¹Laboratoire d'Immunologie des Tumeurs, Institut Paoli-Calmettes, Université de la Méditerranée, Marseille, France

²Institut National de la Santé et de la Recherche Médicale (INSERM) U119, Marseille, France

Correspondence to: D Olive or B Gaugler, Immunologie des Tumeurs, Institut Paoli-Calmettes, 232 Bd Ste Marguerite, 13273 Marseille Cedex 09, France; Fax: +33 491 223610

Dendritic cells (DCs) are a system of potent antigen-presenting cells (APCs) specialized to initiate primary immune responses. DCs are considered important elements in the induction of specific antitumor cytotoxic effectors. At present, because of potential therapeutic implications, the critical role of DCs in cancer patients is under intensive investigation. Interactions between DCs and acute myeloid leukemia cells represent an attractive model for the study of DC physiology. Moreover, DCs can be a valuable therapeutic tool for the adjuvant treatment of leukemic patients. However, DC subsets in vivo may also be affected by leukemogenesis and may contribute to the escape of leukemia from immune control. The aim of this review is to shed further light on this paradoxical picture where the line between immune tolerance and immune defense is narrow.

Leukemia (2002) 16, 2197-2204. doi:10.1038/sj.leu.2402710

leukemia; dendritic cells; immunotherapy

Introduction

Dendritic cells (DCs) are bone marrow-derived leukocytes that exert a sentinel-like function.¹ They are a system of potent antigen-presenting cells (APCs) specialized to initiate primary T cell immune responses. DCs are considered important elements in the induction of specific antitumor immune response and are viewed as potential vehicles for delivery of tumor-specific antigens, both in animals and in patients. As the most potent APCs in vitro and in vivo, DCs have been shown to play a key role in the induction of antigen-specific immune responses against bacteria, viruses, allergens and tumor antigens. They serve as essential constituents of the immune system triggering immune reactions and are therefore considered as promising tools for immunotherapy. DCs ultimately derive from hematopoietic progenitors, although little is known about their lineage of origin. They can be generated in vitro from CD34⁺ cord blood or bone marrow progenitors in the presence of GM-CSF and TNF-,^{2,3,4,5,6,7,8,9,10,11,12} as well as from peripheral blood or cord blood monocytes in the presence of GM-CSF and IL-4 or IL-13.^{13,14,15,16,17,18,19,20,21,22,23,24,25} In vitro-differentiated DCs show functional and phenotypic characteristics of immature DCs, able to capture and process antigens, that can be further differentiated in vitro into mature DCs with microbial agents, inflammatory cytokines or CD40L.¹

For a long time, the critical role of DCs in cancer was underscored by numerous reports in which the presence of DCs in tumor tissues was associated with good clinical prognosis of the disease.^26,27,28 However, more recently, several groups have described multiple defective functions of DCs in animal models and in cancer patients.^29,30,31,32 The major findings in these studies were the lack of expression of co-stimulatory molecules in tumor-associated DCs. For example, DCs infiltrating colon carcinoma were shown to express MHC class II molecules, but these cells did not express co-stimulatory molecules,³⁰ eg certain skin cancers where less than 1% of DCs expressed CD80 and CD86.^31,33 Consistent with these findings, tumor-associated DCs have a low allostimulatory capacity, particularly if isolated from progressing metastatic lesions as in malignant melanoma.³⁴ A population of DC isolated from the peripheral blood of patients with breast, head or neck cancer demonstrated significantly reduced ability to stimulate allogeneic and Ag-specific T cell responses.^35,36 DCs isolated from tumor-bearing mice were unable to induce effective peptide-specific and antitumor cytotoxic immune responses, and were therefore ineffective as a tumor vaccine.^37,38 To investigate defective DC functionality in tumor-bearing hosts, previous studies have shown that several tumor-derived factors such as VEGF, IL-6, IL-10, M-CSF and gangliosides can affect DC maturation in vitro^39,40,41 as well as other yet unspecified factors,⁴² and render tumor-specific T cells anergic through a variety of mechanisms, reducing the likelihood of effective CTL responses. All this accumulating evidence highlights the fact that DCs can be considered one of the key players of tumor escape from control by the immune system.

On the other hand, there is now some evidence that malignant cells of many tumor types may be immunologically recognized and eliminated.⁴³ The unique properties of DCs have suggested that they may have the potential to reverse the immunological unresponsiveness generally seen in cancer patients.^44,45 This can occur through a more effective presentation of tumor epitopes that may be more efficient inducers of helper and cytotoxic T cells. At present, there is no doubt that, at least in animal models, regression of established tumors or protection against tumors can be effectively induced by DCs.^46,47,48,49 A number of reports also show the clinical feasibility of DC-based immunotherapy in a wide variety of human cancers.^{50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65} Many of these ongoing clinical trials, that will not be described here in detail, provided encouraging results, but the real clinical benefit of this promising approach is still yet to be validated.

At present, little is known about the relationship between DCs and hematologic malignancies, with this field rapidly growing. Initial reports show that DC numbers can be increased in certain hematological diseases such as Hodgkin disease,⁶⁶ but the significance of this observation is unknown. Acute myeloid leukemia (AML) is characterized by clonal proliferation of hematopoietic myeloid progenitor cells that do not differentiate into functional leukocytes.^67,68 Self-renewal capacity of one or several leukemia-initiating cells is necessary to initiate the leukemic process, and is followed by a commitment of low proliferative blasts into particular lineages characterizing the different subtypes of AML. Interactions between DCs and AML cells might represent an attractive model where DCs can become a valuable therapeutic tool for the adjuvant treatment of leukemic patients. However, DC subsets in vivo may also be affected by leukemogenesis and may contribute to the escape of leukemia from immune control. The aim of this work is to shed further light on this paradoxical picture where the line between immune tolerance and immune defense is narrow.

Immunoregulatory dysfunction of leukemic DCs in vivo

The potency of DCs for induction of immune responses can be affected by a number of aspects related to their maturation stage and state of activation. As mentioned above, DCs in vivo might represent a favored target for cancer evasion from immune control through a number of different mechanisms, resulting in a lack of efficient immune response. The interference between DCs and hematological disorders, especially AML, is not yet well characterized. Numerous difficulties have to be overcome. One major issue being the lack of a simple and clear definition of a DC. In addition, uncertainty as to the ontogeny and differentiation pathways of DCs, limited and somewhat contradictory data as to the interrelationship, role and function of different DC subsets, raised unsolved questions. DCs are phenotypically and functionally heterogeneous in vivo. In humans, in addition to tissue-specific DCs, two distinct subsets of blood DCs have been characterized based on the differential expression of CD11c.⁶⁹ Myeloid DCs (MDC) and plasmacytoid DCs (PDC) were shown to be able to promote polarization of naive T cells into Th1 or Th2.^70,71,72,73 The balance of these cells in vivo determines the character of cell-mediated immune and inflammatory responses.⁷⁴ Recently, for the first time, we investigated the status of circulating peripheral blood DCs in 37 AML patients belonging to different FAB subtypes.⁷⁵ First, we asked whether circulating DCs could be detected in the peripheral blood of patients with AML. Next, we examined the functional properties of these cells. We could show a dramatic quantitative imbalance in blood DC subsets among the majority of patients. Both MDC and PDC subsets were found to exhibit the original leukemic chromosomal abnormality as visualized by FISH. Leukemic PDC had impaired in vitro maturation capacity, a decreased allostimulatory activity and were altered in their ability to secrete IFN- after microbial stimulation. Our results established a clear difference in the function of leukemic circulating DCs compared to their non-leukemic counterparts. Stimulation via CD40 pathway failed to enhance the allostimulatory capacity of PDC from leukemic patients, which is compatible with the absence or low expression of HLA-DR and costimulatory molecules.⁷⁵ Furthermore, defective function of leukemic PDC would have serious consequences on the induction of anti-leukemic immune response. The main distinguishing feature of PDC is their ability to secrete large quantities of IFN-.⁷⁶ The in vivo effects of type I IFN include a broad spectrum of cellular targets.^{77,78,79,80,81,82,83,84,85,86,87,88,89} IFN- could contribute in activating cytotoxic effector cells and helping to eradicate leukemic blasts. Thus, the PDC dysfunction can dysregulate the putative anti-leukemic immune response and can exert indirect potent immunosuppressive properties. Since AML encompasses a biologically heterogeneous group of clonal disorders of myeloid precursors, with multiple prognostic factors, therapeutic approaches and clinical outcomes, it is still difficult at this stage to draw conclusions as to the direct clinical relevance of expanded blood DCs in AML patients. Further studies are warranted to clarify these issues.

Furthermore, preliminary data from Chaperot et al⁹⁰ suggested that a rare sub-type of AML can arise from transformed cells of the lymphoid-related PDC subset. Although various aspects of this entity still remain controversial,⁹¹ the analysis of malignant cells from seven patients showed that the majority of CD4⁺CD56⁺ leukemic cells share some phenotypic and functional features with the normal PDC subset, suggesting that CD4⁺CD56⁺ leukemic cells could represent the malignant counterpart of PDC.⁹⁰ These data need yet to be confirmed in larger series, and the exact origin of this specific AML sub-type is now under investigation by different collaborative groups.⁹¹

The role of MDC in AML patients is less clear. Although immature circulating blood MDC have preserved maturation capacities after culture in vitro,⁷⁵ recent data suggest that immature monocyte-derived DCs can induce regulatory T cells both in vitro and in vivo.^92,93 Thus, these expanded immature MDC might induce regulatory or suppressive T cells impairing the quality of anti-leukemia immune response. This critical issue is now under intensive investigation in our laboratory.

Our observation that leukemic PDC, like leukemic MDC, can exhibit the same original chromosomal abnormality of the myeloid leukemic clone,⁷⁵ adds some knowledge to the understanding of DC ontogeny. It has been proposed that human circulating blood DCs may belong to distinct lineages.^76,94,95 However, despite an ever growing body of data, the phylogenetic affiliation of these cells remains controversial since they can differentiate from both lymphoid⁹⁶ and myeloid⁹⁴ progenitors. Our finding of a clonal relationship between MDC and PDC is in line with other data demonstrating that plasmacytoid T cell lymphoma cells, related to the PDC subset, can share a common precursor with myelomonocytic leukemic cells obtained from the same patients.^97,98,99 Our results support evidence that leukemia initiating progenitors are located at the very early level of hematopoietic stem cells, but also raise the intriguing possibility of the in vivo existence of an early common DC progenitor (CDCP) capable of giving rise to MDC or PDC under specific circumstances that do not necessarily belong to distinct and completely independent lineages. This hypothesis is in line with recent data reporting in a mouse model the characterization of a DC-committed precursor population, which has the capacity to generate all the DC subpopulations present in mouse lymphoid organs, but which is devoid of myeloid or lymphoid differentiation potential. These data support an alternative model of DC development, in which there is an independent, common DC differentiation pathway.¹⁰⁰ Therefore, it can be proposed that an oncogenic event associated with the leukemic transformation, can affect this CDCP and thus, be responsible for the defective functions of leukemic DCs in vivo.

Overall, this rapidly growing body of data brings new insights towards understanding of AML biology, offers a unique opportunity to decipher the mechanisms regulating DC ontogeny, and provides evidence that DC subsets and dendritopoiesis in vivo are affected by leukemogenesis and may contribute to the escape of leukemia from immune control.

Potential therapy with leukemia-derived DCs

Allogeneic bone marrow transplantation has proven to be an efficient treatment for patients with AML.^{101,102,103,104,105,106,107} This is mainly attributed to the so-called graft-versus-leukemia effect mediated by the donor-derived immune system, especially T cells.¹⁰⁸ Thus, modulation of the immune system appears to be an attractive modality for the treatment of AML patients, especially those patients at high risk of relapse who cannot benefit from allogeneic stem cell transplantation. More than 20 years ago, some patients with AML received pooled, irradiated allogeneic leukemic cells in order to enhance their immune system.¹⁰⁹ At present, donor lymphocyte infusions (DLI) following allogeneic stem cell transplantation is the treatment of choice for relapse in chronic and acute myeloid leukemia.¹¹⁰ Unfortunately, DLI is less successful in the treatment of AML patients. One possible reason for this decreased efficiency could be related to the fact that AML blasts are poor APCs devoid of co-stimulatory molecules^{111,112,113,114} and thus, fail to induce a potent and sustained antileukemic immune response.¹¹⁵

We and other investigators have described the successful differentiation of leukemia-derived DCs from patients with AML. The original observation that the leukemic blasts of AML may express the features of the well-known monocyte-derived DC subset was made by Santiago-Schwarz et al in 1994.¹¹⁶ Subsequently and simultaneously with the MD Anderson group, we were able to show that myeloid blasts may be driven to differentiate ex vivo into fully functional DCs capable of inducing leukemia-specific CTL.^117,118 These leukemia-derived DCs could be obtained after a short-term culture in the presence of GM-CSF, IL-4 and CD40L. They exhibited a typical DC morphology, had a phenotype of mature DCs, especially the expression of co-stimulatory molecules, and could induce a potent proliferative response in naive CD4⁺ T cells, while still retaining the leukemic chromosomal abnormality of the original blasts as ascertained by FISH. These cells secreted significant amounts of IL-12p70, and in some cases highly efficient autologous leukemia-specific CTL were obtained.¹¹⁷ All these features are in accordance with DC properties currently accepted for the characterization of DC subsets.¹¹⁹ Similar findings have since been reported by other investigators.^{120,121,122,123,124,125,126,127,128,129,130,131,132} The high number of efficient co-stimulatory, adhesion and MHC molecules present on the membrane of these leukemic DCs could allow recruitment and activation of the rare specific anti-tumoral T cells that are supposed to belong to the naive lymphocyte pool. Moreover, to overcome the absence of identified leukemia-associated antigens, in the case of leukemic DCs, tumor cells themselves are used as immunogens. The latter could allow the induction of a T cell response against a wide variety of peptides, which would avoid their escape from CTL specific for one peptide only. In addition, this approach can allow bypassing the potential obstacle represented by the defective function of DCs demonstrated in vivo.

Unfortunately, in all published studies, including the report from our group and despite the use of a great variety of cytokine combinations, leukemia-derived DCs could not be obtained from all AML patients. Furthermore, yields of leukemic DC were very heterogeneous between patients, even among patients with the same leukemia subtype. In all the aforementioned studies, it was not possible to postulate any characteristic of leukemic cells predictive for the ability to generate DC. Since leukemic blasts are heterogeneous at the stage of maturation, we raised the question of the nature of the blast compartment that can be induced to acquire DC features in vitro. Our aim was to identify a blast subset capable of giving rise to fully functional leukemic DCs after a short-term culture with a minimal combination of cytokines. Such a rapid and predefined culture protocol, avoiding patienttailored techniques, long-term in vitro manipulations and complex and expensive cytokine combinations would allow access to this strategy to the highest number of patients. We could demonstrate that in most cases, CD14⁺ blasts are the cells capable of differentiating into fully functional DCs after a short-term culture (5 to 7 days) in the presence of GM-CSF and IL-4 or GM-CSF and clinical grade IL-13. For clinical application, these cells could also be grown in clinical grade serum-free medium (Mohty et al, unpublished observations).

Another major feature of DC physiology concerns the expression of chemokine receptors. Chemokines and their receptors play a critical role in the selective attraction of various subsets of leukocytes and DCs. Along with the acquisition of adhesion and costimulatory molecules, the immune response requires a timely interaction among different cell types within distinct microenvironments. The migration of DCs to the secondary lymphoid organs is believed to be one of the critical events.¹³³ CCR-7 is a very important receptor for T lymphocyte and DC trafficking to secondary lymphoid organs through high endothelial venules. As a way of understanding the regulation of leukemia-derived DCs migration, we examined the chemokine receptor expression on their surface in comparison to normal mature monocyte-derived DCs. Flow cytometry analysis revealed that after maturation, leukemia-derived DCs do not express CCR-5, a marker of immature DCs, but could acquire the expression of CCR-7 (Mohty et al, unpublished observations). Although transmigration studies are needed before drawing firm conclusions as to the functional significance of CCR-7 expression, after injection in vivo, it could be hypothesized that these leukemia-derived DCs would be trapped in T cell areas of lymph nodes where the initiation of immune responses take place. In addition, for optimal efficiency, one could assume that leukemia-derived DCs must already retain at least some leukemia-related proteins avoiding the antigen capture step and homing directly into lymph nodes where they would be able to initiate an efficient anti-tumor immune response. In this respect, a critical parameter is to retain integrity of tumor-associated antigens during in vitro differentiation. All investigators who performed FISH analysis confirmed that leukemia-derived DCs still retain the same cytogenetic aberration expressed by the non-differentiated leukemic blasts. Therefore, leukemia-derived DCs from AML patients may retain at least some features of the malignant clone like some leukemia-related proteins associated with the cytogenetic abnormality. Although the latter does not necessarily mean that they will be efficiently presented to T cells, one could assume that leukemia-derived DCs, while directing a Th1 response profile, will help in generating antileukemic cytotoxic responses better than fresh tumor cells. Indeed, in our recent work, we have shown that CD14⁺ blast-derived DCs can drive naive T cells towards a Th1 response with secretion of IFN- (Mohty et al, unpublished observations). It has been demonstrated that the immune balance (Th1/Th2 balance) controlled by cytokines produced by Th1 and Th2 cells plays an important role in immune regulation, including anti-tumor immunity.¹³⁴ The balance of these cells in vivo determines the character of cell-mediated immune and inflammatory responses.⁷⁴ Although it remains unclear how Th1 or Th2 immunity is involved in in vivo anti-tumor responses, several studies suggested that Th1 dominant immunity is superior in the induction of cytolytic effectors.^{135,136,137,138,139,140,141,142,143,144,145,146,147,148,149} The Th1 cells that produce IFN- have been shown to exert a powerful anti-tumor effect, whereas a Th2 profile may have an opposite effect, that is, down-regulation of innate and acquired anti-tumor immunity. The corollary of these observations is that a Th1 profile may be cancer protective, whereas a Th2 profile may promote tumor growth and dissemination.

The strategy leading to induction or increase of AML cells immunogenicity while acquiring essential chemokine receptors for trafficking into secondary lymphoid organs, may help in vivo to generate anti-leukemia cytotoxic T cell effectors in an autologous setting, or identify AML tumor-associated antigens that might prove active as a cell-free vaccine. Moreover, this strategy is also ripe for therapeutic manipulations and refinement in the allogeneic setting. Prior to DLI, leukemia-derived DCs might be used in vitro to elicit a more active, specific and less toxic responder antileukemic T cells in the pool of allogeneic donor lymphocytes. This strategy can minimize the possible deleterious complications of graft-versus-host disease usually associated with allogeneic DLI.¹¹⁰

Studies of leukemic DCs provide new insights towards understanding both leukemogenesis and the physiology of DCs, and illustrate the fine line between immune tolerance and activation. In AML and other leukemias, the generation of potent tumor-specific cytotoxic effectors capable of tumor control may be subsequently counterbalanced by a variety of mechanisms leading to anergy. The availability of leukemia-derived DCs and their capacity to enhance tumor recognition is a promising approach to immunotherapy in AML, paving the way for therapeutic options in other hematological malignancies. The design of a clinical DC-based vaccine immunotherapy protocol requires a concise functional characterization of DCs as well as reflection on the crucial role of route and timing of vaccine delivery to ensure potent specific cytotoxic effectors and helper T lymphocytes. If DC-based therapy is to benefit patients, this will probably be in the setting of minimal residual disease following or accompanying other established therapies. The optimization of DC-based vaccines ranks on the same level as the development of sensitive techniques to monitor minimal residual disease and reliable methods of measuring patient responses to DC vaccines.

Acknowledgements

This work was supported by a grant from the 'Fondation de France', and from the 'Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)' (to M Mohty) Paris, France. We would like to thank Pr Didier Blaise (Institut Paoli-Calmettes) for his continuous support, helpful discussions and critical reading of the manuscript.

1 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392: 245-252. Article MEDLINE

2 Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 1992; 360: 258-261. MEDLINE

3 Santiago-Schwarz F, Belilos E, Diamond B, Carsons SE. TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages. J Leukoc Biol 1992; 52: 274-281.

4 Santiago-Schwarz F, Divaris N, Kay C, Carsons SE. Mechanisms of tumor necrosis factor-granulocyte-macrophage colonystimulating factor-induced dendritic cell development. Blood 1993; 82: 3019-3028.

5 Szabolcs P, Feller ED, Moore MA, Young JW. Progenitor recruitment and in vitro expansion of immunostimulatory dendritic cells from human CD34+ bone marrow cells by c-kit-ligand, GM-CSF, and TNF alpha. Adv Exp Med Biol 1995; 378: 17-20. MEDLINE

6 Santiago-Schwarz F, Rappa DA, Laky K, Carsons SE. Stem cell factor augments tumor necrosis factor-granulocyte-macrophage colony-stimulating factor-mediated dendritic cell hematopoiesis. Stem Cells 1995; 13: 186-197.

7 Young JW, Szabolcs P, Moore MA. Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. J Exp Med 1995; 182: 1111-1119. MEDLINE

8 Strunk D, Rappersberger K, Egger C, Strobl H, Kromer E, Elbe A, Maurer D, Stingl G. Generation of human dendritic cells/Langerhans cells from circulating CD34+ hematopoietic progenitor cells. Blood 1996; 87: 1292-1302. MEDLINE

9 Saraya K, Reid CD. Stem cell factor and the regulation of dendritic cell production from CD34+ progenitors in bone marrow and cord blood. Br J Haematol 1996; 93: 258-264. MEDLINE

10 Caux C, Vanbervliet B, Massacrier C, Dezutter-Dambuyant C, de Saint-Vis B, Jacquet C, Yoneda K, Imamura S, Schmitt D, Banchereau J. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. J Exp Med 1996; 184: 695-706. MEDLINE

11 Szabolcs P, Ciocon DH, Moore MA, Young JW. Growth and differentiation of human dendritic cells from CD34+ progenitors. Adv Exp Med Biol 1997; 417: 15-19.

12 Caux C, Massacrier C, Vanbervliet B, Dubois B, Durand I, Cella M, Lanzavecchia A, Banchereau J. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor alpha: II. Functional analysis. Blood 1997; 90: 1458-1470. MEDLINE

13 Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994; 179: 1109-1118. MEDLINE

14 Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch PO, Steinman RM, Schuler G. Proliferating dendritic cell progenitors in human blood. J Exp Med 1994; 180: 83-93. MEDLINE

15 Xu H, Kramer M, Spengler HP, Peters JH. Dendritic cells differentiated from human monocytes through a combination of IL-4, GM-CSF and IFN-gamma exhibit phenotype and function of blood dendritic cells. Adv Exp Med Biol 1995; 378: 75-78.

16 Piemonti L, Bernasconi S, Luini W, Trobonjaca Z, Minty A, Allavena P, Mantovani A. IL-13 supports differentiation of dendritic cells from circulating precursors in concert with GM-CSF. Eur Cytokine Netw 1995; 6: 245-252.

17 Kiertscher SM, Roth MD. Human CD14+ leukocytes acquire the phenotype and function of antigen-presenting dendritic cells when cultured in GM-CSF and IL-4. J Leukoc Biol 1996; 59: 208-218. MEDLINE

18 Pickl WF, Majdic O, Kohl P, Stockl J, Riedl E, Scheinecker C, Bello-Fernandez C, Knapp W. Molecular and functional characteristics of dendritic cells generated from highly purified CD14+ peripheral blood monocytes. J Immunol 1996; 157: 3850-3859. MEDLINE

19 Chapuis F, Rosenzwajg M, Yagello M, Ekman M, Biberfeld P, Gluckman JC. Differentiation of human dendritic cells from monocytes in vitro. Eur J Immunol 1997; 27: 431-441.

20 Morse MA, Zhou LJ, Tedder TF, Lyerly HK, Smith C. Generation of dendritic cells in vitro from peripheral blood mononuclear cells with granulocyte-macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha for use in cancer immunotherapy. Ann Surg 1997; 226: 6-16. Article MEDLINE

21 Sung SS, Guo CY, Weed JM. Monoclonal antibodies against human dendritic cell-like peripheral blood monocytes activated by granulocyte/macrophage-colony-stimulating factor plus interleukin 4. Cell Immunol 1997; 182: 113-124.

22 Sato K, Nagayama H, Tadokoro K, Juji T, Takahashi TA. Interleukin-13 is involved in functional maturation of human peripheral blood monocyte-derived dendritic cells. Exp Hematol 1999; 27: 326-336.

23 Alters SE, Gadea JR, Holm B, Lebkowski J, Philip R. IL-13 can substitute for IL-4 in the generation of dendritic cells for the induction of cytotoxic T lymphocytes and gene therapy. J Immunother 1999; 22: 229-236.

24 Morse MA, Lyerly HK, Li Y. The role of IL-13 in the generation of dendritic cells in vitro. J Immunother 1999; 22: 506-513.

25 Zheng Z, Takahashi M, Narita M, Toba K, Liu A, Furukawa T, Koike T, Aizawa Y. Generation of dendritic cells from adherent cells of cord blood by culture with granulocyte-macrophagecolony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha. J Hematother Stem Cell Res 2000; 9: 453-464.

26 Ambe K, Mori M, Enjoji M. S-100 protein-positive dendritic cells in colorectal adenocarcinomas. Distribution and relation to the clinical prognosis. Cancer 1989; 63: 496-503. MEDLINE

27 Fox SB, Jones M, Dunnill MS, Gatter KC, Mason DY. Langerhans cells in human lung tumours: an immunohistological study. Histopathology 1989; 14: 269-275.

28 Schroder S, Schwarz W, Rehpenning W, Loning T, Bocker W. Dendritic/Langerhans cells and prognosis in patients with papillary thyroid carcinomas. Immunocytochemical study of 106 thyroid neoplasms correlated to follow-up data. Am J Clin Pathol 1988; 89: 295-300. MEDLINE

29 Thurnher M, Radmayr C, Ramoner R, Ebner S, Bock G, Klocker H, Romani N, Bartsch G. Human renal-cell carcinoma tissue contains dendritic cells. Int J Cancer 1996; 68: 1-7. MEDLINE

30 Chaux P, Moutet M, Faivre J, Martin F, Martin M. Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7-1 and B7-2 costimulatory molecules of the T-cell activation. Lab Invest 1996; 74: 975-983. MEDLINE

31 Nestle FO, Burg G, Fah J, Wrone-Smith T, Nickoloff BJ. Human sunlight-induced basal-cell-carcinoma-associated dendritic cells are deficient in T cell co-stimulatory molecules and are impaired as antigen-presenting cells. Am J Pathol 1997; 150: 641-651. MEDLINE

32 Chaux P, Favre N, Martin M, Martin F. Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats. Int J Cancer 1997; 72: 619-624. Article MEDLINE

33 Viac J, Schmitt D, Claudy A. CD40 expression in epidermal tumors. Anticancer Res 1997; 17: 569-572. MEDLINE

34 Enk AH, Jonuleit H, Saloga J, Knop J. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer 1997; 73: 309-316. Article MEDLINE

35 Tas MP, Simons PJ, Balm FJ, Drexhage HA. Depressed monocyte polarization and clustering of dendritic cells in patients with head and neck cancer: in vitro restoration of this immunosuppression by thymic hormones. Cancer Immunol Immunother 1993; 36: 108-114.

36 Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP. Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 1997; 3: 483-490. MEDLINE

37 Gabrilovich DI, Nadaf S, Corak J, Berzofsky JA, Carbone DP. Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. Cell Immunol 1996; 170: 111-119. Article MEDLINE

38 Gabrilovich DI, Ciernik IF, Carbone DP. Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 1996; 170: 101-110. Article MEDLINE

39 Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2: 1096-1103. MEDLINE

40 Ishida T, Oyama T, Carbone DP, Gabrilovich DI. Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hemopoietic progenitors. J Immunol 1998; 161: 4842-4851. MEDLINE

41 Steinbrink K, Jonuleit H, Muller G, Schuler G, Knop J, Enk AH. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 1999; 93: 1634-1642. MEDLINE

42 Buggins AG, Lea N, Gaken J, Darling D, Farzaneh F, Mufti GJ, Hirst WJ. Effect of costimulation and the microenvironment on antigen presentation by leukemic cells. Blood 1999; 94: 3479-3490. MEDLINE

43 Houghton AN. Cancer antigens: immune recognition of self and altered self. J Exp Med 1994; 180: 1-4. MEDLINE

44 Young JW, Inaba K. Dendritic cells as adjuvants for class I major histocompatibility complex-restricted antitumor immunity. J Exp Med 1996; 183: 7-11. MEDLINE

45 Schuler G, Steinman RM. Dendritic cells as adjuvants for immune-mediated resistance to tumors. J Exp Med 1997; 186: 1183-1187. Article MEDLINE

46 Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 1994; 264: 961-965. MEDLINE

47 Porgador A, Gilboa E. Bone marrow-generated dendritic cells pulsed with a class I-restricted peptide are potent inducers of cytotoxic T lymphocytes. J Exp Med 1995; 182: 255-260. MEDLINE

48 Zitvogel L, Mayordomo JI, Tjandrawan T, DeLeo AB, Clarke MR, Lotze MT, Storkus WJ. Therapy of murine tumors with tumorpeptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med 1996; 183: 87-97. MEDLINE

49 Toes RE, Ossendorp F, Offringa R, Melief CJ. CD4 T cells and their role in antitumor immune responses. J Exp Med 1999; 189: 753-756. Article MEDLINE

50 Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998; 4: 328-332. MEDLINE

51 Thurner B, Haendle I, Roder C, Dieckmann D, Keikavoussi P, Jonuleit H, Bender A, Maczek C, Schreiner D, von den Driesch P, Brocker EB, Steinman RM, Enk A, Kampgen E, Schuler G. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 1999; 190: 1669-1678. Article MEDLINE

52 Fujii S, Shimizu K, Fujimoto K, Kiyokawa T, Shimomura T, Kinoshita M, Kawano F. Analysis of a chronic myelogenous leukemia patient vaccinated with leukemic dendritic cells following autologous peripheral blood stem cell transplantation. Jpn J Cancer Res 1999; 90: 1117-1129. MEDLINE

53 Titzer S, Christensen O, Manzke O, Tesch H, Wolf J, Emmerich B, Carsten C, Diehl V, Bohlen H. Vaccination of multiple myeloma patients with idiotype-pulsed dendritic cells: immunological and clinical aspects. Br J Haematol 2000; 108: 805-816. Article MEDLINE

54 Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Pennington R, Watson TM, Reynolds CW, Gause BL, Duffey PL, Jaffe ES, Creekmore SP, Longo DL, Kwak LW. Complete molecular remissions induced by patient-specific vaccination plusgranulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med 1999; 5: 1171-1177. Article MEDLINE

55 Kugler A, Stuhler G, Walden P, Zoller G, Zobywalski A, Brossart P, Trefzer U, Ullrich S, Muller CA, Becker V, Gross AJ, Hemmerlein B, Kanz L, Muller GA, Ringert RH. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med 2000; 6: 332-336. Article MEDLINE

56 Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 2000; 96: 3102-3108. MEDLINE

57 Lau R, Wang F, Jeffery G, Marty V, Kuniyoshi J, Bade E, Ryback ME, Weber J. Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma. J Immunother 2001; 24: 66-78.

58 Rains N, Cannan RJ, Chen W, Stubbs RS. Development of a dendritic cell (DC)-based vaccine for patients with advanced colorectal cancer. Hepatogastroenterology 2001; 48: 347-351.

59 Sadanaga N, Nagashima H, Mashino K, Tahara K, Yamaguchi H, Ohta M, Fujie T, Tanaka F, Inoue H, Takesako K, Akiyoshi T, Mori M. Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas. Clin Cancer Res 2001; 7: 2277-2284. MEDLINE

60 Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 2001; 61: 6451-6458. MEDLINE

61 Geiger JD, Hutchinson RJ, Hohenkirk LF, McKenna EA, Yanik GA, Levine JE, Chang AE, Braun TM, Mule JJ. Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res 2001; 61: 8513-8519. MEDLINE

62 Andersen MH, Keikavoussi P, Brocker EB, Schuler-Thurner B, Jonassen M, Sondergaard I, Straten PT, Becker JC, Kampgen E. Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: cessation of CTL responses is associated with disease progression. Int J Cancer 2001; 94: 820-824.

63 Hernando J, Park TW, Kubler K, Offergeld R, Schlebusch H, Bauknecht T. Vaccination with autologous tumour antigen-pulsed dendritic cells in advanced gynaecological malignancies: clinical and immunological evaluation of a phase I trial. Cancer Immunol Immunother 2002; 51: 45-52.

64 Santin AD, Bellone S, Ravaggi A, Roman JJ, Pecorelli S, Parham GP, Cannon MJ. Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer. Br J Cancer 2002; 86: 151-157.

65 Timmerman JM, Czerwinski DK, Davis TA, Hsu FJ, Benike C, Hao ZM, Taidi B, Rajapaksa R, Caspar CB, Okada CY, vanBeckhoven A, Liles TM, Engleman EG, Levy R. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 2002; 99: 1517-1526. MEDLINE

66 Facchetti F, De Wolf-Peeters C, van den Oord JJ, Desmet VJ. Plasmacytoid monocytes (so-called plasmacytoid T cells) in Hodgkin's disease. J Pathol 1989; 158: 57-65. MEDLINE

67 Fialkow PJ, Singer JW, Raskind WH, Adamson JW, Jacobson RJ, Bernstein ID, Dow LW, Najfeld V, Veith R. Clonal development, stem-cell differentiation, and clinical remissions in acute nonlymphocytic leukemia. N Engl J Med 1987; 317: 468-473.

68 Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730-737. MEDLINE

69 Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med 1997; 185: 1101-1111. Article MEDLINE

70 Rissoan MC, Soumelis V, Kadowaki N, Grouard G, Briere F, de Waal Malefyt R, Liu YJ. Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999; 283: 1183-1186. Article MEDLINE

71 Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 1999; 5: 919-923. Article MEDLINE

72 Cella M, Facchetti F, Lanzavecchia A, Colonna M. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization. Nat Immunol 2000; 1: 305-310. Article MEDLINE

73 Kadowaki N, Antonenko S, Lau JY, Liu YJ. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J Exp Med 2000; 192: 219-226. Article MEDLINE

74 Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383: 787-793. MEDLINE

75 Mohty M, Jarrossay D, Lafage-Pochitaloff M, Zandotti C, Briere F, de Lamballeri XN, Isnardon D, Sainty D, Olive D, Gaugler B. Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment. Blood 2001; 98: 3750-3756. MEDLINE

76 Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Liu YJ. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999; 284: 1835-1837. Article MEDLINE

77 Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli H, Afkarian M, Murphy TL. Signaling and transcription in T helper development. Annu Rev Immunol 2000; 18: 451-494. Article MEDLINE

78 Pfeffer LM, Dinarello CA, Herberman RB, Williams BR, Borden EC, Bordens R, Walter MR, Nagabhushan TL, Trotta PP, Pestka S. Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Res 1998; 58: 2489-2499. MEDLINE

79 Marrack P, Kappler J, Mitchell T. Type I interferons keep activated T cells alive. J Exp Med 1999; 189: 521-530. Article MEDLINE

80 Sun S, Zhang X, Tough DF, Sprent J. Type I interferon-mediated stimulation of T cells by CpG DNA. J Exp Med 1998; 188: 2335-2342.

81 Morris A, Zvetkova I. Cytokine research: the interferon paradigm. J Clin Pathol 1997; 50: 635-639.

82 Cataldi A, Santavenere E, Vitale M, Trubiani O, Lisio R, Tulipano G, Di Domenicantonio L, Zamai L, Miscia S. Interferon affects cell growth progression by modulating DNA polymerases activity. Cell Prolif 1992; 25: 225-231.

83 Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J Exp Med 1993; 178: 1655-1663. MEDLINE

84 Finkelman FD, Holmes J, Katona IM, Urban JF Jr, Beckmann MP, Park LS, Schooley KA, Coffman RL, Mosmann TR, Paul WE. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol 1990; 8: 303-333. Article MEDLINE

85 Demeure CE, Wu CY, Shu U, Schneider PV, Heusser C, Yssel H, Delespesse G. In vitro maturation of human neonatal CD4 T lymphocytes. II. Cytokines present at priming modulate the development of lymphokine production. J Immunol 1994; 152: 4775-4782.

86 Biron CA. Activation and function of natural killer cell responses during viral infections. Curr Opin Immunol 1997; 9: 24-34.

87 Kayagaki N, Yamaguchi N, Nakayama M, Eto H, Okumura K, Yagita H. Type I interferons (IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on human T cells: A novel mechanism for the antitumor effects of type I IFNs. J Exp Med 1999; 189: 1451-1460. Article MEDLINE

88 Rogge L, D'Ambrosio D, Biffi M, Penna G, Minetti LJ, Presky DH, Adorini L, Sinigaglia F. The role of Stat4 in species-specific regulation of Th cell development by type I IFNs. J Immunol 1998; 161: 6567-6574. MEDLINE

89 Schmid DS, Rouse BT. The role of T cell immunity in control of herpes simplex virus. Curr Top Microbiol Immunol 1992; 179: 57-74. MEDLINE

90 Chaperot L, Bendriss N, Manches O, Gressin R, Maynadie M, Trimoreau F, Orfeuvre H, Corront B, Feuillard J, Sotto JJ, Bensa JC, Briere F, Plumas J, Jacob MC. Identification of a leukemic counterpart of the plasmacytoid dendritic cells. Blood 2001; 97: 3210-3217.

91 Feuillard J, Jacob MC, Valensi F, Maynadie M, Gressin R, Chaperot L, Arnoulet C, Brignole-Baudouin F, Drenou B, Duchayne E, Falkenrodt A, Garand R, Homolle E, Husson B, Kuhlein E, Le Calvez G, Sainty D, Sotto MF, Trimoreau F, Bene MC. Clinical and biologic features of CD4+CD56+malignancies. Blood 2002; 99: 1556-1563.

92 Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000; 192: 1213-1222. Article MEDLINE

93 Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 2001; 193: 233-238. Article MEDLINE

94 Young JW, Steinman RM. The hematopoietic development of dendritic cells: a distinct pathway for myeloid differentiation. Stem Cells 1996; 14: 376-387. MEDLINE

95 Shortman K, Caux C. Dendritic cell development: multiple pathways to nature's adjuvants. Stem Cells 1997; 15: 409-419.

96 Ardavin C, Wu L, Li CL, Shortman K. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature 1993; 362: 761-763. MEDLINE

97 Baddoura FK, Hanson C, Chan WC. Plasmacytoid monocyte proliferation associated with myeloproliferative disorders. Cancer 1992; 69: 1457-1467.

98 Mongkonsritragoon W, Letendre L, Qian J, Li CY. Nodular lesions of monocytic component in myelodysplastic syndrome. Am J Clin Pathol 1998; 110: 154-162.

99 Ferry JA, Harris NL. Plasmacytoid monocytes? Am J Clin Pathol 1999; 111: 569.

100 del Hoyo GM, Martin P, Vargas HH, Ruiz S, Arias CF, Ardavin C. Characterization of a common precursor population for dendritic cells. Nature 2002; 415: 1043-1047.

101 Appelbaum FR. Allogeneic hematopoietic stem cell transplantation for acute leukemia. Semin Oncol 1997; 24: 114-123. MEDLINE

102 Proctor SJ, Taylor PR, Stark A, Carey PJ, Bown N, Hamilton PJ, Reid MM. Evaluation of the impact of allogenic transplant in first remission on an unselected population of patients with acute myeloid leukaemia aged 15-55 years. The Northern Regional Haematology Group. Leukemia 1995; 9: 1246-1251.

103 Morley AA. Treatment of acute myelogenous leukemia. N Engl J Med 1995; 332: 1717, discussion. 1718-1719.

104 Jourdan E, Maraninchi D, Reiffers J, Archimbaud E, Michallet M, Harousseau JL, Ifrah N, Rio B, Guyotat D, Guilhot F. Allogeneic bone marrow transplantation remains an efficient consolidation for adults with acute myeloid leukemia even when performed very soon after diagnosis. The SFGM (Societe Francaise de Greffe de Moelle). Leukemia 1995; 9: 1068-1071.

105 Lowenberg B. Post-remission treatment of acute myelogenous leukemia. N Engl J Med 1995; 332: 260-262.

106 Bortin MM, Horowitz MM, Gale RP, Barrett AJ, Champlin RE, Dicke KA, Gluckman E, Kolb HJ, Marmont AM, Mrsic M. Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s. JAMA 1992; 268: 607-612. MEDLINE

107 Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie A, Jouet JP, Milpied N, Attal M, Michallet M, Ifrah N. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse. Blood 1992; 79: 2578-2582. MEDLINE

108 Antin JH. Graft-versus-leukemia: no longer an epiphenomenon. Blood 1993; 82: 2273-2277. MEDLINE

109 Powles RL, Russell J, Lister TA, Oliver T, Whitehouse JM, Malpas J, Chapuis B, Crowther D, Alexander P. Immunotherapy for acute myelogenous leukaemia: a controlled clinical study 2 1/2 years after entry of the last patient. Br J Cancer 1977; 35: 265-272.

110 Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 1995; 86: 2041-2050. MEDLINE

111 Costello RT, Mallet F, Sainty D, Maraninchi D, Gastaut JA, Olive D. Regulation of CD80/B7-1 and CD86/B7-2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition. Eur J Immunol 1998; 28: 90-103. Article MEDLINE

112 Boyer MW, Vallera DA, Taylor PA, Gray GS, Katsanis E, Gorden K, Orchard PJ, Blazar BR. The role of B7 costimulation by murine acute myeloid leukemia in the generation and function of a CD8+ T-cell line with potent in vivo graft-versus-leukemia properties. Blood 1997; 89: 3477-3485. MEDLINE

113 Mutis T, Schrama E, Melief CJ, Goulmy E. CD80-Transfected acute myeloid leukemia cells induce primary allogeneic T-cell responses directed at patient specific minor histocompatibility antigens and leukemia-associated antigens. Blood 1998; 92: 1677-1684. MEDLINE

114 Matulonis U, Dosiou C, Freeman G, Lamont C, Mauch P, Nadler LM, Griffin JD. B7-1 is superior to B7-2 costimulation in the induction and maintenance of T cell-mediated antileukemia immunity. Further evidence that B7-1 and B7-2 are functionally distinct. J Immunol 1996; 156: 1126-1131. MEDLINE

115 Falkenburg JH, Smit WM, Willemze R. Cytotoxic T-lymphocyte (CTL) responses against acute or chronic myeloid leukemia. Immunol Rev 1997; 157: 223-230. MEDLINE

116 Santiago-Schwarz F, Coppock DL, Hindenburg AA, Kern J. Identification of a malignant counterpart of the monocyte-dendritic cell progenitor in an acute myeloid leukemia. Blood 1994; 84: 3054-3062. MEDLINE

117 Charbonnier A, Gaugler B, Sainty D, Lafage-Pochitaloff M, Olive D. Human acute myeloblastic leukemia cells differentiate in vitro into mature dendritic cells and induce the differentiation of cytotoxic T cells against autologous leukemias. Eur J Immunol 1999; 29: 2567-2578. Article MEDLINE

118 Choudhury BA, Liang JC, Thomas EK, Flores-Romo L, Xie QS, Agusala K, Sutaria S, Sinha I, Champlin RE, Claxton DF. Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. Blood 1999; 93: 780-786. MEDLINE

119 Hart DN. Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 1997; 90: 3245-3287. MEDLINE

120 Robinson SP, English N, Jaju R, Kearney L, Knight SC, Reid CD. The in-vitro generation of dendritic cells from blast cells in acute leukaemia. Br J Haematol 1998; 103: 763-771. MEDLINE

121 Cignetti A, Bryant E, Allione B, Vitale A, Foa R, Cheever MA. CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells. Blood 1999; 94: 2048-2055. MEDLINE

122 Brouwer RE, van der Hoorn M, Kluin-Nelemans HC, vanZelderen-Bhola S, Willemze R, Falkenburg JH. The generation ofdendritic-like cells with increased allostimulatory function from acute myeloid leukemia cells of various FAB subclasses. Hum Immunol 2000; 61: 565-574. MEDLINE

123 Oehler L, Berer A, Kollars M, Keil F, Konig M, Waclavicek M, Haas O, Knapp W, Lechner K, Geissler K. Culture requirements for induction of dendritic cell differentiation in acute myeloid leukemia. Ann Hematol 2000; 79: 355-362. Article MEDLINE

124 Kohler T, Plettig R, Wetzstein W, Schmitz M, Ritter M, Mohr B, Schaekel U, Ehninger G, Bornhauser M. Cytokine-driven differentiation of blasts from patients with acute myelogenous and lymphoblastic leukemia into dendritic cells. Stem Cells 2000; 18: 139-147. MEDLINE

125 Harrison BD, Adams JA, Briggs M, Brereton ML, Yin JA. Stimulation of autologous proliferative and cytotoxic T-cell responses by 'leukemic dendritic cells' derived from blast cells in acute myeloid leukemia. Blood 2001; 97: 2764-2771. Article MEDLINE

126 Woiciechowsky A, Regn S, Kolb HJ, Roskrow M. Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia. Leukemia 2001; 15: 246-255.

127 Hulette BC, Rowden G, Ryan CA, Lawson CM, Dawes SM, Ridder GM, Gerberick GF. Cytokine induction of a human acute myelogenous leukemia cell line (KG-1) to a CD1a+ dendritic cell phenotype. Arch Dermatol Res 2001; 293: 147-158.

128 Hagihara M, Shimakura Y, Tsuchiya T, Ueda Y, Gansuvd B, Munkhbat B, Chargui J, Ando K, Kato S, Hotta T. The efficient generation of CD83 positive immunocompetent dendritic cells from CD14 positive acute myelomonocytic or monocytic leukemia cells in vitro. Leuk Res 2001; 25: 249-258.

129 Narita M, Takahashi M, Liu A, Ayres F, Satoh N, Abe T, Nikkuni K, Furukawa T, Toba K, Aizawa Y. Generation of dendritic cells from leukaemia cells of a patient with acute promyelocytic leukaemia by culture with GM-CSF, IL-4 and TNF-alpha. Acta Haematol 2001; 106: 89-94.

130 Rigolin GM, Della Porta M, Bigoni R, Tieghi A, Cuneo A, Castoldi G. Dendritic cells in acute promyelocytic leukaemia. Br J Haematol 2001; 114: 830-833.

131 Panoskaltsis N, Belanger TJ, Liesveld JL, Abboud CN. Optimal cytokine stimulation for the enhanced generation of leukemic dendritic cells in short-term culture. Leuk Res 2002; 26: 191-201.

132 Re F, Arpinati M, Testoni N, Ricci P, Terragna C, Preda P, Ruggeri D, Senese B, Chirumbolo G, Martelli V, Urbini B, Baccarani M, Tura S, Rondelli D. Expression of CD86 in acute myelogenous leukemia is a marker of dendritic/monocytic lineage. Exp Hematol 2002; 30: 126-134.

133 Sallusto F, Lanzavecchia A. Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression. Immunol Rev 2000; 177: 134-140. MEDLINE

134 Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996; 17: 138-146. Article MEDLINE

135 Powrie F, Menon S, Coffman RL. Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol 1993; 23: 3043-3049. MEDLINE

136 Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 1993; 5: 1461-1471. MEDLINE

137 Powrie F, Coffman RL. Inhibition of cell-mediated immunity by IL4 and IL10. Res Immunol 1993; 144: 639-643.

138 Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, Sato T, Habu S, Tashiro H, Sato M, Ohta A. Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo. J Exp Med 1999; 190: 617-627. Article MEDLINE

139 Egeter O, Mocikat R, Ghoreschi K, Dieckmann A, Rocken M. Eradication of disseminated lymphomas with CpG-DNA activated T helper type 1 cells from nontransgenic mice. Cancer Res 2000; 60: 1515-1520. MEDLINE

140 Song K, Chang Y, Prud'homme GJ. Regulation of T-helper-1 versus T-helper-2 activity and enhancement of tumor immunity by combined DNA-based vaccination and nonviral cytokine gene transfer. Gene Ther 2000; 7: 481-492. Article MEDLINE

141 Tasaki K, Yoshida Y, Maeda T, Miyauchi M, Kawamura K, Takenaga K, Yamamoto H, Kouzu T, Asano T, Ochiai T, Sakiyama S, Tagawa M. Protective immunity is induced in murine colon carcinoma cells by the expression of interleukin-12 or interleukin-18, which activate type 1 helper T cells. Cancer Gene Ther 2000; 7: 247-254. Article MEDLINE

142 Xiang J, Moyana T. Regression of engineered tumor cells secreting cytokines is related to a shift in host cytokine profile from type 2 to type 1. J Interfer Cytok Res 2000; 20: 349-354.

143 Reuben JM, Lee BN, Johnson H, Fritsche H, Kantarjian HM, Talpaz M. Restoration of Th1 cytokine synthesis by T cells of patients with chronic myelogenous leukemia in cytogenetic and hematologic remission with interferon-alpha. Clin Cancer Res 2000; 6: 1671-1677.

144 Nishimura T, Nakui M, Sato M, Iwakabe K, Kitamura H, Sekimoto M, Ohta A, Koda T, Nishimura S. The critical role of Th1-dominant immunity in tumor immunology. Cancer Chemother Pharmacol 2000; 46: S52-61.

145 Casares N, Lasarte JJ, de Cerio AL, Sarobe P, Ruiz M, Melero I, Prieto J, Borras-Cuesta F. Immunization with a tumor-associated CTL epitope plus a tumor-related or unrelated Th1 helper peptide elicits protective CTL immunity. Eur J Immunol 2001; 31: 1780-1789. Article MEDLINE

146 Yoo EK, Cassin M, Lessin SR, Rook AH. Complete molecular remission during biologic response modifier therapy for Sezary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity. J Am Acad Dermatol 2001; 45: 208-216.

147 Bockenstedt LK, Kang I, Chang C, Persing D, Hayday A, Barthold SW. CD4+ T helper 1 cells facilitate regression of murine Lyme carditis. Infect Immunol 2001; 69: 5264-5269.

148 Weber KS, Grone HJ, Rocken M, Klier C, Gu S, Wank R, Proudfoot AE, Nelson PJ, Weber C. Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II. Eur J Immunol 2001; 31: 2458-2466.

149 Riemensberger J, Bohle A, Brandau S. IFN-gamma and IL-12 but not IL-10 are required for local tumour surveillance in a syngeneic model of orthotopic bladder cancer. Clin Exp Immunol 2002; 127: 20-26.