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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-01-0231.
IMMUNOBIOLOGY
From the Department of Dermatology, University of
Pennsylvania, Philadelphia; the Department of Dermatology, Geneva
University Hospital, Switzerland; and The Wistar Institute,
Philadelphia, PA.
Sézary syndrome (SzS) is an advanced form of cutaneous T-cell
lymphoma associated with involvement of the peripheral blood by
malignant T cells. The disease is defined by impaired cell-mediated immunity and the production of interferon- Cutaneous T-cell lymphoma (CTCL) is a
lymphoproliferative disorder characterized by the clonal expansion of
malignant CD4+ T cells. Early stages of CTCL are
characterized by localization of the disease process primarily to the
skin, with the presence of patches or plaques. Tumor nodules may also
appear. The most common form of this disorder is mycosis fungoides.
Progressive disease is associated with the dissemination of malignant T
cells to the lymph nodes and peripheral blood. Sézary syndrome
(SzS) is a form of the disease manifested by erythroderma and
circulating malignant T cells.1,2 Previous studies have
demonstrated that progression to Sézary syndrome is associated
with a decrease in cell-mediated immunity typified by depressed
T-helper type 1 (TH1) responses characterized by defects in
the production of interferon- Recent studies have also demonstrated that peripheral blood mononuclear
cells (PBMCs) from SzS patients produce significantly decreased levels
of IL-12, an immunoregulatory cytokine that is a key factor in the
induction of TH1 responses and a major inducer of IFN- Dendritic cells and monocytes/macrophages are major producers of
IL-12 in response to infectious pathogens.8 However, it has been demonstrated that dendritic cells and monocytes are able to produce IL-12 if they are stimulated by activated T cells through CD40/CD40L interaction.9,10 Activation of this pathway not only stimulates the secretion of IL-12, it enhances the antigen presentation capabilities of dendritic cells and increases the expression of cell surface costimulatory molecules such as CD80 and
CD86 on dendritic cells and monocytes, resulting in priming and
expansion of CD4+ and CD8+ cytotoxic T cells in
response to antigenic stimulation.11-15 It has also been
shown that CD40/CD40L interaction is critical for the development of
protective tumor immunity.16-18
Dendritic cells are the only antigen-presenting cells (APCs)
with the ability to prime naive T cells to an antigen.19
In addition to their role in adaptive immunity, they are instrumental in innate immunity by producing cytokines involved in host defense, such as IL-15, IL-18, IFN- Recently, 2 distinct lineages of dendritic cells have been defined.
Myeloid dendritic cells (DC1) originate from myeloid bone marrow
precursors. In human peripheral blood, DC1 are negative for lymphoid
cell- and myeloid cell-specific markers (lineage negative; Lin
1 In this report we examine the role of dendritic cells in the
pathogenesis of impaired cell-mediated immunity and deficient IL-12
production in SzS patients. We demonstrate that CD123+ and
CD11c+ populations of dendritic cells are markedly
decreased in SzS patients and that they exhibit an associated decrease
in production of IFN- Patients
Mononuclear cells
Flow cytometric analysis To detect CD11c+ and CD123+ subsets of peripheral blood dendritic cells, approximately 106 PBMCs per sample, resuspended in Dulbecco phosphate-buffered saline (PBS; BioWhittaker, Walkersville, MD) with 5% fetal calf serum, were stained with lineage cocktail (Lin 1-fluorescein isothiocyanate [FITC], containing antibodies against CD3, CD14, CD16, CD19, CD20, CD56; BD Biosciences, San Jose, CA), anti-HLA-DR PerCP (BD Biosciences), and anti-CD11c-phycoerythrin (PE) (Caltag, Burlingame, CA) or anti-CD123-PE (BD Biosciences). Murine immunoglobulins of appropriate isotypes were used as a control. Cells were incubated with antibodies for 30 minutes on ice in the dark, then washed twice with PBS containing 0.1% gelatin, resuspended in 1% paraformaldehyde, and analyzed. To analyze monocytes, PBMCs were stained with anti-CD14-PE (PharMingen, San Diego, CA).Intracellular IL-12 staining was performed on whole blood from patients or healthy donors as described.31,32 Briefly, 1 mL blood, diluted 1:1 with RPMI 1640 medium, was cultured with fixed Staphylococcus aureus Cowan strain 1 (SAC), 1:10 000 wt/vol (Pansorbin; Calbiochem-Behring, La Jolla, CA) in the presence of Brefeldin A (10 µg/mL; Sigma, St Louis, MO) for 5.5 hours followed by 30 minutes of incubation on ice with 30 µL of 0.5 M EDTA (ethylenediaminetetraacetic acid) added to each sample. Aliquots of blood were then stained for 15 minutes in the dark with Lin 1-FITC, HLA-DR-PerCP, CD11c-APC (BD Biosciences), or appropriate isotype controls, treated with fixation medium A (Fix & Perm; Caltag) and permeabilization medium B (Caltag), stained with anti-IL-12 p40/p70-PE antibody (PharMingen), and followed by a wash with PBS. To analyze monocytes, blood samples were stained with anti-CD14-APC (BD Bioscience) and anti-IL-12 p40/p70-PE (PharMingen). To analyze CD80 expression on dendritic cells and monocytes (anti-CD80-PE; PharMingen), whole blood was stimulated with rCD40L (2 µg/mL; Immunex, Seattle, WA) in the absence of Brefeldin A for 8 hours followed by the staining procedure previously described. Cells were analyzed with the FACScalibur (Becton Dickinson) flow cytometer. We collected 150 000 and 50 000 events to analyze dendritic cells and monocytes, respectively, using CellQuest software (Becton Dickinson). Cytokine assays To induce cytokine production, PBMCs from patients and healthy donors were cultured in 48-well plates at a density of 1 × 106/mL per well in the presence of SAC, 14 HAU influenza virus (PR8), or allantoic fluid. Previously frozen PBMCs were cultured for 48 hours, and freshly isolated PBMCs were cultured for 24 hours. Supernatants were harvested and tested for the presence of IL-12 by a 2-sided radioimmunoassay, as described previously, with two antibody pairs provided by the Wistar Institute C11.79 and C8.6 (sensitivity, 50-100 pg/mL) for IL-12 p40 and 20C2 and C8.6
(sensitivity, 10 pg/mL) for IL-12 p70.7 Recombinant IL-12,
used as a standard, was kindly provided by Genetics Institute
(Cambridge, MA). IFN- was assayed through enzyme-linked
immunosorbent assay (ELISA) using a kit from Endogen (Woburn, MA)
according to the manufacturer's recommendations (sensitivity, 10 pg/mL). Recombinant IFN- from R&D Systems (Minneapolis, MN) was used
as a standard.
Statistical analysis To determine statistical significance, percentages of dendritic cells and monocytes and levels of cytokines were compared between healthy donors and patients using the unpaired Student t test. Level of significance assumed in these comparisons was P < .05.
CTCL patients demonstrate a stage-dependent decrease in numbers of circulating dendritic cells To study the mechanisms underlying decreased cell-mediated immunity and IL-12 production in patients with Sézary syndrome (SzS), we examined the cellular composition of CD11c+ and CD123+ dendritic cells. Flow cytometric analysis of PBMCs from patients with a high burden of malignant T cells in peripheral blood demonstrated significantly decreased numbers of CD123+ and CD11c+ dendritic cells than in healthy donors (Figure 1A). We examined the peripheral blood of healthy donors, patients with CTCL with skin disease but without overt involvement of the peripheral blood (mycosis fungoides), and patients with SzS determined to have low, medium, or high circulating burdens of malignant T cells for the presence of CD123+, CD11c+, and CD14+ cells. Although CTCL patients with skin-restricted disease were shown to have comparatively normal populations of dendritic cells and CD14+ monocytes, SzS patients were observed to have a decrease in circulating dendritic cells that correlated with the relative level of tumor burden (Figure 1B). The decrease in the CD123+ population of dendritic cells ranged from a 1.5-fold decrease among patients with a low tumor burden of circulating malignant T cells (P < .034) to a 3- to 6-fold decrease among patients with a medium or heavy circulating burden of malignant T cells, respectively (P < .002). Although CD11c+ dendritic cell levels were not significantly lower in the circulation of patients with low tumor burden (0.35% in control and 0.29% in patients), a 3-fold decrease was observed among patients with more advanced disease (0.09% among patients with medium tumor burden and 0.1% among patients with high tumor burden; P < .01 and P < .002, respectively). In contrast to significant decreases in peripheral blood dendritic cells among patients with SzS, circulating numbers of CD14+ monocytes were observed to be comparable to normal among all patients with SzS, which is consistent with previous observations.7
Decreased number of peripheral blood dendritic cells in SzS correlates with impaired production of IL-12 and IFN Because dendritic cells are critical producers of IL-12 and IFN-, we examined whether decreased numbers of peripheral blood dendritic cells could be correlated with decreased production of these
cytokines by PBMCs stimulated by SAC or influenza virus, respectively,
in patients with SzS. PBMCs from patients with mycosis fungoides or SzS
with different levels of peripheral blood tumor burden produced
decreased levels of IL-12 p40 not statistically significantly different
than those from healthy donors (Figure 2A). In contrast, though the PBMCs of
patients with mycosis fungoides produced levels of IL-12 p70 comparable
to those of healthy donors, levels of PBMC production in SzS patients
were profoundly decreased in relation to peripheral blood tumor burden
(Figure 2A). Although the PBMCs of healthy controls on average produced
a mean of 49 ± 15 pg/mL IL-12 p70 in response to SAC, the PBMCs of
patients with low tumor burden produced a mean of 15.9 ± 12 pg/mL
IL-12 p70, and the PBMCs of patients with medium and high tumor burden produced a mean of 8.1 ± 7 pg/mL and 9.9 ± 8 pg/mL, respectively (Figure 2A). Flow cytometric analysis of intracellular IL-12
production on whole blood from selected SzS patients further confirmed
a marked reduction in the ability of CD11c+ dendritic cells
from patients with high tumor burden to produce IL-12 in response to
SAC (Figure 2B). The anti-IL-12 antibody used for intracellular
staining does not distinguish between IL-12 p40 and IL-12 p70. In
a representative experiment, 15.4% of CD11c+ cells from a
healthy donor and 14.9% of CD11c+ cells from a patient
with low tumor burden demonstrated intracellular IL-12, but only 3.5%
of CD11c+ cells from a patient with high tumor burden were
positive for intracellular IL-12 (Figure 2B). In contrast to a decrease
in CD11c+ dendritic cell production of IL-12 among patients
with SzS, a similar percentage of CD14+ cells in the blood
of healthy donors and patients with SzS produced IL-12.
As shown in Figure 1, the number of IFN-
Intermittent GM-CSF treatment increases the number of peripheral blood dendritic cells in CTCL patients Studies of animal tumor models have demonstrated that granulocyte macrophage-colony-stimulating factor (GM-CSF)-based therapy can augment cellular immunity that is dependent on CD4+ and CD8+ T cells.33 Furthermore, an important component of its effects is related to its ability to promote the differentiation of hematopoietic precursors to dendritic cells.34 Based on these results, intermittent GM-CSF therapy was introduced to treat some of our patients with SzS. All SzS patients received identical therapy in the form of extracorporeal photopheresis, with 2 consecutive daily treatments administered every 3 to 4 weeks.30 Seven patients with SzS received GM-CSF (Leukine; Immunex) in a dose of 125 µg administered subcutaneously after each photopheresis treatment for a period of at least 6 months. To determine the effect of GM-CSF on the number and function of peripheral blood dendritic cells, cryopreserved PBMCs from patients before and after the initiation of GM-CSF treatment were analyzed for the presence of dendritic cell populations and the ability to produce IL-12 and IFN-. All 7 SzS patients demonstrated significant increases in peripheral blood dendritic cell numbers during GM-CSF treatment, though increases in dendritic cell numbers occurred predominantly within the CD123+ population.
Increases in CD11c+ cells were also observed among patients
treated with GM-CSF, but these changes were not statistically
significant (Table 1). With the exception
of SzS patient 7, who manifested a low circulating burden of malignant
T cells and whose number of peripheral blood dendritic cells were
within the normal range at the start of GM-CSF treatment, the remaining
SzS patients treated with GM-CSF were determined to have either a
medium or a high tumor burden along with a decreased number of
dendritic cells. GM-CSF treatment of patients with medium and high
tumor burden was associated with significant increases in
CD123+ cells, with an average increase of 2.3-fold.
However, intermittent GM-CSF treatment failed to elevate the
percentages of CD123+ cells in patients to levels observed
in healthy donors. In patient 7, GM-CSF treatment also increased the
number of CD123+ cells by 2.4-fold, from 0.34% of total
PBMCs before treatment to 0.84% on the completion of
treatment.
Although 4 patients experienced a 2-fold increase in
CD11c+ cell numbers, overall this increase was not
significant. Despite observing increases in the number of dendritic
cells during GM-CSF treatment, the PBMCs of such patients did not
manifest an increased ability to produce IL-12 or IFN- Recombinant CD40L in vitro partially restores IL-12 production by dendritic cells and monocytes of SzS patients Because CD40-CD40L interactions are known to play an important role in the activation of dendritic cells and in the induction of IL-12 production, we examined whether recombinant CD40L in vitro could stimulate the PBMCs of SzS patients to produce IL-12.9,11-15,23 Following the culture of patient PBMCs with CD40L plus recombinant IFN- for 24 hours, high levels of IL-12
p40 and p70 were detected in culture supernatants of patients with low,
medium, and high tumor burden (Figure 4).
CD40L alone was not capable of inducing the production of IL-12 in
PBMCs of healthy donors or SzS patients; however, IFN- induced
significant levels of IL-12 p40 and IL-12 p70 by the PBMCs of healthy
donors and SzS patients. Importantly, the combination of CD40L plus
IFN- worked synergistically, resulting in a 2- to 10-fold increase
in IL-12 production compared with IFN- alone. Furthermore, evidence
that CD40L can activate CD11c+ dendritic cells in SzS
patients was provided following the stimulation of patient PBMCs with
rCD40L for 8 hours, which resulted in the significant up-regulation of
CD80 cell surface expression (Figure 5A,B). A lesser degree of CD80
up-regulation was observed on patients CD14+ monocytes
following 8-hour culture with CD40L.
Patients with Sézary syndrome demonstrate a stage-related
impairment of cell-mediated immunity, including a decrease in
IFN- It remains to be determined whether a diminution in dendritic cell numbers in the circulation reflects elimination of these cells or a different pattern of dendritic cell trafficking in SzS patients. Contrary to dendritic cell populations, the number of CD14+ monocytes was not significantly decreased in the blood of patients with advanced CTCL in comparison with those in healthy age-matched donors. An examination of IL-12 production by the PBMCs of our SzS patients revealed that the levels of IL-12 p40 detected in culture supernatants, though decreased 3-fold in some of the patients with medium and high tumor burden, were on average similar in healthy donors and patients. This observation suggests that most IL-12 p40 may be produced by monocytes because dendritic cell numbers were significantly reduced. Furthermore, intracellular staining for IL-12 induced by SAC demonstrated almost no difference between the monocytes of healthy donors and patients. Nevertheless, the percentage of CD11c+ dendritic cells producing IL-12 p40 was lower in patients, proportional to an overall lower number of dendritic cells. In contrast to the near normal findings among SzS patients with regard
to IL-12 p40 production, the production of biologically active IL-12
p70 was profoundly decreased by the PBMCs of all patients with SzS,
even among those with a low tumor burden, suggesting that SzS patients
exhibit a marked defect in forming IL-12 p70. Unless IFN- The decrease in peripheral blood CD123+ dendritic cells
correlates with the production of significantly lower levels of IFN- Clearly, IFN- Like IFN- We have also shown that exogenously added IL-12 improves the
cell-mediated immune responses of SzS patients.7 Phase 1 trials of the use of recombinant IL-12 in CTCL have confirmed this
observation in vivo and have indicated that IL-12 may have substantial
clinical benefit for this patient population.57 Thus,
enhancing the ability of SzS patients to secrete endogenous IL-12 is an
important goal of anti-CTCL therapy. Although CD40L expression is
impaired on the T cells of SzS patients, CD40 expression seems to be
comparable to that on normal dendritic cells and monocytes (L.E.F.,
manuscript in preparation). Therefore, when rCD40L in combination with
IFN- All participating patients in this study were treated with extracorporeal photopheresis (ECP). In this regard, it is important to stress that Berger et al58 have demonstrated the potent capacity of ECP treatment to rapidly induce the differentiation of monocytes into large numbers of functional dendritic cells. This effect likely represents one of the most important mechanistic aspects of ECP therapy; the end result is the enhanced processing of apoptotic malignant T cells by the expanded dendritic cell population, leading to a more efficient "immunization" process against the tumor cells. Although our patients did not experience significant changes in dendritic cell numbers while they were observed (data not shown), it is entirely possible that long-term treatment with ECP prevented a further disease-associated decline in total dendritic cell numbers. In summary, in this report we show that impaired cell-mediated immunity
of SzS patients may result from decreased numbers of dendritic cells
and a marked defect in the production of IL-12 p70 and IFN-
Submitted January 24, 2002; accepted June 13, 2002.
Prepublished online as Blood First Edition Paper, July 12, 2002; DOI 10.1182/blood-2002-01-0231.
Supported in part by a grant from the Leukemia and Lymphoma Society and by grants CA 10815 (A.H.R.) and CA 20833 (L.M.) from the National Institutes of Health.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Alain H. Rook, Department of Dermatology, University of Pennsylvania, 3600 Spruce St, Philadelphia, PA 19104; e-mail: arook{at}mail.med.upenn.edu.
1. Edelson RL. Cutaneous T cell lymphoma: mycosis fungoides, Sézary syndrome, and other variants. J Am Acad Dermatol. 1980;2:89-106[Medline] [Order article via Infotrieve]. 2. Haynes BF, Bunn P, Mann D, et al. Cell surface differentiation antigens of the malignant T cell in Sézary syndrome and mycosis fungoides. J Clin Invest. 1981;67:523-530[Medline] [Order article via Infotrieve].
3.
Rook AH, Vowels BR, Jaworsky C, Singh A, Lessin SR.
The immunopathogenesis of cutaneous T-cell lymphoma: abnormal cytokine production by Sézary T cells.
Arch Dermatol.
1993;129:486-489 4. Lessin SR, Vowels BR, Rook AH. Th2 cytokine profile in cutaneous T-cell lymphoma. J Invest Dermatol. 1995;105:855-856[CrossRef][Medline] [Order article via Infotrieve]. 5. Vowels BR, Cassin M, Vonderheid EC, Rook AH. Aberrant cytokine production by Sézary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J Invest Dermatol. 1992;99:90-94[CrossRef][Medline] [Order article via Infotrieve]. 6. Vowels BR, Lessin SR, Cassin M, et al. Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol. 1994;103:669-673[CrossRef][Medline] [Order article via Infotrieve]. 7. Rook AH, Kubin M, Cassin M, et al. IL-12 reverses cytokine and immune abnormalities in Sézary syndrome. J Immunol. 1995;154:1491-1498[Abstract]. 8. Trinchieri G. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv Immunol. 1998;70:83-243[Medline] [Order article via Infotrieve].
9.
Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G.
Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation.
J Exp Med.
1996;184:747-752 10. Shu U, Kiniwa M, Wu CY, et al. Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol. 1995;25:1125-1128[Medline] [Order article via Infotrieve]. 11. Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR. Help for cytotoxic T-cell responses is mediated by CD40 signalling. Nature. 1998;393:478-480[CrossRef][Medline] [Order article via Infotrieve]. 12. DeKruyff RH, Gieni RS, Umetsu DT. Antigen-driven but not lipopolysaccharide-driven IL-12 production in macrophages requires triggering of CD40. J Immunol. 1997;158:359-366[Abstract]. 13. Kennedy MK, Picha KS, Fanslow WC, et al. CD40/CD40 ligand interactions are required for T cell-dependent production of interleukin-12 by mouse macrophages. Eur J Immunol. 1996;26:370-378[Medline] [Order article via Infotrieve]. 14. Peng X, Kasran A, Warmerdam PA, de Boer M, Ceuppens JL. Accessory signaling by CD40 for T cell activation: induction of Th1 and Th2 cytokines and synergy with interleukin-12 for interferon-gamma production. Eur J Immunol. 1996;26:1621-1627[Medline] [Order article via Infotrieve]. 15. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998;393:480-483[CrossRef][Medline] [Order article via Infotrieve]. 16. Hoffmann TK, Meidenbauer N, Muller-Berghaus J, Storkus WJ, Whiteside TL. Proinflammatory cytokines and CD40 ligand enhance cross-presentation and cross-priming capability of human dendritic cells internalizing apoptotic cancer cells. J Immunother. 2001;24:162-171[CrossRef][Medline] [Order article via Infotrieve].
17.
Mackey MF, Gunn JR, Maliszewsky C, Kikutani H, Noelle RJ, Barth RJ Jr.
Dendritic cells require maturation via CD40 to generate protective antitumor immunity.
J Immunol.
1998;161:2094-2098 18. Toes RE, Schoenberger SP, van der Voort EI, Offringa R, Melief CJ. CD40-CD40 ligand interactions and their role in cytotoxic T lymphocyte priming and anti-tumor immunity. Semin Immunol. 1998;10:443-448[CrossRef][Medline] [Order article via Infotrieve]. 19. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245-252[CrossRef][Medline] [Order article via Infotrieve]. 20. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767-811[CrossRef][Medline] [Order article via Infotrieve].
21.
Kohrgruber N, Halanek N, Groger M, et al.
Survival, maturation, and function of CD11c 22. Robinson SP, Patterson S, English N, Davies D, Knight SC, Reid CD. Human peripheral blood contains two distinct lineages of dendritic cells. Eur J Immunol. 1999;29:2769-2778[CrossRef][Medline] [Order article via Infotrieve]. 23. Macatonia SE, Hosken NA, Litton M, et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995;154:5071-5079[Abstract].
24.
Rissoan MC, Soumelis V, Kadowaki N, et al.
Reciprocal control of T helper cell and dendritic cell differentiation.
Science.
1999;283:1183-1186
25.
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 26. Cella M, Jarrossay D, Facchetti F, et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med. 1999;5:919-923[CrossRef][Medline] [Order article via Infotrieve].
27.
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
28.
Siegal FP, Kadowaki N, Shodell M, et al.
The nature of the principal type 1 interferon-producing cells in human blood.
Science.
1999;284:1835-1837 29. Murphy GF. Cutaneous T-cell lymphoma. Adv. Pathol. 1988;1:131-156. 30. Rook AH, Suchin KR, Kao DM, et al. Photopheresis: clinical applications and mechanism of action. J Investig Dermatol Symp Proc. 1999;4:85-90[Medline] [Order article via Infotrieve]. 31. Bueno C, Almeida J, Alguero MC, et al. Flow cytometric analysis of cytokine production by normal human peripheral blood dendritic cells and monocytes: comparative analysis of different stimuli, secretion-blocking agents and incubation periods. Cytometry. 2001;46:33-40[CrossRef][Medline] [Order article via Infotrieve]. 32. Zaki M, Douglas R, Patten N, et al. Disruption of the IFN-gamma cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis. Leuk Res. 2000;24:611-621[CrossRef][Medline] [Order article via Infotrieve].
33.
Dranoff G, Jaffee E, Lazenby A, et al.
Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.
Proc Natl Acad Sci U S A.
1993;90:3539-3543
34.
Inaba K, Inaba M, Romani N, et al.
Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.
J Exp Med.
1992;176:1693-1702 35. Fitzgerald-Bocarsly P. Human natural interferon-alpha producing cells. Pharmacol Ther. 1993;60:39-62[CrossRef][Medline] [Order article via Infotrieve].
36.
Chehimi J, Campbell DE, Azzoni L, et al.
Persistent decreases in blood plasmacytoid dendritic cell number and function despite effective highly active antiretroviral therapy and increased blood myeloid dendritic cells in HIV-infected individuals.
J Immunol.
2002;168:4796-4801
37.
Goriely S, Vincart B, Stordeur P, et al.
Deficient IL-12(p35) gene expression by dendritic cells derived from neonatal monocytes.
J Immunol.
2001;166:2141-2146
38.
Hayes MP, Wang J, Norcross MA.
Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-gamma of lipopolysaccharide-inducible p35 and p40 genes.
Blood.
1995;86:646-650
39.
Kubin M, Chow JM, Trinchieri G.
Differential regulation of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-1 beta production in human myeloid leukemia cell lines and peripheral blood mononuclear cells.
Blood.
1994;83:1847-1855
40.
Ma X, Chow JM, Gri G, et al.
The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells.
J Exp Med.
1996;183:147-157 41. Zaki MH, Shane RB, Geng Y, et al. Dysregulation of lymphocyte interleukin-12 receptor expression in Sézary syndrome. J Invest Dermatol. 2001;117:119-127[CrossRef][Medline] [Order article via Infotrieve].
42.
Showe LC, Fox FE, Williams D, Au K, Niu Z, Rook AH.
Depressed IL-12-mediated signal transduction in T cells from patients with Sézary syndrome is associated with the absence of IL-12 receptor beta 2 mRNA and highly reduced levels of STAT4.
J Immunol.
1999;163:4073-4079
43.
McDyer JF, Goletz TJ, Thomas E, June CH, Seder RA.
CD40 ligand/CD40 stimulation regulates the production of IFN-gamma from human peripheral blood mononuclear cells in an IL-12- and/or CD28- dependent manner.
J Immunol.
1998;160:1701-1707 44. Huang YM, Xiao BG, Westerlund I, Link H. Phenotypic and functional properties of dendritic cells isolated from human peripheral blood in comparison with mononuclear cells and T cells. Scand J Immunol. 1999;49:177-183[CrossRef][Medline] [Order article via Infotrieve].
45.
Marrack P, Kappler J, Mitchell T.
Type I interferons keep activated T cells alive.
J Exp Med.
1999;189:521-530
46.
Muller U, Steinhoff U, Reis LF, et al.
Functional role of type I and type II interferons in antiviral defense.
Science.
1994;264:1918-1921 47. Palucka K, Banchereau J. Linking innate and adaptive immunity. Nat Med. 1999;5:868-870[CrossRef][Medline] [Order article via Infotrieve]. 48. Cho SS, Bacon CM, Sudarshan C, et al. Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J Immunol. 1996;157:4781-4789[Abstract]. 49. 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[CrossRef][Medline] [Order article via Infotrieve]. 50. Olsen EA, Bunn PA. Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9:1089-1107[Medline] [Order article via Infotrieve].
51.
Brossart P, Grunebach F, Stuhler G, et al.
Generation of functional human dendritic cells from adherent peripheral blood monocytes by CD40 ligation in the absence of granulocyte-macrophage colony-stimulating factor.
Blood.
1998;92:4238-4247
52.
Pulendran B, Banchereau J, Burkeholder S, et al.
Flt3-ligand and granulocyte colony-stimulating factor mobilize distinct human dendritic cell subsets in vivo.
J Immunol.
2000;165:566-572
53.
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 54. Zhou LJ, Tedder TF. Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily. J Immunol. 1995;154:3821-3835[Abstract].
55.
Blom B, Ho S, Antonenko S, Liu YJ.
Generation of interferon alpha-producing predendritic cell (Pre-DC)2 from human CD34(+) hematopoietic stem cells.
J Exp Med.
2000;192:1785-1796
56.
Banchereau J, Pulendran B, Steinman R, Palucka K.
Will the making of plasmacytoid dendritic cells in vitro help unravel their mysteries?
J Exp Med.
2000;192:F39-F44
57.
Rook AH, Wood GS, Yoo EK, et al.
Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses.
Blood.
1999;94:902-908 58. Berger CL, Xu AL, Hanlon D, et al. Induction of human tumor-loaded dendritic cells. Int J Cancer. 2001;91:438-447[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  M. Wysocka, B. M. Benoit, S. Newton, L. Azzoni, L. J. Montaner, and A. H. Rook Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15 Blood, December 15, 2004; 104(13): 4142 - 4149. [Abstract] [Full Text] [PDF]
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 A. K. De, K. Laudanski, and C. L. Miller-Graziano Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating Factor-Driven Macrophage Differentiation J. Immunol., June 15, 2003; 170(12): 6355 - 6362. [Abstract] [Full Text] [PDF]
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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Abstract
Introduction
), but they are
HLA-DR+/CD11c+.
2
signaling receptor for IL-12 on the normal T cells of SzS patients and
its complete absence on malignant T cells results in a lack of
IL-12-dependent IFN-