FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2000749507> ?p ?o ?g. }

• W2000749507 endingPage "473" @default.
• W2000749507 startingPage "459" @default.
• W2000749507 abstract "DCs are antigen-presenting cells that regulate several components of the immune system. The mature or terminal stage of DC development induces specific T-cell immunity and resistance to experimental tumors in vivo. However, DC maturation is induced by inflammatory and microbial stimuli, so it is unlikely that mature DCs normally present antigens from tumor cells in cancer patients. Accordingly, clinical studies have begun in which DCs are generated ex vivo, charged with tumor antigens, exposed to maturation stimuli and reinfused to immunize patients. This approach has the potential to control responses to cancer antigens in a specific and nontoxic manner, in both vaccination and therapeutic settings. DCs can mobilize several immune resistance mechanisms. These include CD8+ CTLs, CD4+ helper T cells, NK and NKT cells. Each of these lymphocytes recognizes targets through a distinct mechanism and has the capacity to kill tumor cells and release valuable protective cytokines like IFN-γ. CD4+ T cells also provide essential help for the expansion and maintenance of CD8+ cytolytic cells, while NK and NKT cells can eliminate targets that dampen presentation on MHC class I to escape CTL recognition. The stimulation and concerted action of these classes of lymphocytes can now be studied directly in patients, using ex vivo–derived DCs. Several findings have emerged from studies of healthy volunteers who have been immunized with DCs charged with model antigens, KLH protein and influenza virus matrix peptide. Mature DCs elicit a polarized Th1 type of CD4 T-cell response, only a single injection being required. Vaccination with antigen-bearing DCs also markedly improves the functional affinity of CD8+ T cells. These findings are important in the context of immunotherapy because Th1 cells are more efficient helper cells in experimental models of viral infection and tumors, while high-affinity CTLs should improve recognition of tumor-derived peptides. An important caution also has surfaced when DCs are not adequately differentiated. Immature DCs can silence adaptive T-cell responses, e.g., by inducing IL-10–producing, T-reg cells. DC-based active immunization does not result in major short-term toxicity in healthy subjects or cancer patients. Tumor-specific T-cell responses have been induced and detected in fresh blood specimens without the need for restimulation in vitro. However, the immune responses observed in the first protocols are still smaller than those seen naturally in acute viral infections. Occasional clinical regressions have been noted in these initial feasibility studies, particularly in melanomas, pediatric tumors, lymphomas, prostate cancers and renal cell cancers. This information, coupled with progress in DC biology, suggests many ways to improve the efficacy of this new therapy. Some relevant topics include antigen loading and DC maturation procedures, frequency and route of DC injection, efficiency of DC homing to lymphoid tissues and their longevity once there and the role of distinct DC subsets. A valuable positive control in active immunization protocols is to include an aliquot of DCs pulsed with a viral peptide to verify that the DCs and the patient's immune system are measurably competent. Most of the first vaccination protocols have used DCs charged with synthetic, HLA-binding tumor peptides. Many methods are in place to allow DCs to process a broader array of peptides appropriate for the patient's MHC haplotype. These include transfection (RNA, DNA and viral vectors), select pathways of adsorptive endocytosis, exosomes and tumor cell fusion. An intriguing new approach involves the processing of whole tumor cells. Immature DCs are able to internalize tumor cells, including melanoma, EBV lymphoma and prostate carcinoma cell lines. Following maturation, the processing of tumor cells leads to presentation of multiple epitopes on both MHC class I and II products of DCs. Basic issues in human cancer immunology can be investigated with ex vivo–based DC immunization. Some topics for the near future are the extent to which tumor-specific tolerance is an obstacle to immune therapy and the need to mobilize several adaptive and innate mechanisms in tandem, including Th1 type CD4+ helper T, NK and NKT cells. Progress is also being made in manipulating DCs directly in vivo. This will help to design vaccine adjuvants that improve presentation of tumor cells in patients. Although tumors challenge the immune system in formidable ways relative to infectious diseases, it is now feasible to use active immunotherapy and DC biology to manipulate and study the human response to cancer. CTL, cytolytic T lymphocyte; DC, dendritic cell; EBV, Epstein-Barr virus; KAR, killer activating receptor; KIR, killer inhibitory receptor; KLH, keyhole limpet hemocyanin; MAb, monoclonal antibody; NK, natural killer; NKT cell, natural killer T cell; ODN, oligodeoxynucleotide; TRAIL, TNF-related apoptosis-inducing ligand; TRANCE, TNF-related activation-induced cytokine; T-reg, T-regulatory. Antigen-presenting DCs activate several cell types (Fig. 1) that can resist tumors.1, 2, 3, 4, 5 We will discuss one way in which to exploit and study DC function in the setting of human cancer: generation of large numbers of DCs from a patient ex vivo, charging cells with tumor antigens and then readministering them to enhance cell-mediated resistance. This approach may appear more complicated than direct immunostimulation of patients. However, the ex vivo method ensures access of tumor antigens to the DCs and provides a means to manipulate the quality of the DCs, 2 critical control points in the active immunization process. Distinct cell-mediated resistance mechanisms against cancer. Four types of lymphocyte are able to kill transformed human cells directly and make abundant IFN-γ. Additional resistance mechanisms exist in the immune system, e.g., those mediated by antibodies and phagocytes. Each cell in this diagram has a distinct mechanism of antigen recognition, allowing the cells to work together to increase resistance to tumors. CD8+ CTLs recognize tumor peptides presented on MHC class I products and then kill the targets by a rapid granzyme-dependent mechanism. However, tumors often escape CTLs by dampening class I presentation. CD4+ T cells recognize tumor peptides presented on MHC class II products and kill targets through a slower, fasL-dependent mechanism. However, most tumors do not express MHC class II. Nevertheless, CD4+ T cells can recognize antigen on other antigen-presenting cells in the tumor, thereby recruiting phagocytes with antitumor potential, at least in mice.278 Tumor-specific CD4+ T cells can also activate DCs via CD40 and improve presentation to CD8+ T cells. NK cells have a 2-stage recognition mechanism to kill targets. First, KIRs263 recognize MHC class I. If targets lack MHC class I264 (Karre's “missing self” hypothesis289), inhibition ceases and a second set of natural cytotoxicity receptors or KARs264 (ligands unknown) takes over, allowing lysis of tumors that have subverted MHC I presentation. NK cells also express Fcγ receptors, to kill opsonized targets. NKT cells express select T-cell receptors for lipids and glycolipids presented on CD1d. NKT cells can have striking effects on a spectrum of mouse tumors in vivo273 and human cell lines.276 The interaction of these lymphocytes with DCs allows DCs to produce cytokines, especially large amounts of IL-12. Mature DCs are the final immunostimulatory stage of DC differentiation. In mice, mature DCs are more immunogenic than their immature counterparts.6, 7, 8, 9 During maturation, DCs regulate several valuable components of the immunization process (Fig. 2). These include higher levels of MHC–peptide complexes,9, 10, 11 numerous lymphocyte costimulatory molecules (e.g., cytokines and members of the B7 family),12, 13 important TNF and TNF-receptor molecules (e.g., CD40, 4-1BB-L and TRANCE receptor)14, 15, 16 and many chemokines and chemokine receptors that help attract T cells and guide DCs to lymphoid tissues.17 DC family maturation is induced by many stimuli, ligation of TNF and Toll receptors being the best studied. DC maturation also can be blocked by several mechanisms, such as ligation of the thrombospondin receptor CD4718 and tumor-derived cytokines like IL-10.19, 20 DC maturation. Antigen-capturing, immature DCs have many uptake receptors, including FcγR and receptors for cells dying by apoptosis and necrosis. Immature DCs have numerous endocytic compartments rich in MHC class II and other molecules, like the invariant chain and HLA-DM, to help load MHC II with peptides.11 Shortly after receiving a maturation stimulus (*), DCs produce IL-12 and other cytokines and chemokines80, 83 and start to form large amounts of MHC–peptide complexes clustered with CD86 costimulators.12 These move to the surface at the same time that DCs express new chemokine receptors,17, 290, 291 upregulate many costimulators like CD40 and CD5813, 86 and display markers of unknown function, such as surface CD83292 and intracellular DC-LAMP.293 Each lymphocyte subset in Figure 1 has distinct antigen-recognition mechanisms and functions. As a result, their action in concert has greater potential to resist tumors. CD4+ and CD8+ T cells are the adaptive arms of cell-mediated immunity, differentiating upon antigen encounter to produce cytokines and lytic products, expanding clonally and establishing memory. T cells recognize peptides derived from proteins within tumors and can resist the growth of experimental tumors, even eradicating established cancers.21, 22 NK and NKT cells have innate functions, already prepared to kill and produce cytokines upon tumor recognition. These cells can recognize targets lacking MHC class I products (NK) as well as glycolipids (NKT), thus providing ways to kill tumors that, by one mechanism or another, fail to present peptide antigens to T cells. NK and NKT cells grow upon exposure to cytokines like IL-2, but they are not known to establish memory with expanded cell numbers or improved function. DCs have several mechanisms to link innate and adaptive components of the immune response, especially their rapid production of large amounts of cytokines like IL-1223 and IFNs α and γ.24, 25 Active immunization with DCs has the potential to mobilize in patients each of the cellular resistance mechanisms in Figure 1. In addition to their tumor lytic capacities, these cells can produce large amounts of IFN-γ. This cytokine upregulates expression of MHC products on tumors so that the presentation of peptides is enhanced. IFN-γ also has antiangiogenic effects.26, 27 Tumor-specific CD4+ IFN-γ–secreting cells even eliminate MHC class II-negative cancers in mice, presumably when activated by antigen-presenting cells in the tumor milieu.28 Impressively, IFN-γ-deficient but otherwise immunocompetent mice show decreased tumor surveillance to spontaneous tumor development29 and to chemical carcinogens.30 Admittedly, tumors are much more formidable opponents than most infections, which are the established targets for cell-mediated immunity.31 Tumors may tolerize reactive T cells in the same way that self tissues maintain tolerance against autoimmunity. Tumors typically dampen the expression MHC class I,32 the antigen-presenting molecules for CD8+ CTLs and valuable tumor antigens may not be processed and presented.33 Tumors may block the development of immunity more globally by inhibiting the differentiation of active DCs.20 Tumors develop antiapoptotic mechanisms, where apoptosis is the basis for tumor killing by immune cells. Apoptosis also provides a means for DCs to capture and process antigens from tumors, as we will discuss. Despite these challenges, several developments in lymphocyte and DC biology are intensifying their use in vaccine and therapeutic approaches to human cancer. For one thing, antigens have now been identified in many tumors;34, 35, 36 for another, sensitive and quantitative assays are available to monitor the immune response. Antigens and assays are not enough, however, as illustrated by the demands of developing an HIV-1 vaccine. HIV-1 genes, proteins and assays have long been available, but strong T-cell immunity to HIV-1 has been difficult to induce. Instead, control of cell-mediated resistance is much more complex and, in particular, requires enhancers or adjuvants. DCs are “nature's adjuvants”, capable of processing complex antigens like whole tumor cells and then delivering the resulting MHC–peptide complexes in such a way that strong cell-mediated immunity ensues.1, 2, 3, 4, 5 Intriguingly, certain DC subsets or states of maturation can additionally control self-tolerance and immune regulation.37, 38, 39 Therefore, DCs can enhance or dampen antigen-specific responses. We will review 5 features of this new use of DCs to manipulate and study the human immune response to cancer antigens: (i) the control of the quality of the T-cell response by DCs, (ii) areas of DC biology to consider in the near future to improve control of the human immune system, (iii) approaches to the loading of DCs with a broad array of tumor antigens, (iv) initial results from DC vaccination studies in human cancer and (v) some important unknowns in cancer immunology that can be pursued with DCs as adjuvants. The first clinical studies of DC therapy were performed in the setting of advanced cancer. Several of the initial studies reported occasional regressions of metastatic lesions following DC vaccination.40, 41, 42 There were few side effects of repeated injections of autologous DCs, especially in the report from Schuler's group,42, 43 who first used potent mature DCs in patients with stage IV melanoma. They found that the mature, immunostimulatory stage of DC differentiation was nontoxic but at the same time could expand tumor antigen-specific immunity.42, 43 Being aware of the lack of overt toxicity, we used DCs to immunize healthy volunteers to model foreign antigens. Such protocols would allow key functions of DCs and T cells to be assessed in the absence of potentially confounding features of tumor-bearing patients. Antigen-bearing DCs reliably and rapidly expanded antigen-specific T-cell immunity in healthy individuals.44 Standard T-cell proliferation assays on blood mononuclear cells from the vaccinees showed that CD4+ T cells were rapidly primed to the protein, KLH and boosted to tetanus toxoid. In both ELISPOT (IFN-γ secretion) and cytotoxicity (51Cr-release) assays, CD8+ T cells specific for an influenza viral peptide were also increased with DC-based immunization. These immune responses were detected in fresh blood samples, whereas prior tumor vaccinations required prolonged tissue culture assays to detect T-cell immunity.45, 46 The capacity of DCs to expand multiple arms of the human T-cell response is valuable in light of evidence that resistance to experimental tumors is enhanced when both CD4+ and CD8+ T cells are engaged.47, 48 For example, tumor-specific CD4+ T cells express CD40L more effectively than CD8+ T cells, leading to activation of DCs via CD40. This in turn improves their antigen presentation to CD8+ killer cells49, 50, 51 and leads to production of valuable cytokines such as IL-12 and IFN-γ, to mobilize NK cells. Subsequent studies in small groups of healthy individuals have reported 3 surprising findings (discussed below) that reveal the capacity of DCs to control critical qualitative features of the human immune response. In 4/4 volunteers tested, a single dose of mature, KLH-pulsed DCs induced specific CD4+ T cells polarized to produce IFN-γ but not IL-4.39 This polarization to Th1 is potentially an important component of effective host resistance. In mice, T cells specific for the LCMV nucleoprotein were polarized ex vivo with IL-12 or IL-4 to produce virus-specific, IFN-γ–producing Th1 and IL-4/ IL-5–producing Th2 subsets, respectively.52 Upon adoptive transfer to naive animals, both Th1 and Th2 cells helped B cells to produce neutralizing antibody but Th1 cells were decidedly more protective in T cell–dependent immunity. In an analogous fashion, ovalbumin-specific Th1 and Th2 T-cell lines were produced and used to provide resistance to tumors bearing ovalbumin as a surrogate tumor antigen. Again, both Th1 and Th2 cells resisted the tumor but only the Th1 cells helped to establish memory for tumor-specific CTL responses.53 Analogous Tc1 and Tc2 subsets of CD8+ CTLs also were produced against an influenza viral antigen. The former IFN-γ–producing CD8+ T cells were more protective in an influenza model.54 Other studies indicated that IFN-γ–producing CD4+ T cells are better at protecting mice against chronic viral infection.55, 56 Th1 cells may be more valuable because they home better to sites of inflammation57 due to different chemokine receptors.58 For example, DCs induce Th1 cells expressing CXCR6 receptors, which mediate migration to inflammatory foci.59 Th1 cells may activate DCs better to sustain CD8 T-cell function,49, 50, 51 especially in the setting of a persistent viral or tumor antigen load. Th1 cells exert fasL-dependent cytotoxicity.60, 61 As mentioned, IFN-γ has antiangiogenic effects26, 27 and is able to mediate tumor regression even when the CD4+ helper cell recognizes MHC II–peptide on adjacent antigen-presenting cells.28 Therefore, it will be important to pay attention to the distinction between Th1 and Th2 when exploiting DCs to bring about stronger cell-mediated immunity in humans. DCs also play a role in the establishment and maintenance of T-cell memory.62, 63, 64 This in part may be due to production of IL-15,65, 66, 67 a cytokine that sustains memory CD8+ T cells.68 When 3 volunteers were given a second booster of mature DCs pulsed with an influenza virus peptide, the functional affinity of the memory cells was greatly increased.69 The boosted CD8+ T cells could be activated with much smaller doses of viral peptide, 10 to 100 times lower. This finding has parallels in mice, where higher-affinity T cells develop upon multiple immunizations.70, 71 Improved functional affinity of tumor-specific CD8+ T cells could prove vital for the success of immune therapy because tumors may express only small amounts of some antigenic peptides. In adoptive transfer models, higher-affinity T cells can elicit superior protection against tumor and viral infection.72, 73 The near future would benefit from further analysis of the functional affinity of tumor-reactive T cells. A fascinating development comes from 2 reports, one with CD438 and one with CD839 human T cells, that immature DCs are not simply ignored by the immune system. This had been assumed in prior mouse studies reporting that immature DCs were decidedly less immunogenic. Indeed, immature DCs are able to silence an immune response and this is associated with the formation of T-reg cells. T-reg cells produce the suppressive cytokine IL-10, but a cell contact-dependent mechanism also appears to be needed for full regulatory function.74 The new human studies show that immature DCs can elicit antigen-specific T-reg cells and that CD8+ T cells are subject to regulation and silencing much like CD4+ T cells. Jonuleit et al.38 studied immature DCs and T-reg cells in vitro. The induced T-reg cells severely dampened Th1 cells activated by mature DCs. We worked in vivo in healthy volunteers,39 injecting immature DCs pulsed with influenza virus peptide. Upon immature DC immunization, the peptide-specific, IFN-γ–secreting CD8+ T cells fell substantially and did not return to preimmunization values for more than 3 months. For at least 1 month after immunization, peptide-specific, IL-10–producing CD8+ T cells were detected. In tissue culture, antigen-specific (MHC I tetramer binding) T cells were evident, but these could not form virus-specific CTLs when boosted with mature DCs. Current studies indicate that CD8+ T cells, after immunization with immature DCs, inhibit IFN-γ–secreting CD8+ T cells in preimmunization and recovery blood samples. This silencing of effector T cells by immature DCs may provide a way to dampen unwanted T-cell responses, as in autoimmunity and transplantation. However, in the context of immunotherapy, induction of T-reg cells would be anathema. Since mature DCs charged with MHC class I and II binding peptides are able to elicit specific T-cell responses in humans, the stage is set to interface research on antigen-pulsed DCs with additional pertinent areas in DC biology (Table I). There is a potential methodologic gap and variable, which is to quantify the amount and longevity of the MHC–peptide complexes being displayed by the DCs under different conditions of antigen loading. Perhaps this can be explored by developing reagents that specifically recognize complexes of MHC products and a tumor peptide, e.g., soluble T-cell receptors75 or MAbs.9, 76 Although T cells begin to respond at much lower doses of ligand than can be detected by MAbs, specific antibodies allow direct assessment of the level of antigen presentation (MHC–peptide complexes) at the single-cell level. High levels of MHC peptide may prove valuable for skewing the immune response toward Th1 and for increasing the longevity of the immune stimulus. Soluble T-cell receptors and MAbs also help to monitor the distribution of MHC–peptide complexes on DCs. In one system, where hen egg lysozyme was processed onto mouse MHC class II, the MHC–peptide complexes formed clusters that included the CD86 costimulatory molecule at the DC surface. It is postulated that the coclustering of MHC–peptide and CD86 allows DCs to set up effective immunologic synapses for signaling naive T cells and initiating immunity.12 As mentioned above, mature DCs are more immunogenic in mice. There is preliminary evidence in cancer patients that even when DCs are directly injected into the node, mature DCs induce stronger T-cell responses than immature DCs.77 As discussed above, DCs can rapidly polarize the human immune response to the Th1 type. DCs can produce high levels of the Th1-inducing cytokine IL-12 in vivo,23 as well as the IL-23 homologue,78 especially when they are exposed to additional cytokines such as GM-CSF and IL-479, 80 and select chemokines.81 However, prolonged culture of DCs in a CD40L maturation stimulus “exhausts” much of the capacity of the DCs to produce IL-12 and induce Th1 cells in culture.80, 82, 83 These tissue culture data contrast with in vivo observations that mature DCs effectively elicit Th1 responses39 as well as in vitro findings that CD40L DCs are valuable for expanding melanoma-specific CD8+ CTLs and Th1 CD4+ cells from tumor-infiltrating lymphocytes.84 Perhaps the loss of high level IL-12 production during the later stages of maturation primarily dampens the capacity of DCs to influence other cells, like NK cells, in a paracrine fashion. Sufficient amounts of IL-12 or IL-23 may still be produced to act locally to polarize T cells toward the Th1 type. The B7 family of costimulatory molecules85 also is regulated during maturation and influences the production of Th1 and Th2 cytokines. For example, CD86 is upregulated markedly,86 and newly expressed CD86 is expressed in clusters with MHC–peptide molecules.12 In contrast, mature DCs may downregulate the ICOS ligand, which polarizes toward potentially undesirable Th2 cells.87 Mature DCs also express the B7-DC/PD-L2 molecule. This molecule may enhance Th1 cytokine production by naive T cells88 and suppress cytokine formation by activated T cells.89 B7-H3 is yet another B7 homologue, cloned from DCs, which also costimulates IFN-γ production.90 When MAbs to this intricate B7 family become available in the near future, it will be valuable to monitor the expression of B7 family members during DC maturation and vaccination studies. Although DCs most likely should be given a maturation stimulus prior to their use in immunotherapy, the time of stimulation in vitro needs evaluation. For example, it might be important to test DCs that have been matured for shorter times than the 1- to 3-day periods used to date. On the one hand, prolonged maturation may diminish IL-12 production (“exhaustion”), but on the other hand, the capacity of DCs to resist the immunosuppressive effects of IL-10 may be enhanced.91 The efficiency with which DCs home to the draining lymph node and their longevity once they reach the node are research areas for improving the efficacy of current active immunization protocols. In mice, only small numbers of the injected DC inoculum are found in the draining lymph node,63 where the immune response begins.92, 93 Recovery of injected DCs is increased if the DCs are treated with viability-enhancing CD40L or TRANCE/RANKL prior to injection.63 Nevertheless, fewer than 10% of injected DCs can be identified in the draining lymph node. CD40 may be essential for at least epidermal DCs to migrate to lymph nodes.94 In humans, migration efficacy can be followed with DCs labeled with 111indium.95 The near future will hopefully use tracers of this kind to determine the efficacy with which DCs leave the injection site and home to lymphoid organs. In this way, alternative methods of DC injection and conditioning of the injection sites could be evaluated. DC migration is an elegant area of DC biology and ostensibly one of the key control points in the efficacy of immune activation. DC migration is regulated through multidrug resistance receptors, which pump select compounds like cysteinyl leukotrienes.96, 97 These in turn modulate the responses of chemokine receptors, especially CCR7, on DCs. The respective chemokines (CCL19 or MIP-3β and CCL21 or SLC), which are made by the lymphatics and select lymph node cells, including DCs themselves, influence DC movement and other functions.98, 99 The efficacy of injected antigen-bearing DCs therefore may require that the investigator learn to control the availability of these leukotrienes and chemokines. We feel that current methods of active DC-based immunization do not optimize either DC migration into lymphatics or their life span upon reaching the lymph node. These functions, if improved, could markedly increase the efficacy of DCs. DC dose may influence the quality of the T-cell response since, at least in vitro, a low dose of DCs,100 like a low dose of antigen,101, 102 can polarize toward Th2. The injected dose also could be too large for the DCs to gain access to the lymphatics or, as mentioned above, the injection site may need to be further conditioned to allow efficient homing in vivo. Another concern with some of the initial DC vaccine studies is that a rapid injection schedule induced active CTLs, which then killed the booster doses of DCs and reduced efficacy.103 The immunogenicity of DCs after different routes of administration in humans also needs to be compared. Some data suggest that the s.c. and i.d. routes lead to greater nodal migration over the i.v. route104, 105 and improved Th1 polarization.106 Direct injection into the lymph node is thought to facilitate the access of DCs to T cells,41 yet this also needs to be proven. A new approach is to directly inject DCs into tumor deposits,107 as a way of initiating the afferent limb of immunity in vivo. Interestingly, some DCs have the capacity to directly kill tumor targets, e.g., via TNF family members like TRAIL.108, 109, 110, 111 The near future would benefit from randomized 2-arm studies to document responses under defined conditions of DC dose, frequency and route. Most studies to date have used monocyte-derived DCs. These offer the advantages of high yield, purity and feasibility, especially when leukapheresis is used to collect the starting monocytes.111, 112 It currently is feasible to obtain from patients with advanced melanoma 500 million mature DCs (current protocols use approx. 5 million DCs per vaccination). Monocyte-derived DCs can be successfully cryopreserved, even after the DCs have been loaded with antigen, though this needs more testing. The Dendreon firm's methodology (Seattle, WA), in contrast, depends on a small fraction of DCs that are normally present in blood after 1 to 2 days in culture.113, 114 The vaccine then uses the equivalent of an entire leukapheresis for each immunization. The alternative approach of differentiating large numbers of monocytes to DCs requires exogenous cytokines and longer culture periods (6 days or more), but the yield of potent DCs is much larger and the cells are more homogenous. In current practice, a single leukapheresis provides sufficient monocyte-derived DCs for dozens of vaccinations. It also may be feasible to cryopreserve the antigen-bearing mature cells, greatly facilitating vaccination and therapy.111, 112 DC maturation from CD34+ progenitors also is being characterized.115 A clinical study with CD34-derived DCs has shown immune and some clinical efficacy in the short term.116 These cells consist of 2 subsets, termed Langerhans cells or epidermal DCs and monocyte-derived or interstitial (dermal) DCs.117, 118, 119 The 2 DC subsets differ in markers and some functions. For example, Langerhans cells are ineffective at stimulating B-cell development directly,120 a function that may require the BAFF/BlyS TNF family molecule on monocyte-derived DCs. CD34+-derived DCs may have improved efficacy at eliciting CTLs.121, 122 Cells with some of the features of Langerhans cells could also be derived from monocytes, TGFβ being a key determinant.123, 124 It should be possible in the near future to look more closely at the immunogenicity of Langerhans cells relative to other forms of DCs. Yet another DC subset is the plasmacytoid DC or preDC2.125 These CD11c-low precursors have some very different features relative to monocyte precursors or preDC1. Plasmacytoid cells respond to IL-3 and express CD62L or L-selectin, thereby homi" @default.
• W2000749507 created "2016-06-24" @default.
• W2000749507 creator A5066273096 @default.
• W2000749507 creator A5088696429 @default.
• W2000749507 date "2001-11-15" @default.
• W2000749507 modified "2023-10-06" @default.
• W2000749507 title "Active immunization against cancer with dendritic cells: The near future" @default.
• W2000749507 cites W137756652 @default.
• W2000749507 cites W1444462873 @default.
• W2000749507 cites W1479742818 @default.
• W2000749507 cites W1479813612 @default.
• W2000749507 cites W1482806584 @default.
• W2000749507 cites W1483922594 @default.
• W2000749507 cites W1486301687 @default.
• W2000749507 cites W1488377901 @default.
• W2000749507 cites W1489870404 @default.
• W2000749507 cites W1494401243 @default.
• W2000749507 cites W1496239631 @default.
• W2000749507 cites W1501518736 @default.
• W2000749507 cites W1503066288 @default.
• W2000749507 cites W1511403203 @default.
• W2000749507 cites W1513178664 @default.
• W2000749507 cites W1517310071 @default.
• W2000749507 cites W1517875520 @default.
• W2000749507 cites W1521600055 @default.
• W2000749507 cites W1523931076 @default.
• W2000749507 cites W1524274652 @default.
• W2000749507 cites W1534709281 @default.
• W2000749507 cites W1543454781 @default.
• W2000749507 cites W1545583588 @default.
• W2000749507 cites W1558372199 @default.
• W2000749507 cites W1561591381 @default.
• W2000749507 cites W1571520647 @default.
• W2000749507 cites W1572267688 @default.
• W2000749507 cites W1572881837 @default.
• W2000749507 cites W1581050933 @default.
• W2000749507 cites W1585007382 @default.
• W2000749507 cites W1585754595 @default.
• W2000749507 cites W1589948634 @default.
• W2000749507 cites W1592425735 @default.
• W2000749507 cites W1600015917 @default.
• W2000749507 cites W1602608371 @default.
• W2000749507 cites W1602824038 @default.
• W2000749507 cites W1604363681 @default.
• W2000749507 cites W1609504261 @default.
• W2000749507 cites W1626388077 @default.
• W2000749507 cites W1627965833 @default.
• W2000749507 cites W1633651476 @default.
• W2000749507 cites W1642873092 @default.
• W2000749507 cites W1643293176 @default.
• W2000749507 cites W1644577573 @default.
• W2000749507 cites W1667816862 @default.
• W2000749507 cites W1669165205 @default.
• W2000749507 cites W1669763596 @default.
• W2000749507 cites W1678167583 @default.
• W2000749507 cites W1708153904 @default.
• W2000749507 cites W1761643547 @default.
• W2000749507 cites W1769686661 @default.
• W2000749507 cites W1782545213 @default.
• W2000749507 cites W1790202563 @default.
• W2000749507 cites W1839651929 @default.
• W2000749507 cites W1843613114 @default.
• W2000749507 cites W1866642200 @default.
• W2000749507 cites W1893411048 @default.
• W2000749507 cites W1894308601 @default.
• W2000749507 cites W192003713 @default.
• W2000749507 cites W1934655176 @default.
• W2000749507 cites W1935511302 @default.
• W2000749507 cites W193748226 @default.
• W2000749507 cites W1943853832 @default.
• W2000749507 cites W1964416857 @default.
• W2000749507 cites W1965410838 @default.
• W2000749507 cites W1967994686 @default.
• W2000749507 cites W1968663882 @default.
• W2000749507 cites W1969705214 @default.
• W2000749507 cites W1969823334 @default.
• W2000749507 cites W1970743210 @default.
• W2000749507 cites W1971631427 @default.
• W2000749507 cites W1972365190 @default.
• W2000749507 cites W1972486638 @default.
• W2000749507 cites W1979565071 @default.
• W2000749507 cites W1981746803 @default.
• W2000749507 cites W1983268059 @default.
• W2000749507 cites W1983806918 @default.
• W2000749507 cites W1987009989 @default.
• W2000749507 cites W1987046764 @default.
• W2000749507 cites W1988437817 @default.
• W2000749507 cites W1988488249 @default.
• W2000749507 cites W1989527030 @default.
• W2000749507 cites W1992945893 @default.
• W2000749507 cites W1993027053 @default.
• W2000749507 cites W1995529916 @default.
• W2000749507 cites W1995667011 @default.
• W2000749507 cites W1996483176 @default.
• W2000749507 cites W1997196319 @default.
• W2000749507 cites W1998470464 @default.
• W2000749507 cites W2001656273 @default.
• W2000749507 cites W2001824569 @default.

• next