After allogeneic blood or bone marrow transplantation, donor T cells interact with a distorted antigen-presenting cell (APC) environment in which some, but not all, host APCs are replaced by APCs from the donor. Significantly, host APCs are required for the priming of acute graft-versus-host disease (GVHD). Donor APCs play a lesser role in the induction of acute GVHD despite their predicted capacity to cross-present host antigens. In contrast, donor APCs may play a role in perpetuating the tissue injury observed in chronic GVHD. Host APCs are also required for maximal graft-versus-leukemia responses. Recent studies have suggested potential strategies by which the continued presence of host APCs can be exploited to prime strong donor immunity to tumors without the induction of GVHD.

Introduction

Forty years ago, Richard Billingham proposed that graft-versus-host reactions could be explained by the response of donor immunocompetent cells to recipient antigens in recipients who are unable to reject donor cells.1  To this day, the central tenets of this hypothesis remain intact, but rapid advances in our understanding of innate and adaptive immunity have allowed refinements of the model. Thus, T cells were demonstrated to be the primary immunocompetent cells that induce graft-versus-host disease (GVHD)2  or graft-versus-leukemia (GVL) responses.3  Several groups4,5,6,7,8,9,1011  demonstrated the importance of the initial inflammatory response to conditioning-induced injury. More recently, the role of additional cell populations such as natural killer (NK) cells,12  γδ T cells,13,14  and regulatory T cells15,16,17,1819  have been incorporated into a more complex conceptual framework that explains the pathogenesis and modulation of graft-versus-host responses.

Another major advance in our understanding is the demonstration of the critical role of professional antigen-presenting cells (APCs) in GVHD20,2122  and GVL.23,2425  In this review, we attempt to place these findings in context by exploring how APC functions integrate with those of other accessory or effector cell populations or cytokines that play a role in the graft-versus-host response. We then examine the potential implications for the design of novel strategies to boost GVL responses and reduce GVHD after transplantation.

Antigen-presenting cell populations

Many cell types, including both hematopoietic cells and nonhematopoietic cells (eg, endothelial cells), may participate in the process of antigen presentation with varying levels of efficiency.26,27  Professional APCs are hematopoietic cells that have a specialized role in processing and presenting antigens and do so with an effectiveness that is above the threshold required to promote an adaptive immune response. They include B cells, macrophages, and dendritic cells (DCs), although other hematopoietic cells such as CD34+ progenitor cells28  or γδ T cells29  and nonhematopoietic cells can develop antigen-presenting ability under specific conditions. Professional APCs are highly efficient at loading peptide antigens onto major histocompatibility complex (MHC) molecules and then delivering them to the cell surface as composite structures with costimulatory and leukocyte adhesion molecules that together aid formation of an immunological synapse with the T cell.30  The major APC populations occupy distinct strategic locations and recirculatory patterns. Naïve B cells are absent from the skin and most mucosal sites, but instead recirculate between blood and the secondary lymphoid organs. Here, they pick up antigens through specific B cell receptors for presentation on MHC class II and become competent APC on interaction with CD40L+ CD4+ T cells.31  Macrophages are resident at most sites, but are actively recruited to sites of inflammation, wherein a subset of cells develop a DC-like phenotype.32  Crucially, DCs possess the additional capacity to pick up antigens in peripheral tissues and traffic to secondary lymphoid organs.30  Accordingly, DCs are the most effective at priming naïve T cells, although the extent to which they do so is heavily dependent on their origin and activation history.

Separate endogenous and exogenous pathways exist for loading peptides onto MHC class I or MHC class II, respectively (see Ackerman and Cresswell33  for review). In the endogenous pathway, proteins or peptides within the cytosol are degraded by the proteasome before being transported into the endoplasmic reticulum where peptides are loaded onto MHC class I molecules. In the exogenous pathway, soluble or particulate antigens are taken up by phagocytosis or micropinocytosis and then hydrolyzed by peptidases before loading of the derived peptides onto MHC class II within the endolysosomal system.33  Certain APCs (eg, CD8α DCs in mice) have the additional capacity to divert proteins derived from particulate antigens (eg, phagocytosed necrotic or apoptotic cells) into the endosomal/cytosolic pathway, allowing the derived peptides to be presented in the context of MHC class I. This phenomenon is termed crosspresentation and is thought to be essential for the development of immunity to infectious agents (in which APCs are themselves not infected) or tumors. Antigen-laden DC populations or DC precursors34,3536  may act as “couriers” by trafficking from tissues to draining lymph nodes, delivering antigen to crosspresenting CD8α DCs.37  Recent studies have suggested that crosspresentation is a highly efficient process, although the extent to which priming occurs depends on whether presentation occurs within the context of an inflammatory or noninflammatory environment.38  After transplantation, host alloantigens may thus be presented directly by host APCs or be crosspresented by donor APCs (Figure 1).

Figure 1

Pathways of antigen presentation after allogeneic stem cell transplantation. Host alloantigens can be presented by host APC (direct presentation) or crosspresented by donor APC after uptake of particulate host material (indirect presentation). In direct presentation, donor T cells can potentially recognize allogeneic MHC antigens on host APC (MHC shown in red with or without a requirement for peptide) or may recognize host alloantigens (including allogeneic MHC or minor H antigens) that have been processed and presented by host APC. Alternatively, host allogeneic MHC or minor H antigens may be presented indirectly by donor APC.

Figure 1

Pathways of antigen presentation after allogeneic stem cell transplantation. Host alloantigens can be presented by host APC (direct presentation) or crosspresented by donor APC after uptake of particulate host material (indirect presentation). In direct presentation, donor T cells can potentially recognize allogeneic MHC antigens on host APC (MHC shown in red with or without a requirement for peptide) or may recognize host alloantigens (including allogeneic MHC or minor H antigens) that have been processed and presented by host APC. Alternatively, host allogeneic MHC or minor H antigens may be presented indirectly by donor APC.

The turnover of antigen-presenting cell populations after transplantation

After lethal conditioning and allogeneic hematopoietic stem cell transplantation (HSCT), the APC environment undergoes dramatic distortion. Radio- or chemosensitive APC and precursor populations derived from the host are lost within the first few days after transplantation. The void in host APC numbers is filled by differentiated APCs contained within the donor graft or by differentiation from donor progenitor cells. Numerical recovery of DCs and macrophages is more rapid than that of B cells,39  although the kinetics of full functional reconstitution are not known, especially in the context of posttransplantation immune suppression. The kinetics of the switch to donor APC populations is primarily dependent on the mode of conditioning, the site, and the presence or absence of donor T cells in the graft. After myeloablative conditioning, this process can be very rapid as indicated by data from animal models40,4142  and a number of recent clinical studies.43,44  In contrast and as expected, the extent and/or rate of switching are decreased after reduced intensity conditioning.44,45  However, even after myeloablative conditioning, the macrophage and skin DC (dermal DC and epithelial Langerhans cell [LC]) compartment appear fairly resistant to conversion to full donor chimerism, a fact that may reflect the capacity of these populations to be maintained by resident, radioresistant precursor cells.40,41,43,44,4546  Thus, recipient DCs continue to be present for a considerable time posttransplantation within the skin epithelia, or draining lymph nodes.40,46  The presence of T cells in the donor graft is also critical, because residual host LCs are targeted to some extent by the developing graft-versus-host reaction.40,41  However, host LC can persist even in the presence of donor T cells40  (M. Sykes, W. Caughman, S. Katz, and D.H. Sachs, 1987, unpublished data).

Antigen-presenting cells and acute graft-versus-host disease

After their transfer to freshly irradiated allogeneic recipients, naïve donor T cells are initially retained within secondary lymphoid tissues.47  Within the lymph nodes, spleen, and Peyer patches, donor T cells undergo a rapid burst of proliferation. After an interval of 3 to 4 days, large numbers of lymphoblasts enter the peripheral circulation. Recruitment of effector T cells to peripheral tissues such as the skin and gut47,4849  leads to profound tissue injury that characterizes GVHD.

The initial “trapping” of donor T cells within secondary lymph nodes of recipients was originally described by Jonathan Sprent and colleagues in a series of elegant experiments in which they measured the number of graft-versus-host reactive T cells entering the thoracic duct in the first few days after allogeneic bone marrow transplantation (BMT). As graft-versus-host-reactive T cells are sequestered in the lymph nodes, thoracic duct output cells are initially depleted of cells capable of inducing GVHD on transfer to secondary recipients. Using this model in an MHC mismatched strain combination, they demonstrated that host bone marrow-derived cells (presumably host APCs expressing host class II alloantigen) were important but not absolutely critical in the initial retention of CD4+ T cells within the lymph nodes.50  In contrast, although host bone marrow-derived cells contributed to donor CD8+ T cell trapping, other cells also played a major role.51  Because MHC class I expression is ubiquitous (unlike class II), nonbone marrow-derived cells may contribute more to the initial retention of CD8+ than CD4+ T cells. An alternative explanation is that donor APC crosspresent peptides derived from the host to donor T cells.

The issue of whether such crosspresentation is sufficient to prime acute GVHD has been evaluated in experimental models of CD8+ T cell-dependent GVHD developing across MHC-matched, minor histocompatibility (H) antigen mismatched barriers.21,52  Early experiments demonstrating acute GVHD induction after transfer of strain donor b splenocytes to reirradiated strain b → strain a bone marrow chimeras may reflect the use of insufficient total body irradiation (TBI) doses to remove all host (strain a) APCs,52  because the opposite result was more recently obtained in similar experiments using higher TBI doses.21  In the latter study, marked resistance to GVHD was also evident after transfer of CD8+ T cells (from strain b) to irradiated strain a β2M-/-→ strain a chimeras (in which bone marrow-derived host APCs lacked MHC class I expression), indicating a requirement for the presence of host APCs expressing MHC class I.21  Thus, despite the capacity for crosspresentation by donor APCs in this model, no GVHD was observed in mice lacking class I on host APCs, indicating that crosspriming is not sufficient to initiate acute GVHD. A similar interpretation was suggested in the context of CD8+ or CD4+ T cell-dependent GVHD when donor T cells recognized single MHC class I or II alloantigens.53,54  Thus, resident host APCs that survive host conditioning are required and sufficient to initiate acute GVHD. Indeed, very small numbers of host CD11c+ DCs surviving for the first few days after conditioning are able to prime donor T cell activation and effector differentiation.42 

Donor APCs transferred directly with the graft or developing from hematopoietic progenitor cells do not contribute to the initiation of the response, but they may drive further tissue injury by crosspresentation of host antigens. Thus, in experiments in which donor APCs are selectively prevented from crosspresenting host antigens, GVHD still occurs, but its incidence and severity are sharply diminished.55  Donor APCs that produce and present interleukin (IL)-15 through IL-15 receptor α on their cell surface may also be required for perpetuating tissue injury.56  The distinct roles of host and donor APCs that have emerged in these model systems are likely to reflect the fact that in the very early phase after transplantation, too few donor APCs have differentiated sufficiently to process and present host antigens effectively.

The identity or identities of the professional APCs required for inducing acute GVHD have not been established precisely. Depletion of phagocytic DCs and macrophages from the liver and spleen by exposure to liposomal clodronate leads to a specific reduction in donor T cell infiltration of these organs.57  Selective “add back” of individual APC populations to chimeras in which host APCs have been disabled (by failure to express host MHC alloantigen) suggest that host DCs rather than host B cells are important in the induction of both CD4+ and, to a lesser extent, CD8+ T cell-dependent acute GVHD.53  In fact, recent studies indicate that persistent host B cells negatively regulate acute GVHD induction through an IL-10-dependent mechanism.58  In a similar vein, although donor APCs contribute to the overall severity of GVHD, certain donor DC populations (e.g. CD11c+ CD11b+ CD4-CD8α-DCs)59  or reconstituting myeloid cells60  appear to impede its induction.

The role of antigen-presenting cells within graft-versus-host disease target tissues

The pattern of GVHD organ involvement (liver, skin, and gut) is striking. Three potential factors may contribute to this phenomenon. First, highly dense networks of DCs are organized into specific compartments within these tissues (eg, LC in the skin epithelia) and associated lymphoid structures (eg, Peyer patches of the gut). The functional capacities of these cells might also be relevant, as suggested by the increased potential immunogenicity of certain APC populations such as LC.61  Second, the distribution corresponds to the potential sites of exposure to microbes and microbial products through the skin, gut, and portal circulation. Loss of epithelial integrity after conditioning may increase exposure to pathogen-associated molecular patterns such as lipopolysaccharide62  that are recognized by pattern-recognition receptors expressed on APCs and lead to their activation (see subsequently). Third, priming DCs from these sites (eg, the Peyer patches or skin draining lymph nodes) are particularly adept at “imprinting” the expression of tissue-specific homing receptors on activated T cells that bias recirculation of effector T cells back to the tissue from which the DC were derived. For example, Peyer patch-derived DCs prime T cells to express the gut-homing receptors α4β7 and CCR9 and the subsequent recruitment of these cells to the gut.63  Similarly, DCs derived from skin-derived lymph nodes prime functional E/P-selectin ligand expression by activated T cells and selective trafficking to the skin.64  Imprinting could, for example, explain the development of skin GVHD (but not gut or liver GVHD) when naive donor T cells are transferred to allogeneic chimeras in which the only tissue containing host APCs is the skin 40,41  (Figure 2). To date, however, there is no formal proof that this tissue imprinting by APCs applies to the induction of GVHD. Indeed, Peyer patches are not required for the induction of GVHD in freshly irradiated allogeneic recipients, indicating that under these conditions, priming of T cells that home to the gut can occur elsewhere.65 

Figure 2

Antigen-presenting cells can influence development of GVHD at multiple levels. Initial tissue injury and innate immune activation may trigger APC within tissues and induce certain APC populations such as DCs to migrate to draining lymph nodes. Migrating DCs or other lymph node resident APCs “trap” graft-versus-host-reactive T cells at this site for 3 to 4 days where they induce T cell activation and may “imprint” a homing phenotype that permits selective trafficking of effector cells to GVHD target organs. APCs within inflamed tissues may act to amplify the developing GVH response by providing further priming signals to T cells in situ by producing proinflammatory cytokines or actively recruiting T cells and other cellular effectors to this site.

Figure 2

Antigen-presenting cells can influence development of GVHD at multiple levels. Initial tissue injury and innate immune activation may trigger APC within tissues and induce certain APC populations such as DCs to migrate to draining lymph nodes. Migrating DCs or other lymph node resident APCs “trap” graft-versus-host-reactive T cells at this site for 3 to 4 days where they induce T cell activation and may “imprint” a homing phenotype that permits selective trafficking of effector cells to GVHD target organs. APCs within inflamed tissues may act to amplify the developing GVH response by providing further priming signals to T cells in situ by producing proinflammatory cytokines or actively recruiting T cells and other cellular effectors to this site.

The relative importance of APCs versus host epithelial cells in generating the full manifestations of GVHD is controversial. By transferring donor CD4+ T cells to chimeric mice in which bone marrow-derived APCs expressed MHC class II alloantigen but in which other cells in peripheral tissues lacked MHC II expression, Teshima et al54  reported the surprising finding that expression of host alloantigen by epithelial cells was not required for the induction of GVHD. To a lesser extent, this was also true in CD8+ T cell-dependent GVHD directed against a single MHC class I alloantigen. The authors demonstrated that GVHD was mediated in this model by effector cytokines (tumor necrosis factor-α or IL-1β), and one possibility is that this process is amplified by host-derived bone marrow APCs resident within the target organs. In contrast to these findings, donor T cells could induce tissue damage only when alloantigens were expressed on epithelial cells in MHC-matched, minor H antigen mismatched murine models of CD8+ or CD4+ T cell-dependent acute GVHD.66,67  The discrepancy between these results might be explained by lower graft-versus-host reactive T cell precursor frequencies to mismatched minor H antigens versus MHC alloantigens and hence a reduced capacity to provoke an inflammatory cytokine cascade. In the relative absence of effector cytokines, tissue injury would then depend on direct cell-mediated cytotoxicity against epithelial targets expressing class I or class II MHC.68  The sparing of donor skin grafts but not recipient skin after the induction of GVHD in dogs undergoing minor H antigen-mismatched BMT and delayed transfer of donor T cells69  is consistent with this concept.

APCs within tissues may theoretically act at both the priming (including “imprinting”) and effector phase of the graft-versus-host response (Figure 2). In the former case, antigen-loaded tissue DCs could migrate to draining lymph nodes where they prime donor T cells directly or alternatively deliver antigens to specialized resident APC populations. In the latter scenario, tissue-resident APCs might actively recruit activated T cells to target organs through the secretion of inflammatory chemokines. Evidence in support of this latter hypothesis comes from models in which liposomal clodronate was used to selectively deplete host APCs (macrophages and most CD11c+ DCs) from the liver of BMT recipients before the transfer of primed, graft-versus-host reactive effector T cells.57  In these experiments, effector T cells were unable to access liver tissue if host APCs had been depleted just before transfer.

The effect of the posttransplantation environment

There are two distinct phases after myeloablative transplantation that influence the functional status of APCs. In the first, host conditioning leads to a loss of epithelial integrity, systemic exposure to microbial products, and activation of the innate immune system.62  Activation of the innate immune system as a result of direct tissue injury or exposure to microbial products is an important initiating event in the induction of GVHD. NK cells can, through activating receptors, detect altered self-ligands whose expression is increased on cellular stress.70  Mucosal γδ T cells detect microbial antigens (eg, pyrophosphate monoesters) as well as stress-induced self-molecules such as heat shock proteins.71  TBI-induced tissue injury causes translocation of bacterial products such as lipopolysaccharide across damaged epithelium, leading to macrophage activation and the release of proinflammatory cytokines.6,7,9,10  The importance of this pathway in the development of GVHD is emphasized by experiments in which blockade of lipopolysaccharide action efficiently blocks the induction of tissue injury.5  The release of tumor necrosis factor-α or interferon-γ by activated cells or direct cellular interactions contribute significantly to DC maturation with upregulation of costimulatory molecule expression and the release of cytokines that promote T helper type 1 differentiation.72  DC expression of pattern-recognition receptors such as Toll-like receptors (TLR) makes them exquisitely sensitive to microbial stimuli. It has been proposed that TLR triggering is required in cis with adaptive immune signals (eg, ligation of the CD40 receptor by activated T cells) to induce full “licensing” of DCs that then become capable of priming full Th1 responses.73  To what extent such combinatorial signaling mediated through APC is actually required for the induction of GVHD or GVL is not known. The fact that GVHD is apparently induced in Myd88-/-mice, in which host APCs are defective in their capacity to respond to TLR signals, and also in CD40-/-mice, in which APCs cannot be activated by donor T cells expressing CD40L, suggests considerable redundancy in the requirements for APC activation.74  In this setting, inflammation or other changes (such as lymphopenia) generated as a result of irradiation may be sufficient to bypass the requirement for Myd88 pathway activation or CD4+ T cell help. Whatever the mechanism, it is likely that “licensing” of APCs provides an essential checkpoint that controls the initiation of GVHD. It follows that this process must be sufficient to overcome any regulatory mechanisms that induce peripheral tolerance. In the very early phase posttransplantation, depletion of host regulatory T cells and the generation by DC of proinflammatory cytokines (eg, IL-6) that act directly on effector T cells75  may overcome any potential downmodulatory influences on graft-versus-host reactivity.

In the second phase after myeloablative transplantation, resolution of inflammation leads to a new “steady state” in which the capacity of APCs to provoke immunity against the host may be substantially reduced because there are fewer host APCs, and these are no longer activated. In the absence of APC activation, specific targeting of model antigens to DC leads to the abortive proliferation of specific T cells that lack the capacity to generate effector cytokines.76,77  Thus, in the absence of inflammation, tolerance may be induced by “default.” In contrast, if DCs are activated artificially by coadministration of agonistic CD40 antibody or other proinflammatory stimuli, productive immunity is generated.76,77  Consistent with this model, the magnitude of the immune response (in terms of both GVHD and GVL) after delayed donor leukocyte infusions (DLI) to full allogeneic chimeras diminishes significantly with time. In the first few weeks posttransplantation, transfer of donor T cells may induce GVL with a reduced risk of GVHD. However, after 4 to 5 weeks, nearly all graft-versus-host reactivity is lost.78,79  Although there are a number of potential explanations for this phenomenon, including the loss of host APCs and the influence of regulatory cell populations,79  one factor important in the declining response might also be the lack of APC activation. It is also possible that after recovery of acute GVHD, priming APC not only become depleted, but also become “conditioned” and less able to provoke immunity.80 

These temporal changes in GVH reactivity, observed after myeloablative transplantation, are not necessarily reproduced after transplantation using nonmyeloablative protocols. In the early phase, the relative lack of tissue injury may provoke less triggering of the innate immune system and hence less APC activation. If donor hematopoietic progenitor cells are given without donor T cells, host APCs are present in greater numbers than after conventional transplantation. In this setting, delayed transfer of donor T cells can induce very significant graft-versus-host reactivity with no evidence of a decay in the response according to the time of T cell transfer.81  In preclinical models, the GVH response is restricted to the lymphohematopoietic system and no GVHD is observed despite the presence of considerable numbers of host APCs at the time of donor T cell transfer.4,11,23,24  Graft-versus-host-reactive T cells become activated, expand, and acquire homing receptors for GVHD target organs yet fail to access the skin or gut.4  This failure of T cells to traffic and induce tissue injury can be readily reversed in the presence of proinflammatory stimuli. Indeed, localized GVHD can be induced after exposure of the skin to a topical TLR agonist,4  and one potential explanation is that APC activation within tissues is important in the development of wider tissue injury.

Much of the previously mentioned data are derived from preclinical models that by necessity have been designed to reduce the number of potential variables that might influence the development of an immune response after transplantation. For example, models of experimental transplantation in mice rarely incorporate any form of posttransplant immune suppression. In humans, immunosuppressive agents used to prevent GVHD may therefore blunt the effects of priming by APCs on T cells. On withdrawal of immunosuppression, surviving T cells previously activated by host APCs might then be recruited to a developing graft-versus-host response. In this case, donor APCs crosspresenting host alloantigens might have a role in driving the response, as suggested in one study.55  Drugs such as calcineurin inhibitors, glucococorticoids, and mycophenolate mofetil not only modulate T cell activation, but also influence DC functions.82,8384  For example, calcineurin inhibitors inhibit antigen uptake and processing, key elements of the crosspresentation apparatus.82  Glucocorticoids inhibit DC differentiation and cytokine production on exposure to proinflammatory stimuli.84  Granulocyte colony-stimulating factor has a number of distinct effects on APC populations, including differential mobilization of DC subsets,85  alteration of the capacity of DCs to generate cytokines in response to TLR signaling,86  and inhibition of IL-12 production by DCs.87  The precise extent to which any or all of these factors influence the development of GVL or GVHD is unknown.

Antigen-presenting cells and chronic graft-versus-host disease

After myeloablative transplantation, donor hematopoietic progenitors reconstitute the thymocyte and thymic APC compartments, whereas radioresistant cortical and medullary epithelial cells are derived from the host. In this scenario, positive selection of developing donor thymocytes will occur on host epithelia. In contrast, negative selection of cells with potential antihost reactivity may occur either on host-derived medullary epithelial cells (through, for example, autoimmune regulator (AIRE)-dependent expression of host self-antigens88 ) or on donor-derived APCs crosspresenting host antigens within the thymic medulla.89  Host-derived thymic epithelial cells may induce anergy of host-reactive thymocytes90  or positively select regulatory T cells.91  Collectively, these processes must be efficient if T cells with antihost reactivity are not to induce tissue damage within the periphery. Disruption to the thymic architecture after the development of acute GVHD92  may perturb these tolerance mechanisms and lead to the release of alloreactive T cells. Furthermore, the emergent T cell repertoire may also contain increased numbers of cells that are truly autoreactive and thus have the potential to be primed by donor APCs in peripheral tissues.93,94  These findings may help to explain the continuing tissue injury that occurs in chronic GVHD despite the majority of APCs, including DCs, being of donor origin.95  Formal testing of the role of APC populations in the development of chronic GVHD has proven somewhat difficult, because no single model completely represents the delayed onset and complex phenotype observed in human patients. Thus, although both host and donor APCs,96  including B cells,97,98  have been demonstrated to play a role in priming donor CD4+ T cells, the exact clinical relevance of these models is uncertain.

Antigen-presenting cells and graft-versus-leukemia

In experiments using in vivo tumor protection assays in which donor T cells are transferred after a delay to established allogeneic chimeras, host APCs are required to prime maximal GVL activity.23,24  Maximal GVL responses against a host-derived tumor expressing class I but not class II MHC requires expression of not only class I, but also class II MHC by host APCs.23,24  In this model, maximal expansion of graft-versus-host-reactive CD8+ T cells and GVL activity depends on the presence of both CD4+ T cells in the DLI and on host APCs23  consistent with a model in which donor CD4+ T cells “license” host APCs for priming of donor graft-versus-host-reactive T cells. Of note, host APCs do not appear to influence donor T cell effector differentiation as evaluated by cytokine synthesis. Thus, host APCs appear to maximize expansion (through effects on proliferation and/or survival) rather than influence effector functions on a per cell basis. Significantly, in freshly conditioned recipients, CD4+ T cells are not required to provide help for the CD8+ T cell-dependent GVL response.23  This suggests that the ability of conditioning-induced inflammation to activate APCs bypasses the requirement for CD4 help to maximize CD8 effector expansion.

In these and similar assays involving delayed T cell transfer and a highly aggressive tumor, GVL activity is dependent on MHC alloreactivity and little or no GVL activity against minor H antigens or tumor-associated antigens (TAA) is detected.23,99  The requirement for shared alloantigen expression by host APCs and tumor cells has been confirmed in other models, although in cases that involve T cell transfer to freshly irradiated mice, reactivity against minor H antigens is sufficient to induce GVL.25,79  For the most part, crosspresentation of TAA does not lead to any detectable GVL effects.25  However, crosspresentation of alloantigens and/or TAA by donor APCs was sufficient to induce measurable GVL activity under conditions of low tumor bulk.25  It is noteworthy that none of these studies (which involve tumor inoculation after irradiation) have tested the potential of chemotherapy/ radiotherapy during conditioning to enhance crosspresentation. In studies of established tumors, induction of apoptosis by chemotherapy is sufficient to boost crosspresentation of TAA and this area merits further investigation.100 

The role of tumor cells in priming GVL activity is not known. It has been hypothesized that the sensitivity of chronic myeloid leukemia (CML) or low-grade lymphoma to GVL relates to the potential of the neoplastic cells to develop APC functions.101  This concept is attractive, because such cells could then present TAA such as proteinase 3,102  p210 (in CML),103  or idiotype (in lymphoma)104  directly to the immune system. For example, CML stem cells can differentiate into dendritic cells105  and on ligation of CD40, B cells derived from patients with follicular lymphoma develop APC functions.106  It is important to emphasize, however, that GVL responsiveness is not necessarily synonymous with direct priming by tumor cells and such responses might instead reflect increased sensitivity of these cells to the effector phase of the immune response. In fact, to date, there is no evidence from preclinical models that tumor cells can directly prime GVL directed at minor H antigens or TAA even if such cells express costimulatory molecules.25 

For patients with tumors that are sensitive to GVL activity, long-term disease-free survival requires that GVH-reactive T cells eradicate all tumor cells during the initial primary response or that any residual cancerous cells are held in check by memory effectors that can mount a recall response. In many patients, antitumor responses are poorly sustained.101,107  In a model of GVL induced by delayed transfer of donor T cells (mixed with GVH-reactive T-cell receptor (TCR) transgenic CD8+ T cells) to mixed chimeras, graft-versus-host-reactive cytotoxic T lymphocytes (CTL) were shown to undergo initial expansion, followed by deletion, in association with gradual extinction of host-reactive CTL responsiveness. No recall immunity is established and mice are susceptible to tumors on subsequent rechallenge.81  The reasons for this are not clear, but it is known that the initial graft-versus-host response eradicates host APCs, leaving only donor APCs that are less efficient at eliciting GVL. Although “add back” of host DCs at the time of donor T cell transfer to full chimeras can help to prime effective GVL activity,79  it remains to be seen whether a similar strategy can rescue a secondary response. Alternatively, strategies aimed at maximizing the proliferation and/or survival of graft-versus-host-reactive memory stem cells (eg, administration of IL-15)108  in full chimeras might also permit enhancement of GVL activity even in the absence of host APCs.

Novel therapies targeting antigen-presenting cells

The concept of manipulating antigen presentation for therapeutic benefit peritransplantation or posttransplantation is an attractive one. In very general terms, changes in antigen presentation might be achieved by altering APC functions or numbers (Table 1)Preclinical data suggest that depletion of host APCs or interference with their functions would be inappropriate in settings where one is depending on GVL activity to clear residual tumor.23,2425  In contrast, where GVL is not required, such as after transplantation for nonmalignant disorders, reductions in host APC number or function might be an acceptable means of preventing GVHD. One potential advantage of this approach is that avoidance of T cell depletion would permit initial reconstitution by memory T cells and a reduced risk of infection. A potential disadvantage is that a reduction in host APCs might also limit the potential expansion of alloantigen-specific Foxp3+CD4+CD25+ T cells,109  thus negating any potential reduction in the priming of graft-versus-host-reactive effector T cells. An alternative strategy could include administration of FTY720, a novel agent that prevents GVHD induction but allows potent GVL activity.110  Potential mechanisms might include inhibition of activated DC migration to111  and/or reduced egress of effector T cells from secondary lymphoid organs.112 

Table 1

Potential strategies to alter APC numbers or function

Reagent Comment 
CAMPATH-1H Depletes blood DCs118,119  
 Tissue penetration may be limited and LC (which have low CD52 expression) are not depleted significantly118,120  
CMRF-44 IgM antibody, which binds to a determinant on activated DCs and is expressed on both peripheral blood DC and migrating LC 
 Induces depletion by complement-mediated cytotoxicity in vitro121  
UV Ultraviolet (A-B) light leads to host-derived LC migration from the skin and replacement by donor-derived LC progenitors122  
 Short wavelength ultraviolet irradiation effectively depletes host LC and prevents the induction of GVHD,41  although ultraviolet induces other immunomodulatory effects; translation to human setting has proven problematic123  
Alloreactive NK Preconditioning of recipient mice with alloreactive donor NK cells lacking inhibitory receptors for host class I MHC induces resistance to the development of GVHD; alloreactive NK cells deplete host CD11c+ DCs20  
 Clinical applications could include choosing unrelated donors who are mismatched for inhibitory ligands or NK cells from third party donors to deplete host DCs before transplantation 
Costimulatory blockade Inhibit host APC-T cell interactions (see Blazar and Taylor124  for extensive review) 
Regulatory DC Adoptive transfer of IL-10/TGFβ conditioned host DCs highly effective at preventing GVHD125  
FT720 Sphingosine-1-phosphate (S-1-P) analog that inhibits GVHD but preserves GVL110 ; DCs express receptors for S-1-P and are therefore potential targets for this drug; administration of FTY720 inhibits DC migration and is associated with a sharp reduction in their capacity to access secondary lymphoid organs111  
Reagent Comment 
CAMPATH-1H Depletes blood DCs118,119  
 Tissue penetration may be limited and LC (which have low CD52 expression) are not depleted significantly118,120  
CMRF-44 IgM antibody, which binds to a determinant on activated DCs and is expressed on both peripheral blood DC and migrating LC 
 Induces depletion by complement-mediated cytotoxicity in vitro121  
UV Ultraviolet (A-B) light leads to host-derived LC migration from the skin and replacement by donor-derived LC progenitors122  
 Short wavelength ultraviolet irradiation effectively depletes host LC and prevents the induction of GVHD,41  although ultraviolet induces other immunomodulatory effects; translation to human setting has proven problematic123  
Alloreactive NK Preconditioning of recipient mice with alloreactive donor NK cells lacking inhibitory receptors for host class I MHC induces resistance to the development of GVHD; alloreactive NK cells deplete host CD11c+ DCs20  
 Clinical applications could include choosing unrelated donors who are mismatched for inhibitory ligands or NK cells from third party donors to deplete host DCs before transplantation 
Costimulatory blockade Inhibit host APC-T cell interactions (see Blazar and Taylor124  for extensive review) 
Regulatory DC Adoptive transfer of IL-10/TGFβ conditioned host DCs highly effective at preventing GVHD125  
FT720 Sphingosine-1-phosphate (S-1-P) analog that inhibits GVHD but preserves GVL110 ; DCs express receptors for S-1-P and are therefore potential targets for this drug; administration of FTY720 inhibits DC migration and is associated with a sharp reduction in their capacity to access secondary lymphoid organs111  

Several clinical studies have explored the potential for augmentation of GVL after delayed DLI to mixed chimeras. Although this approach has clearly afforded the induction of major antitumor responses,113,114115  no clear relationship is apparent between the degree of myeloid chimerism (in peripheral blood) and disease responses.115  The lack of such a correlation could result from a variety of factors, but may reflect the capacity of crosspresentation of tumor-associated and minor H antigens by donor APC to prime similar antitumor responses as those induced through direct presentation. In contrast, the mouse studies showing the ability of host APC to optimize antitumor effects involved extensive MHC disparities between the donor and host,23,24  and these disparities were critical for achievement of antitumor responses.23,24  In the highly aggressive tumors studied in the mouse model, antiminor H antigen or antiTAA responses were insufficient to induce measurable GVL effects through either direct or crosspresentation to DLI T cells.23  Because GVL is not readily elicited in murine MHC-matched BMT models,23,78,99  the role of host APCs in inducing antitumor responses from DLI has proven difficult to determine. These studies highlight the potential to achieve stronger GVL effects in humans if HLA barriers could be transgressed without severe GVHD.

Even in the absence of HLA disparity, it might be feasible to augment GVL activity at the time of DLI by increasing the number of available APCs (including leukemia-derived DCs) that can present host antigens by using cytokines such as Flt3 ligand116  or GM-CSF.101  This approach could be combined with reagents that induce APC activation such as TLR agonists4,40  or by the blockade of coinhibitory pathways such as PD-1-PD-L1.117  In a similar vein, “add back” of host DCs might boost GVL responses in full allogeneic chimeras.79  It seems likely that such strategies will also increase the risk of GVHD, although this might be acceptable in individuals with few other therapeutic options.

Acknowledgments

We thank Dr. Clare Bennett for helpful review of the manuscript and Ms. Kelly Walsh for expert assistance with the manuscript.

This work was supported by NIH grants RO1 RO1 CA79989, POI CA111519, by a Senior Research Award from the Multiple Myeloma Foundation and by a Senior Bennett Fellowship from the Leukemia Research Fund, United Kingdom.

National Institutes of Health

Authorship

Contribution: R.C. and M.S. cowrote the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Megan Sykes, Transplantation Biology Research Center, Bone Marrow Transplantation Section, Massachusetts General Hospital, Harvard Medical School, Massachusetts General Hospital (MGH)-East Bldg. 149-5102, 13th Street, Boston, MA 02129; e-mail: Megan.Sykes@tbrc.mgh.harvard.edu.

References

References
1
Billingham
RE
The biology of graft-versus-host reactions.
Harvey Lect
1966
62
21
78
2
Korngold
B
Sprent
J
Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow.
J Exp Med
1978
148
1687
1698
3
Bortin
MM
Truitt
RL
Rimm
AA
Bach
FH
Graft-versus-leukaemia reactivity induced by alloimmunisation without augmentation of graft-versus-host reactivity.
Nature
1979
281
490
491
4
Chakraverty
R
Cote
D
Buchli
J
et al. 
An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.
J Exp Med
2006
203
2021
2031
5
Cooke
KR
Gerbitz
A
Crawford
JM
et al. 
LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation.
J Clin Invest
2001
107
1581
1589
6
Guy-Grand
D
Vassalli
P
Gut injury in mouse graft-versus-host reaction. Study of its occurrence and mechanisms.
J Clin Invest
1986
77
1584
1595
7
Hill
GR
Crawford
JM
Cooke
KR
Brinson
YS
Pan
L
Ferrara
JL
Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines.
Blood
1997
90
3204
3213
8
McCarthy
PL
Jr
Abhyankar
S
Neben
S
et al. 
Inhibition of interleukin-1 by an interleukin-1 receptor antagonist prevents graft-versus-host disease.
Blood
1991
78
1915
1918
9
Nestel
FP
Price
KS
Seemayer
TA
Lapp
WS
Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease.
J Exp Med
1992
175
405
413
10
Piguet
PF
Grau
GE
Allet
B
Vassalli
P
Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs-host disease.
J Exp Med
1987
166
1280
1289
11
Sykes
M
Sheard
MA
Sachs
DH
Effects of T cell depletion in radiation bone marrow chimeras. II. Requirement for allogeneic T cells in the reconstituting bone marrow inoculum for subsequent resistance to breaking of tolerance.
J Exp Med
1988
168
661
673
12
Parham
P
McQueen
KL
Alloreactive killer cells: hindrance and help for haematopoietic transplants.
Nat Rev Immunol
2003
3
108
122
13
Maeda
Y
Reddy
P
Lowler
KP
Liu
C
Bishop
DK
Ferrara
JL
Critical role of host gammadelta T cells in experimental acute graft-versus-host disease.
Blood
2005
106
749
755
14
Sakai
T
Ohara-Inagaki
K
Tsuzuki
T
Yoshikai
Y
Host intestinal intraepithelial gamma delta T lymphocytes present during acute graft-versus-host disease in mice may contribute to the development of enteropathy.
Eur J Immunol
1995
25
87
91
15
Cohen
JL
Trenado
A
Vasey
D
Klatzmann
D
Salomon
BL
CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease.
J Exp Med
2002
196
401
406
16
Hoffmann
P
Ermann
J
Edinger
M
Fathman
CG
Strober
S
Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation.
J Exp Med
2002
196
389
399
17
Johnson
BD
Becker
EE
LaBelle
JL
Truitt
RL
Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy.
J Immunol
1999
163
6479
6487
18
Johnson
BD
Konkol
MC
Truitt
RL
CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT.
Biol Blood Marrow Transplant
2002
8
525
535
19
Taylor
PA
Noelle
RJ
Blazar
BR
CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade.
J Exp Med
2001
193
1311
1318
20
Ruggeri
L
Capanni
M
Urbani
E
et al. 
Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.
Science
2002
295
2097
2100
21
Shlomchik
WD
Couzens
MS
Tang
CB
et al. 
Prevention of graft versus host disease by inactivation of host antigen-presenting cells.
Science
1999
285
412
415
22
Teshima
T
Reddy
P
Lowler
KP
et al. 
Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8 alpha(+) dendritic cells and reduces experimental acute graft-versus-host disease.
Blood
2002
99
1825
1832
23
Chakraverty
R
Eom
HS
Sachs
J
et al. 
Host MHC Class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions.
Blood
2006
108
2106
2113
24
Mapara
MY
Kim
YM
Wang
SP
Bronson
R
Sachs
DH
Sykes
M
Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells.
Blood
2002
100
1903
1909
25
Reddy
P
Maeda
Y
Liu
C
Krijanovski
OI
Korngold
R
Ferrara
JL
A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses.
Nat Med
2005
11
1244
1249
26
Marelli-Berg
FM
Lechler
RI
Antigen presentation by parenchymal cells: a route to peripheral tolerance?
Immunol Rev
1999
172
297
314
27
Unanue
ER
Perspective on antigen processing and presentation.
Immunol Rev
2002
185
86
102
28
Rondelli
D
Andrews
RG
Hansen
JA
Ryncarz
R
Faerber
MA
Anasetti
C
Alloantigen presenting function of normal human CD34+ hematopoietic cells.
Blood
1996
88
2619
2675
29
Brandes
M
Willimann
K
Moser
B
Professional antigen-presentation function by human gammadelta T cells.
Science
2005
309
264
268
30
Banchereau
J
Briere
F
Caux
C
et al. 
Immunobiology of dendritic cells.
Annu Rev Immunol
2000
18
767
811
31
Rodriguez-Pinto
D
B cells as antigen presenting cells.
Cell Immunol
2005
238
67
75
32
Geissmann
F
Jung
S
Littman
DR
Blood monocytes consist of two principal subsets with distinct migratory properties.
Immunity
2003
19
71
82
33
Ackerman
AL
Cresswell
P
Cellular mechanisms governing cross-presentation of exogenous antigens.
Nat Immunol
2004
5
678
684
34
Allan
RS
Waithman
J
Bedoui
S
et al. 
Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.
Immunity
2006
25
153
162
35
Inaba
K
Turley
S
Yamaide
F
et al. 
Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells.
J Exp Med
1998
188
2163
2173
36
Tacke
F
Ginhoux
F
Jakubzick
C
van Rooijen
N
Merad
M
Randolph
GJ
Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery.
J Exp Med
2006
203
583
597
37
den Haan
JM
Lehar
SM
Bevan
MJ
CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo.
J Exp Med
2000
192
1685
1696
38
Heath
WR
Carbone
FR
Cross-presentation, dendritic cells, tolerance and immunity.
Annu Rev Immunol
2001
19
47
64
39
Lenarsky
C
Immune recovery after bone marrow transplantation.
Curr Opin Hematol
1995
2
409
412
40
Durakovic
N
Bezak
KB
Skarica
M
et al. 
Host-derived Langerhans cells persist after MHC-matched allografting independent of donor T cells and critically influence the alloresponses mediated by donor lymphocyte infusions.
J Immunol
2006
177
4414
4425
41
Merad
M
Hoffmann
P
Ranheim
E
et al. 
Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease.
Nat Med
2004
10
510
517
42
Zhang
Y
Louboutin
JP
Zhu
J
Rivera
AJ
Emerson
SG
Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease.
J Clin Invest
2002
109
1335
1344
43
Auffermann-Gretzinger
S
Eger
L
Bornhauser
M
et al. 
Fast appearance of donor dendritic cells in human skin: dynamics of skin and blood dendritic cells after allogeneic hematopoietic cell transplantation.
Transplantation
2006
81
866
873
44
Auffermann-Gretzinger
S
Lossos
IS
Vayntrub
TA
et al. 
Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients.
Blood
2002
99
1442
1448
45
Collin
MP
Hart
DN
Jackson
GH
et al. 
The fate of human Langerhans cells in hematopoietic stem cell transplantation.
J Exp Med
2006
203
27
33
46
Bogunovic
M
Ginhoux
F
Wagers
A
et al. 
Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men.
J Exp Med
2006
203
2627
2638
47
Sprent
J
Schaefer
M
Lo
D
Korngold
R
Functions of purified L3T4+ and Lyt-2+ cells in vitro and in vivo.
Immunol Rev
1986
91
195
218
48
Beilhack
A
Schulz
S
Baker
J
et al. 
In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T cell subsets.
Blood
2005
106
1113
1122
49
Panoskaltsis-Mortari
A
Price
A
Hermanson
JR
et al. 
In vivo imaging of graft-versus-host-disease in mice.
Blood
2004
103
3590
3598
50
Gao
EK
Kosaka
H
Surh
CD
Sprent
J
T cell contact with Ia antigens on nonhematopoietic cells in vivo can lead to immunity rather than tolerance.
J Exp Med
1991
174
435
446
51
Kosaka
H
Sprent
J
Tolerance of CD8+ T cells developing in parent—F1 chimeras prepared with supralethal irradiation: step-wise induction of tolerance in the intrathymic and extrathymic environments.
J Exp Med
1993
177
367
378
52
Sprent
J
Korngold
R
H-2-restriction of T cells mediating lethal graft-versus-host-disease to minor histocompatibility determinants.
Adv Exp Med Biol
1982
149
531
536
53
Duffner
UA
Maeda
Y
Cooke
KR
et al. 
Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease.
J Immunol
2004
172
7393
7398
54
Teshima
T
Ordemann
R
Reddy
P
et al. 
Acute graft-versus-host disease does not require alloantigen expression on host epithelium.
Nat Med
2002
8
575
581
55
Matte
CC
Liu
J
Cormier
J
et al. 
Donor APCs are required for maximal GVHD but not for GVL.
Nat Med
2004
10
987
992
56
Blaser
BW
Schwind
NR
Karol
S
et al. 
Trans-presentation of donor-derived interleukin 15 is necessary for the rapid onset of acute graft-versus-host disease but not for graft-versus-tumor activity.
Blood
2006
108
2463
2469
57
Zhang
Y
Shlomchik
WD
Joe
G
et al. 
APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease.
J Immunol
2002
169
7111
7118
58
Rowe
V
Banovic
T
MacDonald
KP
et al. 
Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation.
Blood
2006
108
2485
2492
59
Li
JM
Waller
EK
Donor antigen-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation.
Biol Blood Marrow Transplant
2004
10
540
551
60
Billiau
AD
Fevery
S
Rutgeerts
O
Landuyt
W
Waer
M
Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions.
Blood
2003
102
740
748
61
Mayerova
D
Parke
EA
Bursch
LS
Odumade
OA
Hogquist
KA
Langerhans cells activate naive self-antigen-specific CD8 T cells in the steady state.
Immunity
2004
21
391
400
62
Ferrara
JL
Cooke
KR
Teshima
T
The pathophysiology of acute graft-versus-host disease.
Int J Hematol
2003
78
181
187
63
Mora
JR
Bono
MR
Manjunath
N
et al. 
Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells.
Nature
2003
424
88
93
64
Mora
JR
Cheng
G
Picarella
D
Briskin
M
Buchanan
N
von Andrian
UH
Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues.
J Exp Med
2005
201
303
316
65
Welniak
LA
Kuprash
DV
Tumanov
AV
et al. 
Peyer patches are not required for acute graft-versus-host disease after myeloablative conditioning and murine allogeneic bone marrow transplantation.
Blood
2006
107
410
412
66
Jones
SC
Murphy
GF
Friedman
TM
Korngold
R
Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell-mediated graft-versus-host disease model.
J Clin Invest
2003
112
1880
1886
67
Korngold
R
Sprent
J
Features of T cells causing H-2-restricted lethal graft-vs-host disease across minor histocompatibility barriers.
J Exp Med
1982
155
872
883
68
Parfrey
NA
Ste-Croix
H
Prud'Homme
GJ
Evidence that nonlymphoid tissue injury in acute graft-versus-host disease is limited to epithelial cells aberrantly expressing MHC antigens.
Transplantation
1989
48
655
660
69
Weiden
PL
Storb
R
Tsoi
MS
Graham
TC
Lerner
KG
Thomas
ED
Infusion of donor lymphocytes into stable canine radiation chimeras: implications for mechanism of transplantation tolerance.
J Immunol
1976
116
1212
1219
70
Lanier
LL
NK cell recognition.
Annu Rev Immunol
2005
23
225
274
71
Hayday
AC
γδ cells: a right time and a right place for a conserved third way of protection.
Annu Rev Immunol
2000
18
975
1026
72
Munz
C
Steinman
RM
Fujii
S
Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity.
J Exp Med
2005
202
203
207
73
Sporri
R
Reis e Sousa
C
Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function.
Nat Immunol
2005
6
163
170
74
Shlomchik
WD
Antigen presentation in graft-vs-host disease.
Exp Hematol
2003
31
1187
1197
75
Pasare
C
Medzhitov
R
Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.
Science
2003
299
1033
1036
76
Hawiger
D
Inaba
K
Dorsett
Y
et al. 
Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.
J Exp Med
2001
194
769
779
77
Probst
HC
Lagnel
J
Kollias
G
van den Broek
M
Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance.
Immunity
2003
18
713
720
78
Billiau
AD
Fevery
S
Rutgeerts
O
Landuyt
W
Waer
M
Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants.
Blood
2002
100
1894
1902
79
Xia
G
Truitt
RL
Johnson
BD
Graft-versus-leukemia and graft-versus-host reactions after donor lymphocyte infusion are initiated by host-type antigen-presenting cells and regulated by regulatory T cells in early and long-term chimeras.
Biol Blood Marrow Transplant
2006
12
397
407
80
Mayerova
D
Wang
L
Bursch
LS
Hogquist
KA
Conditioning of Langerhans cells induced by a primary CD8 T cell response to self-antigen in vivo.
J Immunol
2006
176
4658
4665
81
Mapara
MY
Kim
YM
Marx
J
Sykes
M
Donor lymphocyte infusion-mediated graft-versus-leukemia effects in mixed chimeras established with a nonmyeloablative conditioning regimen: extinction of graft-versus-leukemia effects after conversion to full donor chimerism.
Transplantation
2003
76
297
305
82
Lee
YR
Yang
IH
Lee
YH
et al. 
Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells.
Blood
2005
105
3951
3955
83
Mehling
A
Grabbe
S
Voskort
M
Schwarz
T
Luger
TA
Beissert
S
Mycophenolate mofetil impairs the maturation and function of murine dendritic cells.
J Immunol
2000
165
2374
2381
84
Piemonti
L
Monti
P
Allavena
P
et al. 
Glucocorticoids affect human dendritic cell differentiation and maturation.
J Immunol
1999
162
6473
6481
85
Arpinati
M
Green
CL
Heimfeld
S
Heuser
JE
Anasetti
C
Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells.
Blood
2000
95
2484
2490
86
Reddy
V
Hill
GR
Pan
L
et al. 
G-CSF modulates cytokine profile of dendritic cells and decreases acute graft-versus-host disease through effects on the donor rather than the recipient.
Transplantation
2000
69
691
693
87
Morris
ES
MacDonald
KP
Hill
GR
Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?
Blood
2006
107
3430
3435
88
Anderson
MS
Venanzi
ES
Klein
L
et al. 
Projection of an immunological self shadow within the thymus by the AIRE protein.
Science
2002
298
1395
1401
89
Merkenschlager
M
Power
MO
Pircher
H
Fisher
AG
Intrathymic deletion of MHC class I-restricted cytotoxic T cell precursors by constitutive cross-presentation of exogenous antigen.
Eur J Immunol
1999
29
1477
1486
90
Ramsdell
F
Fowlkes
BJ
Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance.
Science
1990
248
1342
1348
91
Ribot
J
Romagnoli
P
van Meerwijk
JP
Agonist ligands expressed by thymic epithelium enhance positive selection of regulatory T lymphocytes from precursors with a normally diverse TCR repertoire.
J Immunol
2006
177
1101
1107
92
Krenger
W
Rossi
S
Piali
L
Hollander
GA
Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells.
Blood
2000
96
347
354
93
Sakoda
Y
Hashimoto
D
Asakura
S
et al. 
Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease.
Blood
2007
109
1756
1764
94
Tivol
E
Komorowski
R
Drobyski
WR
Emergent autoimmunity in graft-versus-host disease.
Blood
2005
105
4885
4891
95
Clark
FJ
Freeman
L
Dzionek
A
et al. 
Origin and subset distribution of peripheral blood dendritic cells in patients with chronic graft-versus-host disease.
Transplantation
2003
75
221
225
96
Anderson
BE
McNiff
JM
Jain
D
Blazar
BR
Shlomchik
WD
Shlomchik
MJ
Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ.
Blood
2005
105
2227
2234
97
Morris
SC
Cheek
RL
Cohen
PL
Eisenberg
RA
Autoantibodies in chronic graft versus host result from cognate T-B interactions.
J Exp Med
1990
171
503
517
98
Zhang
C
Todorov
I
Zhang
Z
et al. 
Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations.
Blood
2006
107
2993
3001
99
Durakovic
N
Radojcic
V
Skarica
M
et al. 
Factors governing the activation of adoptively transferred donor T-cells infused after allogeneic bone marrow transplantation in the mouse.
Blood
2007
; in press.
100
Lake
RA
Robinson
BW
Immunotherapy and chemotherapy—a practical partnership.
Nat Rev Cancer
2005
5
397
405
101
Kolb
HJ
Schmid
C
Barrett
AJ
Schendel
DJ
Graft-versus-leukemia reactions in allogeneic chimeras.
Blood
2004
103
767
776
102
Molldrem
JJ
Lee
PP
Wang
C
et al. 
Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia.
Nat Med
2000
6
1018
1023
103
Bocchia
M
Korontsvit
T
Xu
Q
et al. 
Specific human cellular immunity to bcr-abl oncogene-derived peptides.
Blood
1996
87
3587
3592
104
Kwak
LW
Campbell
MJ
Czerwinski
DK
Hart
S
Miller
RA
Levy
R
Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors.
N Engl J Med
1992
327
1209
1215
105
Terme
M
Borg
C
Guilhot
F
et al. 
BCR/ABL promotes dendritic cell-mediated natural killer cell activation.
Cancer Res
2005
65
6409
6417
106
Vyth-Dreese
FA
Dellemijn
TA
van Oostveen
JW
Feltkamp
CA
Hekman
A
Functional expression of adhesion receptors and costimulatory molecules by fresh and immortalized B-cell non-Hodgkin's lymphoma cells.
Blood
1995
85
2802
2812
107
Peggs
K
Mackinnon
S
Graft-versus-myeloma: are durable responses a clinical reality following donor lymphocyte infusion?
Leukemia
2004
18
1541
1542
; author reply 1542–1543.
108
Zhang
Y
Joe
G
Hexner
E
Zhu
J
Emerson
SG
Host-reactive CD8(+) memory stem cells in graft-versus-host disease.
Nat Med
2005
11
1299
1305
109
Yamazaki
S
Patel
M
Harper
A
et al. 
Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction.
Proc Natl Acad Sci USA
2006
103
2758
2763
110
Kim
YM
Sachs
T
Asavaroengchai
W
Bronson
R
Sykes
M
Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720.
J Clin Invest
2003
111
659
669
111
Lan
YY
De Creus
A
Colvin
BL
et al. 
The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo.
Am J Transplant
2005
5
2649
2659
112
Cyster
JG
Lymphoid organ development and cell migration.
Immunol Rev
2003
195
5
14
113
Bethge
WA
Hegenbart
U
Stuart
MJ
et al. 
Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning.
Blood
2004
103
790
795
114
Dey
BR
McAfee
S
Sackstein
R
et al. 
Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation.
Biol Blood Marrow Transplant
2001
7
604
612
115
Peggs
KS
Thomson
K
Hart
DP
et al. 
Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses.
Blood
2004
103
1548
1556
116
Cui
Y
Kelleher
E
Straley
E
et al. 
Immunotherapy of established tumors using bone marrow transplantation with antigen gene—modified hematopoietic stem cells.
Nat Med
2003
9
952
958
117
Barber
DL
Wherry
EJ
Masopust
D
et al. 
Restoring function in exhausted CD8 T cells during chronic viral infection.
Nature
2006
439
682
687
118
Buggins
AG
Mufti
GJ
Salisbury
J
et al. 
Peripheral blood but not tissue dendritic cells express CD52 and are depleted by treatment with alemtuzumab.
Blood
2002
100
1715
1720
119
Klangsinsirikul
P
Carter
GI
Byrne
JL
Hale
G
Russell
NH
Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution.
Blood
2002
99
2586
2591
120
Ratzinger
G
Reagan
JL
Heller
G
Busam
KJ
Young
JW
Differential CD52 expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic graft-host interactions in transplantation.
Blood
2003
101
1422
1429
121
Collin
MP
Munster
D
Clark
G
Wang
XN
Dickinson
AM
Hart
DN
In vitro depletion of tissue-derived dendritic cells by CMRF-44 antibody and alemtuzumab: implications for the control of graft-versus-host disease.
Transplantation
2005
79
722
725
122
Merad
M
Manz
MG
Karsunky
H
et al. 
Langerhans cells renew in the skin throughout life under steady-state conditions.
Nat Immunol
2002
3
1135
1141
123
Yuksel
M
Baron
E
Camouse
M
et al. 
Peritransplant use of ultraviolet-B irradiation (UV-B) therapy is detrimental to allogeneic stem cell transplantation outcome.
Biol Blood Marrow Transplant
2006
12
665
671
124
Blazar
BR
Taylor
PA
Ferrara
JL
Cooke
KR
Deeg
HJ
The role of T-cell costimulation and regulatory cells in allogeneic hematopoietic cell transplantation.
Graft-versus-Host Disease, 3rd ed
2005
New York
Marcel Dekker
83
124
125
Sato
K
Yamashita
N
Yamashita
N
Baba
M
Matsuyama
T
Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse.
Immunity
2003
18
367
379