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Immunology |
San Raffaele Scientific Institute, Milan, Italy [E. R., A. C., F. B., A. G. S.]; Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892 [E. R., J. W. G., J. S.]; The Randall Institute, King’s College, London, United Kindgom [H. J. G.]; European Institute of Oncology [G. P.] and Department of Biology and Genetics [A. G. S.], University of Milan, Milan, Italy
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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IgE-targeted immediate hypersensitivity and allergic inflammation reactions have been proposed as possible natural mechanisms involved in antitumor immune responses, on the basis of (controversial) epidemiological evidence of an inverse correlation between allergy and the risk of cancer (13, 14, 15, 16, 17) . To test if IgE-driven reactions could be exploited to modify tumor growth, Gould et al. (18) constructed chimeric IgE and IgG1 antibodies with human constant regions and the mouse variable regions of MOv18 antibody, reactive with an ovarian cancer-associated antigen; they demonstrated that MOv18-IgE was significantly more effective than MOv18-IgG1 in the inhibition of tumor growth in a severe combined immunodeficiency mouse xenograft model of ovarian carcinoma.
It is known that IgEs stimulate the secretion, by mast cells and basophils, of mediators of the allergic and inflammatory reactions and cytokines, including granulocyte macrophage colony-stimulating factor, IL-4, IL-5, and tumor necrosis factor-
(19, 20, 21)
. Moreover, several lines of evidence indicate a crucial role of eosinophils and macrophages in tumor eradication through a mechanism involving the production of reactive oxygen metabolites and nitric oxide (2
, 22
, 23)
. Therefore, the effect described by Gould et al. could be interpreted in terms of IgE-driven activation of innate immunity effector mechanisms.
We postulated that IgEs loaded on tumors could also affect tumor immunogenicity by activation of innate immune mechanisms at tumor sites. This would result in an increased local inflammatory response accompanied by tumor cell destruction. The overall aim of this study was to determine whether the induction of such changes might affect the malignant behavior of the tumor cell and provide an approach to control tumor growth. Targeting of IgE onto tumors was performed using a three-step strategy on the basis of biotin-avidin interactions, which had already shown high efficiency in targeting radioisotopes, cytotoxic molecules, and cytotoxic cells on tumor cells both in vitro and in vivo (24, 25, 26, 27, 28, 29, 30) .
For in vivo experimental tumor models, we used the Thy 1.1 transfectant of the immunogenic Rauscher-induced murine lymphoma RMA (RMA-Thy 1.1) and the human CEA transfectant of the weakly immunogenic MC38 murine adenocarcinoma (MC38-CEA-2; Ref. 31
). The results of this study provided evidence that loading tumor cells with IgEs strongly affects in vivo tumor growth, leading, in some instances, to complete tumor rejection and protection against subsequent tumor challenges by a mechanism involving both eosinophils (and possibly other Fc
R positive cells) and T-cell mediated antitumor responses. Moreover, vaccination experiments showed that immunization with very low doses of IgE-loaded irradiated tumor cells induces protection against subsequent tumor challenges.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Antibodies.
Anti-2,4,6-trinitrophenol mouse IgEs were obtained from supernatants of TIB142 hybridoma cells (American Tissue Culture Collection, Rockville, MD) cultured in serum-free, protein-free Ultradoma medium (Bio Whittaker, Walkersville, MD) by ammonium sulfate precipitation and dialysis against PBS. IgE levels in the supernatant were evaluated by ELISA. Anti-2,4-dinitrophenol mouse IgEs (mAb SP6) were purchased from Sigma Chemical Co. (St. Louis, MO). Anti-Thy 1.1 19E12 mAb (IgG2a) was purified from mouse ascitic fluid as described (26)
. COL-1 anti-CEA mAb (IgG2b; Ref. 32
) and BL-3 control mAb (IgG2a) were kindly provided by Diane Milenic (Laboratory of Tumor Immunology and Biology, National Cancer Institute/NIH, Bethesda, MD).
Cell Lines.
The H-2b T-cell lymphoma RMA is a Rauscher MuLV-induced tumor of C57BL/6 origin. RMA Thy 1.1 was derived from a RMA cell line by transfection with a construct encoding the Thy 1.1 allele, inserted into the mammalian expression vector pRS1-neo. Cells were maintained as described (26)
. The MC38-CEA-2 CEA+ cell line was derived from the parental MC38 (H-2b) adenocarcinoma cells by transfection (31)
. The MC38-CEA-2 cells were routinely >90% positive for surface CEA expression as measured by the binding of an anti-CEA mAb, COL-1. EL-4, a chemically induced T-cell lymphoma, and B16-F1, a murine melanoma of C57BL/6 origin, were provided by Drs. Matteo Bellone and Anna Mondino (San Raffaele Scientific Institute, Milan, Italy), respectively. RBL-13, a rat basophilic leukemia cell line expressing high levels of FcRI, was cultured in DMEM supplemented with 2 mM
L-glutamine penicillin-streptomycin and 16% FCS.
Preparation of Biotinylated Antibodies.
mAbs 19E12, COL-1, and BL-3 (IgG2b) mAbs were biotinylated as described previously (26)
. Biotinylation of IgE mAbs was performed using 100 µl of biotin solutions at various concentrations ranging from 0.5 to 0.0625 mg/ml to set optimal reaction conditions for achieving the highest level of biotinylation together with unaltered binding to FcRs. The best results were obtained with sulfo-NHS-LC-biotin (Pierce Chemical Co., Rockford, IL) solution at concentration 0.125 mg/ml, as determined by FACS analysis on RBL-13 cells. Biotinylated mAbs were dialyzed overnight against PBS. The optimal biotin:protein ratio was 
10 as determined by Pierce HABA method.
Flow Cytometry.
For detection of binding of biotinylated-IgE to FcRs, 1 x 106 RBL-13 rat basophilic leukemia cells were incubated for 1 h at 37°C with 100 µl of 30 µg/ml biotinylated or unconjugated IgE in PBS. As a control, RBL-13 cells were incubated with irrelevant IgG antibody at the same concentration. Cells were washed twice in PBS containing 3% FCS and incubated with rat antimouse IgE mAb (PharMingen, San Diego, CA). After further washing, RBL-13 cells were counterstained with FITC-conjugated goat antirat antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and analyzed by FACScan (Becton Dickinson, San Jose, CA). Mean fluorescence intensity on RBL-13 cells treated with IgE and biotinylated IgE was compared, and no significant differences were observed, indicating unaltered binding of biotinylated IgE to FcRs. Alternatively, RBL-13 cells treated with biotinylated IgE were stained with phycoerythrin-conjugated streptavidin (Sigma Chemical Co.).
Biotinylated anti-Thy 1.1 mAb 19E12 and anti-CEA COL-1 mAb were tested for binding to tumor cells (RMA-Thy 1.1 and MC38-CEA-2, respectively) using phycoerythrin-conjugated streptavidin; targeting of biotinylated IgE on tumor cells by biotin-avidin bridging was evaluated by IgE-specific staining as described above.
In Vivo Tumor Targeting with Biotinylated IgEs.
Tumor targeting with biotinylated IgE was performed as described (29)
. Six- to 8-week-old C57BL/6 females were s.c. injected with 3 x 105 MC38-CEA-2 tumor cells. At day 2, the mice were injected i.p. with 40 µg of biotinylated anti-CEA-2 COL-1 mAb to target the tumor. At day 3, 50 µg/mouse of avidin was administered i.p. to chase the unbound mAb, and 4 h later, streptavidin (50 µg/mouse) was injected to create the avidin-biotin bridge. Finally at day 4, 30 µg/mouse of biotin-conjugated IgEs or IgGs (control group) were administered by i.p injection, and tumor growth was monitored every 2nd day by measuring two perpendicular diameters with a caliper. Tumor volume was calculated by the formula V = (S x S) x L/2, where S = short diameter and L = long diameter. Mice were euthanized when tumor size was >500 mm3.
In Vitro Targeting of Tumor Cells with Biotinylated IgE.
Tumor cells were loaded with biotinylated IgE, as described previously (26)
. Briefly, RMA-Thy 1.1 or MC38-CEA-2 cells were treated with biotin-conjugated 19E12 or COL-1 at 10 µg/ml for 10 min on ice (first step). After washing, cells were further incubated with 10 µg/ml avidin (NeutrAvidin; Pierce Chemical Co.) for 10 min on ice (second step) and then with 30 µg/ml of biotinylated IgEs (TIB142 or SP6) or IgGs (BL-3) for 30 min on ice (third step). Optimal cell doses for tumor development were 5 x 104 cells for the RMA Thy 1.1 model and 3 x 105 cells for the MC38-CEA-2 model. The tumor cells were suspended in 100-µl 0.9% NaCl solution and injected s.c. in the right flank.
In Vivo Depletion of CD4+ and CD8+ T Cells and Eosinophils.
For in vivo depletion of CD4+ and CD8+ T-cell subsets in the priming phase of the antitumor immune response, rat antimouse CD4 GK 1.5 and rat antimouse CD8 53.6.72 monoclonal antibodies were used; 300 µg of purified antibodies were administered by i.p. injection at day -6 followed by a second and a third i.p. injection of 200 µg at days -5 and -3 from tumor inoculation. Depletion was maintained during tumor growth by weekly injections of 200 µg of antibody. CD4 or CD8 depletion at the time of tumor inoculation was >90%, as measured by FACS analysis on peripheral blood lymphocytes. Eosinophil depletion was performed by administration of anti-IL-5 antibody TRFK-5 (PharMingen) as described by Garlisi et al. (33)
. Briefly, 1 week before tumor inoculation, mice were injected i.p with 20 µg of TRFK-5 mAb followed by a second injection of 20 µg 5 days after tumor inoculation. The treatment is reported to inhibit the release of eosinophils from bone marrow for at least 8 weeks.
CTL Assay.
Splenocytes were isolated from IgE-treated, tumor-rejecting mice or from control tumor-developing mice and restimulated in vitro with irradiated (10,000 rad) RMA Thy 1.1 cells at a responder:stimulator ratio of 2:1. After 7 days of culture in RPMI 1640 supplemented with L-glutamine, antibiotics, ß-mercaptoethanol, and 10% FCS, the cytotoxic activity of CTLs was tested against RMA-Thy 1.1, parental RMA, and EL-4 or B16 tumor cells. MC38-CEA-2-specific CTL cultures were obtained by in vitro stimulation of splenocytes with MC38-CEA-2 cell lysate in RPMI containing 10 units/ml IL-2. Cytotoxic activity was assayed in standard 5-h 51Cr release assays as described (34)
. In some experiments, cytotoxic activity was evaluated with 111In-labeled target in an 18-h 111In release assay.
T-cell Proliferation Assays.
Splenocytes (105) from immunized mice were cocultivated with 5 x 105 irradiated (2000 rad) syngeneic spleen cells in the presence of various concentrations of the T helper peptide (SLTPRCNTAWNRL), derived from MuLV env antigen and restricted by I-Ab molecules (35)
. After 4 days, 1 µCi [3H]thymidine was added to each well for 18 h. The incorporated radioactivity was measured by liquid scintillation counting.
Vaccination Experiments.
Vaccination experiments were performed by s.c. administration of IgG- or IgE-loaded irradiated (10,000 rad) tumor cells in the left flank at different doses. For vaccination with MC38-CEA-2 cells, 1–30 x 104 cells were injected twice with a 2-week interval. Two weeks after the last immunization, mice were challenged with 3 x 105 MC38 parental tumor cells. For RMA Thy 1.1 vaccination, 1–50 x 103 irradiated cells were administered once, and after 2 weeks, mice were challenged with 5 x 104 RMA tumor cells.
Anti-CEA Antibody ELISA.
Nunc immunoplates (Maxi-Sorb) were coated with 100 ng/well of purified human CEA or ovalbumin and overcoated with 5% BSA. Sera from mice vaccinated with IgE- or IgG-loaded MC38-CEA-2 vaccines and from normal controls were serially diluted 1:5. Bound immunoglobulins were revealed by a horseradish peroxidase-conjugated rat antimouse immunoglobulin secondary antibody. Absorbance values were subtracted of the background values measured with normal mouse sera. Only the two groups of mice receiving the highest cell doses (one IgG and one IgE group) had antibodies with titers 
1:125, whereas all other groups were negative at 1:25.
Statistical Analysis.
Statistical analysis on tumor growth data was performed using covariance analysis (36)
. Differences in tumor growth rate were evaluated by analyzing slope differences, which were assessed by including in the model the interaction term between group and day. Statistical analysis on survival data was performed by the Kaplan-Meier method. Differences were assessed using the Log-rank test. ANOVA was evaluated by the Student t test.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To determine whether in vivo targeting of tumor cells with IgEs could affect tumor growth, mice were inoculated with MC38-CEA-2 adenocarcinoma cells (3 x 105 cells/mouse, s.c.) on day 0 and then treated with: (a) biotinylated anti-CEA mAb (40 µg/mouse, i.p., on day 2); (b) avidin (50 µg/mouse, i.p., on day 3) and streptavidin (50 µg/mouse, i.p., 4 h later); and (c) biotinylated anti-2,4-dinitrophenol IgE mAb or biotinylated IgG control mAb (30 µg/mouse, i.p., on day 4). IgE-treated tumors grew at a significantly (P < 0.001) slower rate than IgG-treated tumors (Fig. 1)
. ANOVA gave increasingly significant differences from day 14 (P = 0.015) to day 19 (P = 0.0012). A significant difference (P = 0.0098) in survival was observed (five of five IgE-treated and only one of five IgG-treated mice survived at day 20); however, the mice bore progressive tumors and died within 40 days.
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and in survival (Fig. 2B)
between mice bearing tumors derived from IgE- or IgG-loaded tumor cells were highly significant (P < 0.001 for tumor growth and P = 0.0001 for survival); moreover, 2 of 10 mice injected with IgE-loaded MC38-CEA-2 completely rejected the tumor after 20 days. The 2 tumor-rejecting mice were later rechallenged with 3 x 105 MC38 cells, and both failed to develop tumors for 60 days, thus showing that protective immunity had been induced. Because the parental (CEA-negative) cell line was used for the rechallenge, it is clear that an anti-CEA response is not involved in the protection mechanism. A control experiment was performed using MC38-CEA-2 cells loaded in the third step with heat-inactivated biotinylated IgE. Fourteen days after injection, the average tumor volume was not significantly different from the control group (188.7 ± 74 versus 168.3 ± 54.1 cubic mm, n = 5 mice), thus suggesting that the Fc portion of IgE plays a crucial role in recruitment and activation of immune effector cells.
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. After day 17, tumors progressively grew in all mice. However, a significant (P < 0.01) increase in survival was observed (Fig. 2D)
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Induction of Tumor Protective Immunity by Suboptimal Doses of IgE-loaded Tumor Cells.
To expand the finding that protective immunity could be elicited by targeting IgE on tumor cells, we inoculated mice with a suboptimal dose of MC38-CEA-2 (3 x 104 cells s.c./mouse), which caused tumors in two of five mice inoculated with IgE-loaded cells and in one of five mice inoculated with IgG-loaded cells (Fig. 3A
, the difference in tumor incidence is statistically not significant; P = 0.49). All of the surviving mice were then challenged with 3 x 105 MC38-CEA-2 cells; four of four mice of the IgG group developed progressively growing tumors, whereas three of three mice of the group primed with IgE-loaded tumor cells did not develop any tumor (P = 0.0081; Fig. 3B
). The same mice were further rechallenged with the CEA-negative parental cell line MC38, and again, all three developed no tumor (data not shown). Analogous results were obtained in mice administered with suboptimal doses of IgE- or IgG-loaded RMA Thy 1.1 cells (1 x 104 s.c. cells/mouse; data not shown).
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. These findings indicate that eosinophils play a role at least in the initial phase of the IgE-induced inhibition of tumor growth and that antitumor immunity is elicited by priming a T-cell-mediated immune response.
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and B16 (data not shown). Spleen cells from mice inoculated with IgE-loaded tumor cells possessed a markedly higher cytotoxic activity against RMA-Thy 1.1 (Fig. 4A)
and parental RMA cells (data not shown), as compared with control spleen cells. Conversely, B16 and EL-4 tumor cells were not lysed. Similar results were obtained in the MC38-CEA-2 tumor model; T-cell cultures from the IgE-primed mice exhibited cytotoxic activity directed to both CEA+ and CEA- adenocarcinoma (data not shown). In the case of the RMA-Thy 1.1 tumors, a peptide-specific CD4 response could be studied, because viral-derived antigens presented by MHC class II molecules have been identified. To detect the presence of tumor-specific CD4 T cells, we performed a T-cell proliferation assay. Mice immunized with IgE-loaded RMA-Thy 1.1 tumor cells showed a dose-dependent proliferative response specific for the MuLV env-derived Th peptide SLTRPCNTAWNRL, whereas spleen cells from mice immunized with either IgG-loaded or untreated RMA-Thy 1.1 cells did not (Fig. 4B)
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). The vaccinated mice were challenged with 3 x 105 MC38 cells on day 0. Within the IgG groups, only mice receiving the highest dose showed protection (significant delay in tumor growth), whereas the other two groups were not protected. All three IgE groups were protected, and 3 of 15 animals remained tumor free (Fig. 5B)
. In these groups of mice, we also measured the serum levels of anti-CEA antibodies to evaluate if vaccination with IgE-loaded tumor cells also induced an increased production of tumor-specific antibodies. Anti-CEA antibodies were only detected in mice vaccinated with the highest dose of cells loaded either with IgG or IgE, thus indicating that IgEs did not increase the tumor-specific antibody response (data not shown).
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1 x 105 cells s.c./mouse but not at lower doses. Conversely, IgE-loaded irradiated cells were highly effective at doses as low as 1 x 103 cells s.c./mouse (data not shown). |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Two recent reports (18 , 40) have shown that exogenous IgE antibodies can activate antitumor effector mechanisms of innate immunity in severe combined immunodeficiency mouse xenograft tumor models. Another study (41) has recently pointed out the capability of IgE to mediate antigen capture and processing by professional APCs in humans, thus leading to the hypothesis that IgEs could also be involved in the modulation of acquired immune responses.
In the tumor therapy model, biotinylated IgE immunoglobulins of irrelevant specificity were administered to tumor-bearing mice using three-step strategy, on the basis of biotin-avidin interactions, which have been used for in vivo targeting of radioisotopes and cytotoxic molecules on tumor cells in both mice and humans (24, 25, 26, 27, 28, 29) . A single injection of biotinylated IgEs in mice bearing tumors significantly decreased tumor progression, thus confirming that the IgE potential to trigger inflammatory and allergic reactions at tumor sites can be exploited for therapeutic purposes (18) .
Unlike IgGs, which have a serum half-life of 23 days, the half-life of unbound IgE immunoglobulins in serum is 2 days; therefore, it is very likely that repeated administration of IgE may improve the therapeutic results and even lead to tumor eradication. However, this first study had the aim to characterize the immunological potential of IgE in tumor immunotherapy, and additional studies will be addressed to define the most effective protocols for tumor therapy and vaccination.
Interestingly, we also found that IgEs of irrelevant specificity loaded on tumor cells strongly affected tumorigenicity and drove acquired tumor-specific immunity by priming CD8 and CD4 T-cell responses. We have found that IgE-loaded tumor cells, besides causing a delay in tumor growth, a significant decrease in the rate of tumor progression, and even tumor rejection, did also confer protective immunity against subsequent challenges with untreated tumor cells.
The phenomenon was observed in both our tumor models: (a) the Rauscher-induced rapidly growing RMA lymphoma, known to be immunogenic; and (b) the weakly immunogenic MC38 colon adenocarcinoma. The protective immunity depends upon priming of a T-cell-mediated immune response, because depletion of either CD4 or CD8 T-cell subsets, before the inoculation of IgE-loaded tumor cells, abrogated the inhibition of tumor growth. In vitro experiments on spleen cell cultures derived from IgE-primed tumor-rejecting mice demonstrated an enhanced tumor-specific CTL activity, thus strongly indicating that the induction of CTL responses is one of the mechanisms accounting for IgE-mediated tumor protection. CD4 T-cell proliferation in response to a tumor-derived I-Ab-restricted Th peptide was also observed in spleen cell cultures from mice immunized with IgE-loaded tumor cells.
It is likely that IgE antibodies trigger an inflammatory reaction at the tumor site by recruitment and activation of FcR-bearing effectors, such as eosinophils, which in turn may favor tumor cell destruction, an essential requirement for an efficient priming of CD4- and CD8-dependent specific immune responses (42, 43, 44)
. Our experiments showed that eosinophil depletion abolished the delay in tumor progression observed after injection of RMA Thy 1.1 cells loaded with IgE, suggesting a role for eosinophils in the induction of tumor-specific immune responses.
It has been reported that IgEs augment antigen presentation by CD23-bearing B cells (45
, 46)
and that human DCs and epidermal Langerhans cells can present antigens internalized as IgE-antigen complexes (41
, 47
, 48)
. However, mouse DCs have been reported to be devoid of FcRs (49)
, thus it is more likely that the mechanism underlying IgE-driven T-cell priming also involves other FcR-positive cell types, which could facilitate the uptake of tumor antigen by APC in either of two ways, by direct tumor cell killing or by causing allergic and inflammatory reactions at tumor sites.
Vaccination experiments confirm that the T-cell-mediated immunity elicited by IgEs loaded on tumor cells can be effectively exploited for tumor prevention. The presence of IgE immunoglobulin on the surface of irradiated tumor cells conferred protection in both tumor models at doses 100-fold lower than corresponding control cells without IgE.
In conclusion, the results reported here shed new light on a role for antibodies of IgE isotype as an effective mean to elicit immune responses against tumors and suggest that IgEs could be included in the design of cell-based antitumor vaccines.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from Associazione Italiana Ricerca sul Cancro, Consiglio Nazionale delle Ricerche (Progetto Finalizzato Biotecnologie), Ministero della Università e Ricerca scientifica (COFIN 2000), and Istituto Superiore di Sanità (Progetto AIDS). 
2 To whom requests for reprints should be addressed, at Laboratory of Tumor Immunology and Biology, NIH, 10 Center Drive, Room 8B04, Bethesda, MD 20892. Phone: (301) 594-8229; Fax: (301) 496-2756; E-mail: realie{at}mail.nih.gov
3 The abbreviation used are: APC, antigen-presenting cell; CEA, carcinoembryonic antigen; FACS, fluorescence-activated cell sorter; FcR, IgE receptor; IL, interleukin; MuLV, murine leukemia virus; mAb, monoclonal antibody; DC, dendritic cell.
Received 1/24/01. Accepted 5/14/01.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-interferon gene transfer into tumor cells generate potent and long lasting antitumor immunity. Cancer Res., 50: 7820-7825, 1990., Granulocyte-macrophage colony stimulating factor, and -interferon gene or admixed with conventional adjuvants. Cancer Res., 54: 6022-6026, 1994.. Cancer Res., 57: 1922-1928, 1997. in mouse models. Cancer Res., 59: 2917-2923, 1999.RI-expressing antigen presenting cells: new players in the atopic game. Immunol. Today, 18: 311-313, 1997.[Medline]
RII by the antigen-anti-FcRII conjugates. J. Immunol., 152: 4388-4396, 1994.[Abstract]
RI as a complex composed of FcRIa and FcRI-chains and can use this receptor for IgE-mediated allergen presentation. J. Immunol., 157: 607-616, 1996.[Abstract]
receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation. J. Immunol., 161: 2731-2739, 1998.RI): from physiology to pathology. Annu. Rev. Immunol., 17: 931-972, 1999.[Medline]This article has been cited by other articles:
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 |
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  E. A. Nigro, A. T. Brini, E. Soprana, A. Ambrosi, D. Dombrowicz, A. G. Siccardi, and L. Vangelista Antitumor IgE Adjuvanticity: Key Role of Fc{epsilon}RI J. Immunol., October 1, 2009; 183(7): 4530 - 4536. [Abstract] [Full Text] [PDF]
|
|
|
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|
|
S. N. Karagiannis, M. G. Bracher, J. Hunt, N. McCloskey, R. L. Beavil, A. J. Beavil, D. J. Fear, R. G. Thompson, N. East, F. Burke, et al. IgE-Antibody-Dependent Immunotherapy of Solid Tumors: Cytotoxic and Phagocytic Mechanisms of Eradication of Ovarian Cancer Cells J. Immunol., September 1, 2007; 179(5): 2832 - 2843. [Abstract] [Full Text] [PDF]
|
|
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|
 |
|
 A. B. Riemer, E. Untersmayr, R. Knittelfelder, A. Duschl, H. Pehamberger, C. C. Zielinski, O. Scheiner, and E. Jensen-Jarolim Active Induction of Tumor-Specific IgE Antibodies by Oral Mimotope Vaccination Cancer Res., April 1, 2007; 67(7): 3406 - 3411. [Abstract] [Full Text] [PDF]
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 |
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 A. K. Kriegeskorte, F. E. Gebhardt, S. Porcellini, M. Schiemann, C. Stemberger, T. J. Franz, K. M. Huster, L. N. Carayannopoulos, W. M. Yokoyama, M. Colonna, et al. NKG2D-independent suppression of T cell proliferation by H60 and MICA PNAS, August 16, 2005; 102(33): 11805 - 11810. [Abstract] [Full Text] [PDF]
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) or control biotinylated IgGs (•) were administered on day 4. Data are expressed as the mean ± 2 SE of tumor volumes. Statistically significant difference was observed between IgE-treated and IgG-treated groups (P < 0.01).
) RMA-Thy 1.1 cells were cocultured with 5 x 105 irradiated syngeneic spleen cells in the presence of various concentrations of SLTPRCNTAWNRL peptide, corresponding to the MuLV env I-Ab-restricted T helper epitope. After 4 days, [3H]Thymidine was added for 18 h. One representative experiment of two is shown.