèle animal montrent que la présence de lymphocytes T « pathogènes » dans l'échantillon traité PUVA est nécessaire au bon fonctionnement du traitement (20,297). Nos données montrent que la réinjection de lymphocytes T « pathogènes » traités PUVA est suffisante à l'obtention de l'effet thérapeutique de la PCE, puisque la réinjection de lymphocytes T issus de souris arthritiques (« pathogènes ») traités PUVA induit une diminution des symptômes. ...
La photochimiothérapie extracorporelle (PCE) est une immunothérapie autologue, basée sur la réinjection de cellules photochimiquement modifiées. La PCE a démontré son efficacité dans le traitement des formes avancées du CTCL, dans la GvHD ainsi que dans d’autres pathologies médiées par la présence de lymphocytes T pathogènes (rejets de greffes d’organes, pathologies auto-immunes), sans provoquer d’immunossupression généralisée. Bien qu’utilisée depuis de nombreuses années, les mécanismes d’action de la PCE restent peu connus. L’objectif de ma thèse était de les étudier et de mettre en place un modèle chez la souris pour permettre une optimisation des protocoles cliniques. Deux hypothèses ont été testées pour expliquer l’efficacité de la PCE : la mort « tolérogène » où l’effet obtenu serait lié à la génération de lymphocytes T régulateurs et la mort « immunogène » où l’effet pourrait s’expliquer par la génération de lymphocytes T cytotoxiques.L’utilisation de cellules mononucléées humaines obtenues chez des donneurs sains nous a permis de générer des lymphocytes T alloréactifs activés et de montrer que les lymphocytes T traités PUVA émettaient une partie des molécules dites de danger (DAMPs), décrites comme immunogènes, telles que la Calréticuline ou encore le HMGB1. Ces cellules sont phagocytées par les macrophages et les moDCs, mais ne sont pas capables d’induire leur maturation, ce qui n’engendre donc pas de stimulation du système immunitaire.L’utilisation d’un modèle murin de polyarthrite rhumatoïde (CIA) nous a permis de montrer l’efficacité de la PCE dans le traitement de cette pathologie. De plus, nos résultats montrent que l’efficacité du traitement repose sur la présence de lymphocytes T issus de souris « arthritique » dans l’échantillon traité.En conclusion, les mécanismes d’action de la PCE ne semblent pas être associés au concept de mort immunogène. Le modèle de polyarthrite rhumatoïde induite par le collagène chez la souris permettra de poursuivre l’étude des mécanismes d’action et d’optimisation de la PCE.
... Certains de ces scores sont uniquement dédiés à la GVHa cutanée (Anderson, McNiff et al. 2003). Les autres évaluent la GVHa de façon plus globale soit en rajoutant au score de Cooke un voire plusieurs critères supplémentaires, en général la diarrhée (Wilson, Cullup et al. 2009, Castor, Rezende et al. 2010, soit en le simplifiant légèrement en retirant un critère , soit enfin en combinant les 2 approches (Budde, Kolb et al. 2014). ...
... Il est important de préciser que tous ces systèmes de classification de la GVHa murine diffèrent aussi grandement dans la façon dont ils sont employés par les différentes équipes de recherches, en termes de fréquence d'utilisation (d'une seule évaluation ponctuelle (Cooke, Kobzik et al. 1996 à une évaluation quotidienne (Wilson, Cullup et al. 2009, Budde, Kolb et al. 2014)) et de recours ou non à des critères éthiques de sacrifice des souris. Ce recours est en effet très aléatoire selon les études, y compris quand le même score clinique est utilisé (Couturier, Lamarthee et al. 2013, Fu, Wang et al. 2015, et les critères de sacrifice retenus correspondent le plus souvent soit à un certain seuil de perte de poids soit à une certaine valeur du score clinique calculé pour chaque souris (Budde, Kolb et al. 2014 Enfin, la cinquième limite des modèles expérimentaux de GVHa est constituée par l'âge des souris donneuses et receveuses. ...
... Il est important de préciser que tous ces systèmes de classification de la GVHa murine diffèrent aussi grandement dans la façon dont ils sont employés par les différentes équipes de recherches, en termes de fréquence d'utilisation (d'une seule évaluation ponctuelle (Cooke, Kobzik et al. 1996 à une évaluation quotidienne (Wilson, Cullup et al. 2009, Budde, Kolb et al. 2014)) et de recours ou non à des critères éthiques de sacrifice des souris. Ce recours est en effet très aléatoire selon les études, y compris quand le même score clinique est utilisé (Couturier, Lamarthee et al. 2013, Fu, Wang et al. 2015, et les critères de sacrifice retenus correspondent le plus souvent soit à un certain seuil de perte de poids soit à une certaine valeur du score clinique calculé pour chaque souris (Budde, Kolb et al. 2014 Enfin, la cinquième limite des modèles expérimentaux de GVHa est constituée par l'âge des souris donneuses et receveuses. En effet, dans la majorité des cas, les modèles murins reposent sur l'utilisation de souris adultes jeunes, à la fois en ce qui concerne les donneuses et les receveuses. ...
Les lymphocytes T régulateurs (Treg) jouent un rôle majeur dans la modulation de l’alloréactivité après allogreffe de cellules souches hématopoïétiques et permettent notamment de contrôler la réaction du greffon contre l’hôte (GVH) dans des modèles expérimentaux. Le potentiel thérapeutique des Treg est donc très important dans ce domaine, mais aussi dans l’auto-immunité ou en cancérologie. Cependant, de nombreuses barrières rendent difficile l’élaboration de stratégies thérapeutiques reposant sur le transfert adoptif de Treg chez l’homme et une meilleure compréhension des facteurs et mécanismes contrôlant la prolifération et les capacités suppressives de ces cellules permettrait de les cibler directement et si possible spécifiquement in vivo.Dans ce travail, après avoir élaboré un nouveau système d’évaluation clinique de la GVH chez la souris et démontré sa simplicité, sa reproductibilité et sa performance, nous avons pu montrer que l’action suppressive des Treg dans la GVH dépendait de l’interaction entre le TNFα produit par les lymphocytes T conventionnels (Tconv) du donneur et le récepteur TNFR2 exprimé par les Treg. En effet, en bloquant cette interaction de 3 façons différentes, à savoir par un anticorps monoclonal bloquant anti-TNFR2, ou en utilisant soit des Treg n’exprimant pas TNFR2 soit des Tconv ne produisant pas de TNFα, nous avons à chaque fois montré que l’effet protecteur des Treg était aboli en l’absence du signal TNF. Le récepteur TNFR2 étant exprimé préférentiellement par les Treg par rapport aux Tconv, nos résultats ouvrent la voie au ciblage des Treg in vivo via TNFR2, soit pour activer ce récepteur par un agoniste et donc stimuler les Treg afin de contrôler la GVH, soit à l’inverse pour bloquer l’axe TNFα/TNFR2 par un antagoniste et ainsi inhiber les Treg, ce qui permettrait alors de lever un frein à l’alloréactivité dans les situations où l’on cherche à la stimuler pour renforcer l’effet anti-tumoral, comme par exemple dans le cas des rechutes post-allogreffe.
... In clinical protocols 8-MOP is added immediately before UVA exposure whereas in ECP mouse models 8-MOP is often pre-incubated for 30 min before UVA exposure [19,20]. Another difference is that in clinical protocols 8-MOP is not removed from the leukocyte suspension after UVA exposure in general, but in many published mouse experiments 8-MOP removal is performed before injection of the treated leukocytes into the animals [20][21][22][23]. One reason for this difference is the in vivo toxicity of 8-MOP in mice, which is why 8-MOP should be removed before injection of the treated cells [24,25]. ...
Extracorporeal photopheresis (ECP) is an important second-line therapy for graft-versus-host disease. A central therapeutic mechanism is the induction of immune tolerance through apoptosis in patient’s leukocytes, caused by ex vivo incubation with 8-methoxypsoralen (8-MOP) and subsequent UVA irradiation.
We hypothesized that different 8-MOP incubation times and an additional 8-MOP removal step could influence the apoptosis kinetics of leukocytes in general and in particular could lead to different apoptotic levels in the leukocyte subpopulations. After 8-MOP/UVA treatment of human leukocytes, cells were cultured and the percentage of annexin V positive cells from several leukocyte subpopulations was determined. Only regulatory T cells (Tregs) were relatively resistant to 8-MOP/UVA induced apoptosis. When cells were incubated for 30 minutes with 8-MOP prior to UVA exposure, higher percentages of annexin V positive cells were detected on day 1 and day 2 after treatment. Removal of 8-MOP after UVA exposure caused no significant changes in the apoptosis kinetics during the 72 h culture period compared with unwashed cells. The results of our in vitro study indicate that it could be possible to adjust the apoptosis kinetics via modulation of the 8-MOP incubation time. In further in vivo studies it should be elucidated to which extent different apoptosis kinetics influence the therapeutic effect of ECP since steady-state apoptosis levels are probably important for establishing a long lasting immune tolerance. Furthermore we found that Tregs, according to their well-known tolerogenic function, are more resistant to apoptosis after 8-MOP/UVA treatment compared to GvHD inducing T cell populations.
... 1 The latter includes atopic dermatitis, for which the first positive results became available recently. 2 The procedure is based on the photochemical inactivation of patient leucocytes collected by apheresis. 3 It is achieved by ex vivo incubation with 8-methoxypsoralen (8-MOP), a naturally occurring furocoumarin that distributes within less than 2 min into DNA strands and binds covalently within milliseconds after UVA exposure (320-370 nm). [4][5][6] The treated white blood cells become apoptotic. ...
Background:
Extracorporeal photopheresis (ECP) is an efficient method to treat various autoimmune diseases, cutaneous T-cell lymphoma, and graft-versus-host disease. It is based on the ex vivo inactivation of lymphocytes by 8-methoxypsoralen (8-MOP)/UV light treatment. Despite the adhesive, lipophilic nature of 8-MOP, no quality control is established for the ECP procedure.
Methods:
We developed a sensitive high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) assay to monitor residual 8-MOP concentration after UVA irradiation in the whole blood supernatant after acetonitrile precipitation.
Results:
The preanalytical stability of 8-MOP exceeded 7 days, allowing batch mode analysis. Linearity was determined with R(2) above 0.99. The 8-MOP concentrations decreased exponentially after UV exposure, with decay constants of 0.0259 in plasma and 0.0528 in saline. The recovery of 8-MOP in photopheresates was about 68%, indicating binding to DNA as well as to plastic structures. UVA induced no 8-MOP fragmentation, but caused self-adducts under extreme conditions (10-fold UV dosage).
Conclusions:
Detection of 8-MOP proved to be feasible and demonstrated that the doses were in the pharmaceutically active range.
... Several studies have found that the effects of ECP are associated with induction of host/recipient immunosuppressive DCs by the clearance of the ECPtreated apoptotic cells, and with increased number or function of CD4 Tregs [109][110][111][112][113][114][115] . Interestingly, ECP does not cause generalized immunosuppression, and the presence of hostreactive T cells in the ECP-treated inoculum seems to correlate directly with the ECP efficacy in GVHD [116][117][118] . Based on these observations, D. Hannani 119 has raised the hypothesis that during ECP, reinfusion of host-reactive T cells undergoing immunogenic cell death provides Ags (host-reactive TCR-derived peptides) plus APC-activating signals to host APCs, which then generate anti-clonotypic CD8 T cells that specifically eliminate the pathogenic T cells responsible for GVHD. ...
The main limitations to the success of transplantation are the anti-graft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the anti-donor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system. This article is protected by copyright. All rights reserved.
