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The disabled dendritic cell

Department of Urology, University of Innsbruck, A-6020 Innsbruck, Austria

¹Correspondence: Department of Urology, Anichstrasse 35, 6020 Innsbruck, Austria. E-mail: martin.thurnher{at}uibk.ac.at

	ABSTRACT

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
Dendritic cells are important antigen-presenting cells of the immune system that induce and modulate immune responses. They interact with T and B lymphocytes as well as with natural killer cells to promote activation and differentiation of these cells. Dendritic cells generated in vitro from monocytes by use of the cytokines GM-CSF and IL-4 are increasingly used clinically to enhance antitumor immunity in cancer patients. However, recent studies revealed that the functional repertoire of monocyte-derived dendritic cells may be incomplete. Important functions of monocyte-derived dendritic cells such as migration or the ability to induce natural killer cell activation or type 2 T helper cell differentiation appear to be impaired. We propose that all these deficiencies relate to a single biochemical deficiency of monocyte-derived dendritic cells. IL-4, which is used to generate monocyte-derived dendritic cells, suppresses phospholipase A2, the enzyme that liberates arachidonic acid from membrane phospholipids and contributes to the synthesis of platelet-activating factor. Monocyte-derived dendritic cells must therefore fail to generate platelet-activating factor as well as arachidonic acid derivatives such as prostaglandins, leukotrienes, and lipoxins, collectively referred to as eicosanoids. Since eicosanoids and platelet-activating factor are known to play an important role in processes such as leukocyte migration, natural killer cell activation, and type 2 T helper cell differentiation, the deficiency in eicosanoid and platelet-activating factor biosynthesis may be responsible for the observed handicaps of monocyte-derived dendritic cells.—Thurnher, M., Zelle-Rieser, C., Ramoner, R., Bartsch, G., Höltl, L. The disabled dendritic cell.

Key Words: interleukin-4 • phospholipase A2 • eicosanoids • platelet-activating factor

	INTRODUCTION

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
DENDRITIC CELLS (DCS) are antigen-presenting cells that induce and modulate immune responses. DCs pick up, process, and present antigens in a major histocompatibility complex (MHC) -restricted fashion to the T cell receptor (TCR) of T lymphocytes (1) . DCs also provide the costimulatory signals required for T cell activation (1) . By elaborating distinct cytokine profiles DCs can influence T helper (Th) cell differentiation (1 , 2) . In addition, DCs interact with B lymphocytes to enhance B cell expansion and antibody production (1) as well as with natural killer (NK) cells to augment NK cell cytolytic activity and interferon (IFN-) production (3) . Thus, DCs appear to play a central role in the induction and regulation of the immune response.

One way to generate DCs in vitro is to differentiate them from CD14⁺ monocytes in a two-step culture system (4 , 5) . In a first step, granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) promote the development of immature DCs with high antigen-capturing capacity (Fig. 1A ). In the second step, proinflammatory factors induce the terminal maturation of CD83⁺ DCs, which stably express MHC–peptide complexes (6) , abundant T cell adhesive and costimulatory molecules, as well as chemokine receptors such as CCR7, which direct DC migration to lymph nodes (7) .

View larger version (32K): [in this window] [in a new window]   Figure 1. Schematic representation of moDC differentiation from monocytes (A) and influence of the cytokines used for moDC generation on the arachidonic acid (aa) metabolism and PAF biosynthesis (B). The most important effect is the inhibition of cPLA2 by IL-4, which abolishes the release of aa and PAF from membrane phospholipids. (+) Stimulatory effects; (-) inhibitory effects.

The feasibility of this culture system has led to the use of monocyte-derived DCs (moDCs) in many clinical studies, most aimed to induce antitumor immunity in cancer patients (8 9 10 11 12 13 14) . In these trials, proof of principle was obtained so that antigen-pulsed moDCs could elicit measurable antigen-specific immunity and occasionally clinical responses. However, evidence was also obtained that moDCs have functional limitations. After intradermal administration most moDCs fail to leave the injection site, which is indicative of some migratory disability (ref 14 ; E. Kämpgen, Expert Meeting on Dendritic Cells in Clinical Trials, Zurich 2000). Moreover, recent evidence suggests that moDCs fail to stimulate type 2 Th cells (2 ; M. Thurnher et al., unpublished observations), which may be more important for tumor rejection than previously believed (see below). In addition, the ability of moDCs to induce humoral immune responses may be suboptimal (8) . In vitro, human moDCs likewise fail to activate NK cells (L. Zitvogel, Expert Meeting on Dendritic Cells in Clinical Trials, Zurich 2000), which are important effector cells in the antitumor immune response (3) . We hypothesize that all these deficiencies are due to a single biochemical deficiency. The high levels of IL-4 continuously present in the moDC culture system suppress phospholipase A2 (PLA2) and thus shut down the eicosanoid metabolism as well as platelet-activating factor (PAF) biosynthesis in these cells (15) . Since eicosanoids and PAF are mediators and regulators of critical immunological processes (15) , the deficiency in eicosanoid and PAF generation may be responsible for the impairment of important moDC functions.

	ARACHIDONIC ACID METABOLISM

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
Arachidonic acid (arachidonate) can be liberated from membrane phospholipids through the action of phospholipases such as PLA2 (Fig. 1B ). Macrophages contain at least three different PLA2s, which have no sequence homology (16) : a cytosolic and a secretory PLA2 (cPLA2 and sPLA2), which both require Ca²⁺ as well as a Ca²⁺-independent PLA2 (iPLA2). sPLA2 requires Ca²⁺ at millimolar levels for catalytic activity whereas cPLA2 requires submicromolar Ca²⁺ concentrations for membrane association. cPLA2 is considered a highly specific enzyme for arachidonate and generates a major pool of arachidonate in response to proinflammatory factors (15 , 16) . Free arachidonate can enter at least three different metabolic pathways (15) . 1) Two cyclooxygenases (COX-1 and COX-2) catalyze the first step in the formation of prostaglandins and thromboxanes (collectively designated as prostanoids) (17) . They differ in their subcellular localization and in their susceptibility to inhibition by nonsteroidal antiinflammatory drugs. COX-1 is a constitutively expressed enzyme that generates prostanoids required for normal cell function. In contrast, COX-2 is inducible and predominantly generates prostanoids at sites of inflammation. 2) The leukotriene (LT) -generating pathway is initiated by 5-lipoxygenase (5-LO), which converts arachidonate into LTA4 via 5-hydroperoxyeicosatetraenoic acid (15) . 5-Lipoxygenation also depends on the 5-LO-activating protein (FLAP), which is thought to act as an arachidonate carrier protein. LTA4 can either be enzymatically hydrolyzed to LTB4 or converted to the cysteinyl-LTs, LTC4, LTD4, and LTE4. Tripeptide glutathione serves as the cysteinyl donor in the formation of cysteinyl-LTs. 3) Multiple routes exist in the biosynthesis of the lipoxins (LXs) A4 and B4 involving both 5-LO and 15-LO (18) . LXs are either generated in the vascular lumen by platelet–leukocyte interactions or at mucosal surfaces by leukocyte–epithelial cell interactions. Such cooperative interactions between two different cell types in the biosynthesis of LXs are referred to as transcellular biosynthesis. In blood, LX biosynthesis involves the generation of LTA4 by the leukocyte 5-LO. LTA4 released from leukocytes can be converted into LXA4 by platelets. At mucosal surfaces, epithelial cell-associated 15-LO, which converts arachidonate into 15(S)-HETE, initiates LX biosynthesis. Extracellular epithelial cell-derived 15(S)-HETE can then be taken up by mucosal leukocytes and converted into LXs. In addition to transcellular pathways, evidence has been gathered that leukocytes primed in vivo in, for instance, asthmatic patients can generate LXs from endogenous sources (19) . Moreover, transcellular LX formation and biosynthesis from endogenous sources can collaborate when primed in vivo.

In addition to the synthesis of arachidonate derivatives, PLA2 has been implicated in the generation of PAF through the so-called remodeling pathway (20) . PLA2 may cleave distinct membrane phospholipids into arachidonate and the 2-lysophospholipid, which can be converted to bioactive PAF (Fig. 1B ), another potent inflammatory mediator.

	ARACHIDONIC ACID METABOLISM IN moDCs

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
IL-4, which promotes DC differentiation from monocytes, has been reported to suppress PLA2 activity and thus arachidonate release in mouse bone marrow-derived mast cells (21) and in human fibroblast-like synoviocytes (22) . In addition to Ca²⁺, cPLA2 activation requires phosphorylation at Ser-505 by members of the mitogen-activated protein kinase cascade (23) . One effect of IL-4 is the inhibition of cPLA2 phosphorylation. Since IL-4 has been shown to have similar effects on human monocytes (24) or macrophage-like cells (25) , moDCs would be expected to lack cPLA2 activity since they are exposed to high concentrations of IL-4 (500 to 1000 U/ml) for several days. We found that mature CD83⁺ moDCs contained cPLA2 mRNA and protein, but indeed lacked cPLA2 activity and failed to generate prostaglandin E2 (PGE2) (C. Zelle-Rieser et al., unpublished observations). The inability of moDCs to synthesize PGE2 also explains the previously reported maturation-enhancing effect of exogenous PGE2 (26 , 27) . moDCs converted exogenous arachidonate into PGE2 (R. Ramoner et al., unpublished observations), indicating that only the release of endogenous arachidonate from membrane phospholipids is blocked in moDCs.

All cytokines used for the generation of DCs from monocytes have been reported to affect eicosanoid generation as well as eicosanoid receptor expression (15) (Fig. 1B ). GM-CSF stimulates expression of both 5-LO and FLAP (28 , 29) whereas IL-4 up-regulates 15-LO in monocytes (30) . IL-4 also induces the message and functional appearance of LXA4 receptors (31) . Thus, IL-4 treatment of monocytes may establish an autocrine LXA4 loop that may be important for DC function. Transforming growth factor ß (TGF-ß), which promotes DC development with a Langerhans cell (LC) phenotype in this culture system (32) , also enhances 5-LO activity (33) . GM-CSF enhances (34) while IL-4 suppresses COX-2 expression (22) . Maturation-inducing stimuli such as lipopolysaccharides, tumor necrosis factor (TNF-), IL-1ß, and IL-6 have all been shown to enhance arachidonate metabolism via the 5-LO and the COX-2 pathway (15) . MoDCs indeed contain transcripts encoding both COX isoforms, 5-LO, FLAP, and 15-LO (R. Ramoner et al., unpublished results), which suggests they may be capable of generating all kinds of eicosanoids from exogenous but not from endogenous arachidonate. The inability, however, to generate eicosanoids from endogenous arachidonate may impair various important functions of moDCs.

	ANTIGEN UPTAKE

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
MoDCs exhibit high endocytic activity and capture soluble antigens by macropinocytosis and receptor-dependent mechanisms (1) . moDCs have also been shown to phagocytose apoptotic cells (35 , 36) . This form of antigen uptake results in enhanced cross-presentation of exogenous antigens on MHC class I, which is important for the development of both cytotoxic T lymphocyte (CTL) -dependent immunity (35) and self-tolerance (36) . LXA4, a major product of the 15-LO pathway, has recently been shown to enhance the uptake of apoptotic neutrophils by monocyte-derived macrophages (37) . IL-4 enhances 15-LO expression (30) and moDCs indeed contain abundant 15-LO transcripts (R. Ramoner et al. unpublished results). However, since they fail to liberate arachidonate they may also fail to generate LXA4. Restoration of LXA4 biosynthesis in moDCs, for instance, by exogenous arachidonate may further enhance phagocytosis of apoptotic cells and possibly other endocytic mechanisms (Fig. 2 ).

View larger version (29K): [in this window] [in a new window]   Figure 2. Effects of lipid mediators (eicosanoids and PAF) on moDC development and function. A) TGF-ß induced 5-LO products (LTs?) mediate LC development in the skin. LXA4 is involved in the phagocytosis of apoptotic cells and perhaps in other forms of endocytosis. PGE2 costimulates TNF--induced terminal maturation of immunostimulatory moDCs. LTC4 and LTD4 play a role in DC migration to regional lymph nodes. B) LTB4 enhances B cell proliferation and antibody production. C) PGE2 prevents activation-induced apoptosis and stimulates Th2 cell differentiation. D) PAF mediates NK cell activation possibly by enhancing LT(B4) synthesis. Likewise, PAF may be involved in other processes of moDC development and functions through enhancement of LT biosynthesis.

	MIGRATION

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
DCs are migratory cells that travel from bone marrow to the various tissues and from there to secondary lymphoid organs (1) . Evidence for a disability of moDCs with respect to migration was obtained in clinical trials. When immature moDCs labeled with indium-111 oxyquinoline were injected intradermally, the majority of the cells remained at the injection site (14) . This inability to migrate was initially attributed to the immature stage of the cells, since immature DCs, for instance, lack the chemokine receptor CCR7 (7) , which directs migration to secondary lymphoid organs. However, the majority (90%) of mature moDCs, which express CCR7 (7) , likewise failed to emigrate from the injection site (E. Kämpgen, Expert Meeting on Dendritic Cells in Clinical Trials, Zurich 2000), strongly suggesting that migration of moDCs is impaired.

Randolph and colleagues have recently shown that multidrug resistance 1 (MDR-1) protein (P-glycoprotein) is important for DC migration (38) . MDR-1 is an effective membrane pump that mediates the efflux of many drugs, including chemotherapeutic agents from the intracellular space, and thereby contributes to drug resistance. One physiological role of MDR-1 is the export of endogenously produced cysteinyl LTs (39) . In fact, MDR-1 appears to be the main LTC4 exporter on LT-synthesizing cells. These LTs, which contain a cysteinyl moiety and therefore fail to passively cross the cell membrane, are actively exported by MDR-1. Together, these data suggest that the cysteinyl-LTs are important for DC migration. In fact, Randolph et al. have shown that the administration of LTC4 and its metabolite LTD4 could rescue the impaired migration of DCs derived from MDR-1 protein-deficient mice (6th International Symposium on Dendritic Cells, Port Douglas 2000), confirming that LTs exported by MDR-1 protein are important for DC migration. However, since moDCs fail to generate free arachidonate due to the lack of PLA2 activity, they must also fail to synthesize LTC4 and LTD4, which would explain the inability of these cells to migrate in vivo. Dendritic LCs in normal human skin are major 5-LO-expressing cells and contain FLAP, LTA4 hydrolase, and LTC4 synthase (37) . Thus, LCs should be capable of producing LTC4, which may play an important role in LC emigration from the skin. LTC4 may also be important for the population of the skin by LCs. The skin of mice deficient in TGF-ß, which is known to enhance 5-LO activity (33) , is devoid of LCs (41) . One possible explanation is that DCs of TGF-ß knockout mice have reduced 5-LO activity and that the resulting lack of 5-LO products such as LTC4 or LTD4 hampers DC migration into the skin. Together, these observations suggest a general role of LTC4 and LTD4 in DC migration (Fig. 2) .

	T CELL DEVELOPMENT, ACTIVATION, AND DIFFERENTIATION

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
Prostanoids such as PGE2 play an important role in regulating T cell development and function. COX-1- and COX-2-dependent PGE2 generation by stromal cells in the thymus support early thymocyte proliferation and differentiation as well as the maturation of the CD4⁺ Th cell lineage (42) . In addition, prostanoids are known to exhibit antiapoptotic effects. PGE2 has been shown to protect T cells from TCR-mediated activation-induced cell death (AICD) (43) , and the protective effect of PGE2 could be attributed to PGE2-induced down-regulation of Fas ligand in activated T cells (44) . We found that restoration of PGE2 production in moDCs by exogenous arachidonate enhanced allogeneic T cell proliferation and resulted in greater T cell yields (M. Thurnher et al., unpublished observations) consistent with reduced AICD. These observations suggested that DC-derived PGE2 may act to prolong the survival of activated T cells (Fig. 2) . Moreover, PGE2 has been shown to play a prominent role in regulating type 1 and type 2 Th cell responses (45) . PGE2 has been reported to inhibit type 1 (46) and to enhance type 2 responses (47) . PGE2 has recently been identified as one of the pivotal factors in the Th2-dominant immune response in BALB/c mice (48) , confirming the Th2-promoting activity of PGE2. MoDCs, which failed to generate PGE2 from endogenous arachidonate, also failed to stimulate IL-4-producing Th cells (M. Thurnher et al., unpublished observations). Likewise, in renal cell carcinoma patients vaccinated with KLH-pulsed moDCs, only IFN- production but not IL-4 synthesis could be detected after in vitro stimulation of peripheral blood mononuclear cells with KLH (49) , indicating that moDCs fail to induce IL-4-producing T cells in vitro and in vivo. Restoration of PGE2 synthesis by exogenous arachidonate also restored the ability of the moDCs to stimulate IL-4 production in Th cells in vitro (M. Thurnher et al., unpublished observations). These findings indicate that DC-derived PGE2 may be a crucial factor in the initiation of Th2 differentiation (Fig. 2) .

Recent work in animal models suggested that immune responses with an extreme Th1 bias (characterized by a lack of Th2 cytokines) may not be suitable for the induction of optimal systemic antitumor immunity (50 , 51) . In contrast, more balanced immune responses involving Th1 and Th2 type cytokines appear to be required. Th2 cytokines such as IL-4 and IL-5 may serve to recruit additional antitumor effector cells such as macrophages (recruited by IL-4) and eosinophils (recruited by IL-5) into the tumor lesion, where they may synergistically enhance their tumoricidal mechanisms (50) . The importance of IL-4 in antitumor immunity was further confirmed in IL-4-deficient mice. CTL-mediated tumor immunity was shown to be impaired in these animals, but could be restored if IL-4 was provided by genetically modified cells (51) . In addition, IL-4 produced by tumor-infiltrating Th2 cells may directly inhibit tumor cell growth (52) . Tumor cell growth inhibition may be due to the IL-4-mediated induction of an autocrine loop involving eicosanoids. IL-4 has been shown to induce 15-LO expression, which results in enhanced production of 15-LO products (15 , 30) , and to stimulate the expression of the peroxisome proliferator-associated receptor- (PPAR-), which binds 15-LO products (53) . As shown for human colon cancer cells, one effect of ligand binding to PPAR- can be cell growth inhibition (54) . Taken together, productive antitumor immune responses may require Th2 elements. MoDCs, however, fail to stimulate type 2 Th cells, probably because they fail to produce eicosanoids such as PGE2. Restoration of the eicosanoid metabolism should therefore improve the efficacy of moDCs as an antitumor vaccine.

	B CELL ACTIVATION

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As well as activating T cells, DCs may directly modulate B cell growth, differentiation and immunoglobulin (Ig) secretion (1 , 55) . A scenario of a three-party cellular interaction has been proposed in which DCs first activate naive antigen-specific T cells in the extrafollicular areas of secondary lymphoid organs. Activated T cells up-regulate CD40 ligand, which triggers CD40 on DCs and induces full activation and maturation of CD83⁺ DCs with high levels of costimulatory molecules. T cell costimulation enhances IL-2 production. Antigen-specific B cells triggered by T cell CD40 ligand and IL-2 differentiate into IgM-secreting plasma cells after close contact with CD40-activated DCs. The effects of DCs on B cell activation partially depended on membrane contact (CD40 ligation) but were also mediated by yet unidentified soluble factors.

LTB4, a 5-LO product of arachidonate, has been shown to enhance activation, proliferation, and differentiation of human tonsillar B lymphocytes. LTB4 enhanced expression of CD23 in resting B cells in synergy with IL-4 or IL-2 (56) . LTB4 augmented DNA synthesis and proliferation in B cells. Moreover, LTB4 enhanced IgM and IgG synthesis of B cell cultures stimulated with Staphylococcus aureus Cowan I. DCs may be an important source of LTB4 (Fig. 2) ; moDCs, which are deficient in LTB4 production, would clearly be less effective in stimulating humoral responses. In cancer patients, the successful induction of antibodies specific for tumor-associated antigens would recruit Fc receptor-expressing effector cells (granulocytes, NK cells, macrophages) as well as complement-mediated cytotoxicity, and could thereby substantially increase the efficacy of the antitumor immune response.

	NK CELL ACTIVATION

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
Besides CTLs, NK cells are important effector cells of a productive antitumor immune response. Mouse DCs directly interact with NK cells to enhance NK cell cytolytic activity and IFN- production (3) . In contrast, human moDCs failed to directly activate NK cells (L. Zitvogel, Expert Meeting on Dendritic Cells in Clinical Trials, Zurich 2000). A low molecular weight soluble factor derived from fibroblast-conditioned medium was shown to restore the ability of human moDCs to activate resting NK cells (L. Zitvogel, Expert Meeting on Dendritic Cells in Clinical Trials, Zurich 2000). PLA2 activation and arachidonate metabolism have been shown to be important for the cytotoxic function of rat NK cells (57) . Inhibitors of arachidonate lipoxygenation also inhibited human NK cell cytotoxicity (58) . LTB4, a 5-LO product of arachidonate, enhanced human NK cell cytotoxic activity by priming NK cells for increased target cell binding (59) . PAF, another product of PLA2 activity, has also been reported to enhance NK cell activity (60) . PAF produced during inflammatory responses is synthesized via the remodeling pathway, which involves PLA2 activity. moDCs lacking PLA2 activity must therefore fail to generate LTB4 and PAF, which may explain their failure to activate NK cells. The stimulatory effect of PAF on NK cells could partially be inhibited by a 5-LO inhibitor, confirming a role for LTs in DC-mediated NK cell activation (Fig. 2) . Likewise, PAF may also affect other DC functions such as migration or B cell activation through enhancement of the 5-LO pathway.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION ARACHIDONIC ACID METABOLISM ARACHIDONIC ACID METABOLISM IN... ANTIGEN UPTAKE MIGRATION T CELL DEVELOPMENT, ACTIVATION,... B CELL ACTIVATION NK CELL ACTIVATION CONCLUSIONS REFERENCES

 
MoDCs lack PLA2 activity due to the culture conditions used for DC generation (Fig. 1B ). As a consequence, moDCs fail to produce important lipid mediators, which otherwise enhance processes such as antigen uptake, DC migration, T cell activation and survival, Th2 differentiation, B cell activation, antibody production, as well as NK cell activation (Fig. 2 and Table 1 ). Restoration of the eicosanoid synthesis in moDCs should greatly improve the efficacy of these cells as adjuvants in clinical immunotherapy settings. Restoration of eicosanoid metabolism could be partially accomplished by providing exogenous arachidonate, which can be converted into PGs (M. Thurnher et al., unpublished observations) and maybe into LTs and LXs. Alternatively, conditions for moDC maturation could be adapted to allow activation of PLA2. This may be accomplished by reducing or completely removing IL-4 from the culture medium during the maturation step and by adding other factors that support PLA2 activation (15 , 16) .

In a recent clinical trial, cell hybrids consisting of tumor cells and moDCs were generated by electrofusion (61) . Tumor cells were autologous whereas moDCs were allogeneic. Patients with metastatic renal cell carcinoma were vaccinated with these cell hybrids, and impressive clinical responses were observed (61) . The success of this approach can be attributed to enhanced MHC class I presentation of tumor antigens as well as to the recruitment of alloreactive T cells into the antitumor immune response. However, another aspect of cell fusion is that the ‘disabled’ moDC adopts the intact lipid mediator metabolism from the tumor cell and thereby complements all the deficiencies described here.

IL-13 is a cytokine closely related to IL-4 (62) . Although the two cytokines share several properties, they can also play distinct roles in mediating physiological responses (62) . Overlapping functions include the support of dendritic cell development from human monocytes (5) . Opposing effects include the effects on PLA2. Whereas IL-4 suppresses PLA2 (22 , 23) , IL-13 may even activate PLA2 (63) . It is also conceivable that IL-4 might differ from IL-13 in its ability to down-regulate LT biosynthesis and up-regulate LX biosynthesis. Thus, moDCs generated with IL-13 may be capable of generating PLA2 products such as eicosanoids and PAF. Another protocol for the generation of DCs from human monocytes has recently been described (64) in which IL-4 is replaced by type I IFN, a known activator of PLA2 (65) . Thus, moDCs generated with type I IFN or IL-13 may have an intact lipid mediator metabolism and may not suffer from the disabilities described for moDCs that develop in the presence of IL-4. Likewise, DCs generated from CD34⁺ hematopoietic stem cells, which occurs in the absence of IL-4 (1) , may have a more complete functional repertoire as compared to IL-4-dependent moDCs.

	ACKNOWLEDGMENTS

 
We thank Dr. Joseph H. Coggin, Jr. and Dr. Adel L. Barsoum for critical review. Our work was supported by grants no. P11758-MED and P14140-MED of the Austrian Science Fund to M.T. The authors apologize for the fact that, owing to space constraints, not all work in this area could be cited.

Received for publication August 15, 2000. Revision received September 25, 2000.

	REFERENCES

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