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CUTTING EDGE |
Departments of
*
Microbiology and
Surgery, Dartmouth Medical School, Lebanon, NH, 03756;
Immunex Corporation, Seattle, WA, 98101; and
§
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-producing) phenotype following cognate interaction
with Ag-pulsed APCs (9).
Although the function of CD40 as a maturational signal for B cells to
differentiate to competent APCs has already been established (10), the
role of CD40 in DC maturation and function in vivo is unresolved. The
question remains as to whether such "professional" APCs must be
matured by a CD40 signal to generate functional cellular responses. In
vitro studies have shown that the triggering of CD40 on DCs is superior
at inducing IL-12 secretion and at enhancing the Ag presentation
capabilities of DCs in comparison with other inflammatory
mediators such as bacterial LPS or TNF-
(6). These data underscore
the potential importance of CD40 as a central component for the
maturation and APC function of DCs in vivo.
We have recently shown that the generation of protective tumor immunity following the administration of normally effective vaccine regimens is dependent upon CD40/CD154 interactions (11). Herein, we demonstrate that DCs fail to generate protective tumor immunity if they do not express CD40; we also provide evidence to suggest that CD40-mediated IL-12 production by DCs and/or macrophages is critical for the generation of effectors that are capable of Th1-type cytokine production following tumor vaccination.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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We obtained 6- to 8-wk-old female BALB/c (H-2d) and C57BL/6 (H-2b) mice from the National Cancer Institute (Bethesda, MD). CD40- (H-2d) and CD154-deficient mice (H-2b) were bred at the Dartmouth-Hitchcock Medical Center (DHMC) and have been described previously (8, 12). All mice were maintained in a specific pathogen-free animal facility at DHMC, and all animal studies were preapproved by the DHMC Institutional Animal Care and Use Committee.
Cell lines and cell culture
The MB49 bladder carcinoma cell line (13), the sarcomas MCA-105 and MCA-205, and the adenocarcinoma TS/A were maintained as described previously (11). The MB49 cell line was doubly infected with two murine stem cell virus retroviruses (14) that were separately carrying the cDNAs for the p35 and p40 subunits of murine IL-12 and were selected for stable expression using G418 and puromycin. It was determined that the MB/IL-12 cell line secreted 2700 pg/ml/2 x 105 cells/36 h of bioactive IL-12 as assessed by ELISA, whereas the amount of IL-12 produced by both parental MB49 and MB/neo (infected with empty virus) was below the limit of detection (data not shown). The parental MB49, MB/IL-12, and MB/neo lines were kindly provided by Dr. John Leonard (Genetics Institute, Andover, MA).
Abs and flow cytometry
The following Abs were used: M5-biotin (MHCII; American Type
Culture Collection (ATCC), Manassas, VA), N418-biotin/FITC (CD11c; a
gift of Ralph Steinman, Rockefeller University, New York, NY),
GL1-biotin (B7-2; ATCC), 1C10-biotin (CD40; a gift of Maureen
Howard, DNAX, Palo Alto, CA), rat Ig-biotin/FITC (Harlan, Indianapolis,
IN), 6B2-biotin (CD45R/B220; ATCC), H-2Dd-biotin, and
B7-1-biotin (PharMingen, San Diego, CA). Abs that had been
conjugated to biotin were detected using either
streptavidin-phycoerythrin or streptavidin-FITC (Southern
Biotechnologies, Birmingham, AL). Cells were analyzed by flow cytometry
according to standard protocols with a FACScan (Becton Dickinson,
Mountain View, CA).
DC preparation
Splenic DCs were prepared as described previously (15). Flt3 ligand (Flt3L)-splenic DCs were generated in vivo as described previously (16) and then isolated from the spleen by the depletion of T cells using anti-Thy1.2 (HO-13-4; ATCC), anti-CD4 (RL172/4; ATCC), and guinea pig complement (Cedarlane, Ontario, Canada); B cells were subsequently removed by panning twice on petri dishes that had been coated with goat anti-mouse Ig (Zymed, San Francisco, CA). Normal and Flt3L-generated DCs were harvested, washed, and analyzed by flow cytometry for purity. Both BALB/c and CD40-deficient DCs expressed N418/CD11c as well as high levels of CD80, CD86, and MHC class II, whereas the expression of CD40 was restricted to the cells derived from BALB/c mice. Preparations were typically between 70 and 80% positive for N418/CD11c (data not shown).
Vaccine protection studies
Vaccines consisted of varying numbers of normal or
Flt3L-generated splenic DCs that were admixed with irradiated TS/A
tumor cells (3,500 or 10,000 rad) and were followed by a live TS/A
challenge as indicated in the figure legends. The adjuvant-enhanced
MCA-105 vaccine was administered as described previously (11). The
mock- and IL-12-transduced MB49 tumor vaccines were administered as
indicated in the figure legends. All tumor diameters were measured
starting at 1 wk after live tumor injection using a caliper. Tumors
were measured every 3 days, and mice whose tumors reached a diameter of
>2 cm were sacrificed as per Institutional Animal Care and Use
Committee guidelines. For protection studies, Fisher’s exact
test was used to compare the proportions of surviving mice, and tumor
growth was measured for 
70 days in all experiments.
Cytokine measurement
Supernatants from draining lymph node (DLN) cells were generated
as indicated in the figure legends; the supernatants were subsequently
assayed for cytokine content by ELISA using unconjugated rat
anti-mouse IL-2, IL-4, and IFN- and hamster/rat anti-mouse
IL-12 (PharMingen) as the capture Abs, followed by detection with
biotinylated rat anti-mouse IL-2, IL-4, IFN-, and IL-12
(PharMingen) as per the manufacturer’s recommendations. The ELISAs
were developed using streptavidin-horseradish peroxidase
(Amersham, Arlington Heights, IL) and
tetramethylbenzidine substrate (Sigma, St. Louis, MO).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The production of Th1-type inflammatory cytokines (IL-2 and
IFN-) clearly aids in the effective generation of tumor-specific
CD8+ CTLs (17, 18), and it is has been demonstrated that
Th1-type responses afford optimal tumor protection (19). T cells are
the therapeutic effectors that are generated by immunization with the
sarcoma MCA-105 in conjunction with the bacterial adjuvant
Corynebacterium parvum, and both CD4+ and
CD8+ T cells are required for the generation of protective
immunity following vaccination with MCA-105 tumor (17). We postulated
that the requirement for CD40/CD154 interactions in the induction of
systemic immunity following MCA-105 vaccination (11) is a reflection of
the fact that a protective Th1-type response is not generated in the
absence of this receptor/ligand pair. To test this hypothesis, mice
that had been treated with anti-CD154 or control hamster Ig (HIg)
were vaccinated with MCA-105 admixed with C. parvum, and DLN
cells were assessed for cytokine production following in vitro
restimulation as described in the figure legends. The production of
both IFN- (Fig. 1
A) and
IL-2 (Fig. 1B) by DLN cells was completely blocked by the
administration of anti-CD154, indicating that the priming of
tumor-specific CD4+ and/or CD8+ T cells for
Th1-type cytokine production is impaired in the absence of CD40/CD154
interactions. The amount of IL-4 production in these experiments was
below detectable levels for all treatment groups (data not shown),
suggesting that a blockade of this receptor/ligand pair did not result
in an overt polarization from a Th1-type (IFN--producing) to a
Th2-type (IL-4-producing) response as has been described by others (8, 12, 20).
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DCs require maturation via CD40 to restore protective tumor immunity in CD40-deficient mice.
A defective priming of T cells to produce Th1-type cytokines as
the result of a CD40/CD154 blockade (Fig. 1
) may suggest that APCs
require a CD40 signal to effectively trigger T cell activation and
differentiation in response to tumor Ag. As CD40-deficient mice exhibit
impaired antitumor responses (11), we next assessed whether the
injection of splenic CD40+/+ DCs with tumor Ag would
reconstitute protective tumor immunity in these animals. As indicated
in Figure 2A, CD40-deficient
mice that had been immunized with tumor cells alone succumbed to a live
tumor challenge with kinetics that were similar to those observed with
unimmunized BALB/c mice. On the other hand, 50% of CD40-deficient mice
that had been immunized with tumor cells and CD40-bearing DCs were
protected from tumor challenge. This experiment is representative of
three experiments that were performed. In total, 10 of 15 (67%)
CD40-deficient mice receiving the DC plus tumor cell vaccine were
protected from tumor challenge compared with only 2 of 18 (11%) mice
that had been immunized with TS/A tumor cells alone
(p = 0.001).
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B, group 3), those mice receiving CD40+/+ DCs
with tumor cells were completely protected from live tumor challenge
(five of five mice, group 4, p = 0.01). Of note,
CD40-deficient mice that were injected with the same dose of TS/A and
the same number of CD40-/- DCs were poorly protected (one
of six mice, group 5); this finding was identical with that seen for
the CD40-deficient mice receiving irradiated tumor cells alone (group
3). In light of the fact that only 50% of CD40+/+ BALB/c
mice that had been immunized with irradiated TS/A cells alone typically
exhibited long-term protection in our study (two of six mice (33%) in
this case, group 2), the ability of the CD40+/+ DCs admixed
with irradiated TS/A cells to induce complete protection in
CD40-deficient mice (group 4) illustrates the efficiency with which
these professional APCs are able to prime naive T cells. Earlier
studies involving the use of DC vaccines have suggested that the
activation of T cells against FCS components within the media such as
BSA leads to a significant degree of nonspecific lytic activity
following the administration of these APCs in vivo (23). Our
observation that CD40-/- DCs do not generate protective
tumor immunity even in the presence of serum suggests that CD40 is
critical for the APC function of DCs, regardless of whether there is
some contribution of FCS-specific T cells to the clearance of live
tumors in our model system.
Similar reconstitution experiments were performed in CD40-deficient
mice using CD40+/+ or CD40-/- DCs that were
derived from mice treated with Flt3L; Flt3L is a recently identified
hematopoietic stem cell growth factor that induces a 17-fold increase
in splenic N418+ MHC class II+ DCs, which are
functionally equivalent to conventional splenic DCs (16). BALB/c and
CD40-deficient mice were vaccinated with irradiated TS/A cells with or
without CD40+/+ or CD40-/- Flt3L DCs and then
challenged with live parental TS/A cells as indicated in the figure
legends. As shown in Figure 2C, CD40-deficient mice that
were vaccinated with TS/A alone exhibited only 13% long-term survival
(one of eight mice, group 3), whereas CD40-/- mice that
were immunized with tumor cells and CD40+/+ Flt3L DCs were
almost completely protected (seven of eight mice, group 4,
p = 0.01). However, vaccination with equal numbers of
tumor cells and CD40-/- Flt3L DCs afforded the
CD40-deficient mice no protection (zero of seven mice, group 5). This
experiment was repeated with analogous results. These data indicate
that Flt3L-generated DCs, like conventional splenic DCs, require
activation via CD40 for their maturation into efficient APCs that are
capable of generating protective tumor immunity.
To our knowledge, these data are the first demonstration of the
absolute requirement for CD40 expression on DCs for their function as
mature APCs in vivo. Consistent with the hypothesis that CD40 plays a
critical role in DC function, CD40-deficient mice are incapable of
generating protective cell-mediated tumor immunity (11). The immune
deficiency in these mice appears to be the result of a lesion in APC
function, in that the coadministration of CD40-bearing DCs with
irradiated tumor cells restores the ability of these mice to clear a
live parental tumor challenge (Fig. 2, A–C). The failure of
CD40-/- DCs to reconstitute tumor protection in this
manner (Fig. 2, B and C) suggests a crucial role
for this receptor in the maturation of both conventional and
Flt3L-generated splenic DCs into efficient APCs. Interestingly, a
number of laboratories have demonstrated that Ag-pulsed DCs fail to
generate protective immune responses in vivo in the absence of
CD4+ T cells (24, 25). Our data suggest that the
requirement for Th cells in these other studies is a reflection of the
fact that DCs require the CD40 maturation signals induced during
cognate interaction with CD154-bearing CD4+ T cells to
become efficient APCs.
Exogenous IL-12 partially bypasses the requirement for CD40/CD154 interactions in the induction of protective tumor immunity
The failure of CD40-/- DCs to restore protective
immunity in CD40-deficient mice (Fig. 2, B and C)
may be due to insufficient costimulatory capacity and/or to their
inability to produce inflammatory cytokines, both of which are
important for the generation of CMI. The cytokine IL-12 has been shown
to play a pivotal role in the differentiation of naive CD4+
T cells toward the Th1 phenotype (9), and recent studies suggest that
IL-12 secretion by DCs following cognate interaction with Th cells is
largely CD40/CD154-dependent (7). As it is generally accepted that
inflammatory Th1-type responses are most beneficial in the context of
tumor protection (18, 19), it is reasonable to postulate that
CD40-mediated IL-12 production may be critical for the generation of
tumor protection, and that a source of exogenous IL-12 may allow for
the induction of systemic tumor immunity in the absence of CD40/CD154
interactions. To test this hypothesis, both C57BL/6 mice that had been
treated with either anti-CD154 or control HIg and CD154-deficient
mice were vaccinated with the syngeneic bladder carcinoma line MB49;
this line was either mock-transduced or transduced with the genes
encoding the p35 and p40 chains of IL-12, leading to the secretion of
bioactive IL-12 from the tumor (see Materials and Methods).
Mice were vaccinated, treated with Ab, and challenged with live
parental MB49 cells as described in Table I. Vaccination with the mock-transduced
MB49 line (MB/neo) almost completely protected all of the C57BL/6 mice
that had been treated with control HIg (96% protection), indicating
that the MB49 line itself was highly immunogenic. However, the ability
of this line to induce systemic tumor immunity is dependent upon
CD40/CD154 interactions, in that the immunization of CD154-deficient or
anti-CD154-treated mice with the same MB/neo vaccine dose failed to
generate a protective immune response in these groups (only 3 of 18
mice protected (17%) and 0 of 10 mice protected (0%), respectively).
However, the secretion of IL-12 by the tumor vaccine appears to
partially bypass the requirement for CD40/CD154 interactions, in that
CD154-deficient and anti-CD154-treated mice that had been
vaccinated with the IL-12-transduced cell line (MB/IL-12) were able to
generate significant protective responses vs those animals receiving
the MB/neo vaccine (58% vs 0% for anti-CD154-treated C57BL/6
mice, p = 0.001; 67% vs 17% for CD154-deficient mice,
p = 0.01).
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Taken together, the data presented in this study suggest that the inability to generate protective tumor immunity in the absence of CD40/CD154 interactions is due to the lack of a strong Th1-type response following vaccination and results from the failure of DCs and/or macrophages to produce IL-12 following CD40 ligation.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Richard J. Barth Jr., Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756. E-mail address:
3 Abbreviations used in this paper: CMI, cell-mediated immunity; DC, dendritic cell; Flt3L, Flt3 ligand; DLN, draining lymph node; HIg, hamster Ig.
Received for publication April 15, 1998. Accepted for publication July 2, 1998.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes. J. Exp. Med. 173:647.This article has been cited by other articles:
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L. A. Lambert, G. R. Gibson, M. Maloney, B. Durell, R. J. Noelle, and R. J. Barth Jr. Intranodal Immunization with Tumor Lysate-pulsed Dendritic Cells Enhances Protective Antitumor Immunity Cancer Res., January 1, 2001; 61(2): 641 - 646. [Abstract] [Full Text]
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J. G. Turner, A. L. Rakhmilevich, L. Burdelya, Z. Neal, M. Imboden, P. M. Sondel, and H. Yu Anti-CD40 Antibody Induces Antitumor and Antimetastatic Effects: The Role of NK Cells J. Immunol., January 1, 2001; 166(1): 89 - 94. [Abstract] [Full Text] [PDF]
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M. Schnurr, F. Then, P. Galambos, C. Scholz, B. Siegmund, S. Endres, and A. Eigler Extracellular ATP and TNF-{alpha} Synergize in the Activation and Maturation of Human Dendritic Cells J. Immunol., October 15, 2000; 165(8): 4704 - 4709. [Abstract] [Full Text] [PDF]
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 J. W. Hodge, A. N. Rad, D. W. Grosenbach, H. Sabzevari, A. G. Yafal, L. Gritz, and J. Schlom Enhanced Activation of T Cells by Dendritic Cells Engineered to Hyperexpress a Triad of Costimulatory Molecules J Natl Cancer Inst, August 2, 2000; 92(15): 1228 - 1239. [Abstract] [Full Text] [PDF]
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A. De Creus, K. Van Beneden, T. Taghon, F. Stolz, V. Debacker, J. Plum, and G. Leclercq Langerhans Cells That Have Matured In Vivo in the Absence of T Cells Are Fully Capable of Inducing a Helper CD4 as Well as a Cytotoxic CD8 Response J. Immunol., July 15, 2000; 165(2): 645 - 653. [Abstract] [Full Text] [PDF]
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P. Terheyden, P. t. Straten, E.-B. Brocker, E. Kampgen, and J. C. Becker CD40-Ligated Dendritic Cells Effectively Expand Melanoma-Specific CD8+ CTLs and CD4+ IFN-{gamma}-Producing T Cells from Tumor-Infiltrating Lymphocytes J. Immunol., June 15, 2000; 164(12): 6633 - 6639. [Abstract] [Full Text] [PDF]
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S. Muerkoster, J. D. Laman, M. Rocha, V. Umansky, and V. Schirrmacher Functional and in Situ Evidence for Nitric Oxide Production Driven by CD40-CD40L Interactions in Graft-versus-Leukemia Reactivity Clin. Cancer Res., May 1, 2000; 6(5): 1988 - 1996. [Abstract] [Full Text] [PDF]
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S. Skov, M. Bonyhadi, N. Odum, and J. A. Ledbetter IL-2 and IL-15 Regulate CD154 Expression on Activated CD4 T Cells J. Immunol., April 1, 2000; 164(7): 3500 - 3505. [Abstract] [Full Text] [PDF]
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C. N. Baxevanis, I. F. Voutsas, O. E. Tsitsilonis, A. D. Gritzapis, R. Sotiriadou, and M. Papamichail Tumor-Specific CD4+ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor J. Immunol., April 1, 2000; 164(7): 3902 - 3912. [Abstract] [Full Text] [PDF]
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R. Josien, H.-L. Li, E. Ingulli, S. Sarma, B. R.Wong, M. Vologodskaia, R. M. Steinman, and Y. Choi Trance, a Tumor Necrosis Factor Family Member, Enhances the Longevity and Adjuvant Properties of Dendritic Cells in Vivo J. Exp. Med., February 7, 2000; 191(3): 495 - 502. [Abstract] [Full Text] [PDF]
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S. Schnell, J. W. Young, A. N. Houghton, and M. Sadelain Retrovirally Transduced Mouse Dendritic Cells Require CD4+ T Cell Help to Elicit Antitumor Immunity: Implications for the Clinical Use of Dendritic Cells J. Immunol., February 1, 2000; 164(3): 1243 - 1250. [Abstract] [Full Text] [PDF]
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S. M. Kiertscher, J. Luo, S. M. Dubinett, and M. D. Roth Tumors Promote Altered Maturation and Early Apoptosis of Monocyte-Derived Dendritic Cells J. Immunol., February 1, 2000; 164(3): 1269 - 1276. [Abstract] [Full Text] [PDF]
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P. A. Taylor, A. Panoskaltsis-Mortari, R. J. Noelle, and B. R. Blazar Analysis of the Requirements for the Induction of CD4+ T Cell Alloantigen Hyporesponsiveness by Ex Vivo Anti-CD40 Ligand Antibody J. Immunol., January 15, 2000; 164(2): 612 - 622. [Abstract] [Full Text] [PDF]
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L. Lefrancois, J. D. Altman, K. Williams, and S. Olson Soluble Antigen and CD40 Triggering Are Sufficient to Induce Primary and Memory Cytotoxic T Cells J. Immunol., January 15, 2000; 164(2): 725 - 732. [Abstract] [Full Text] [PDF]
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M. E. Ozaki, B. A. Coren, T. N. Huynh, D. J. Redondo, H. Kikutani, and S. R. Webb CD4+ T Cell Responses to CD40-Deficient APCs: Defects in Proliferation and Negative Selection Apply Only with B Cells as APCs J. Immunol., November 15, 1999; 163(10): 5250 - 5256. [Abstract] [Full Text] [PDF]
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M. Subklewe, A. Chahroudi, A. Schmaljohn, M. G. Kurilla, N. Bhardwaj, and R. M. Steinman Induction of Epstein-Barr Virus-Specific Cytotoxic T-Lymphocyte Responses Using Dendritic Cells Pulsed With EBNA-3A Peptides or UV-Inactivated, Recombinant EBNA-3A Vaccinia Virus Blood, August 15, 1999; 94(4): 1372 - 1381. [Abstract] [Full Text] [PDF]
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I. F. Hermans, D. S. Ritchie, A. Daish, J. Yang, M. R. Kehry, and F. Ronchese Impaired Ability of MHC Class II-/- Dendritic Cells to Provide Tumor Protection is Rescued by CD40 Ligation J. Immunol., July 1, 1999; 163(1): 77 - 81. [Abstract] [Full Text] [PDF]
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J. E. Buhlmann, M. Gonzalez, B. Ginther, A. Panoskaltsis-Mortari, B. R. Blazar, D. L. Greiner, A. A. Rossini, R. Flavell, and R. J. Noelle Cutting Edge: Sustained Expansion of CD8+ T Cells Requires CD154 Expression by Th Cells in Acute Graft Versus Host Disease J. Immunol., April 15, 1999; 162(8): 4373 - 4376. [Abstract] [Full Text] [PDF]
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R. E.M. Toes, F. Ossendorp, R. Offringa, and C. J.M. Melief CD4 T Cells and Their Role in Antitumor Immune Responses J. Exp. Med., March 1, 1999; 189(5): 753 - 756. [Full Text] [PDF]
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C.G. Begley and N.A. Nicola Resolving Conflicting Signals: Cross Inhibition of Cytokine Signaling Pathways Blood, March 1, 1999; 93(5): 1443 - 1447. [Full Text] [PDF]
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) or 1 x 106
irradiated TS/A cells (
); CD40-deficient mice were injected with the
same tumor vaccine dose either alone (•) or admixed with 1.4 x
105 splenic DCs that had been purified from untreated
BALB/c (CD40+/+) donors (
). All mice were then
challenged s.c. after 14 days with 1.5 x 105 live
parental TS/A cells in the right flank. One representative experiment
of three is shown. In total, 10 of 15 CD40-deficient mice receiving the
DCs plus the tumor cell vaccine were protected from tumor challenge
compared with only 2 of 18 mice that had been immunized with tumor
alone (p = 0.001). B, BALB/c and
CD40-deficient mice were injected with HBSS, with the TS/A vaccine
alone (1 x 106 cells), or with the TS/A vaccine
admixed with 3.25 x 105 splenic DCs that had been
derived from untreated CD40-deficient (CD40-/-) or
wild-type BALB/c (CD40+/+) donors. All mice were then
challenged as indicated above with 5 x 105 live
parental TS/A cells. C, BALB/c and CD40-deficient mice
were injected with HBSS, with the TS/A vaccine alone (1 x
106), or with the TS/A vaccine admixed with 5 x 105 splenic DCs
that had been isolated from CD40-deficient (CD40-/-) or
wild-type BALB/c (CD40+/+) mice treated with Flt3L as
indicated in the Materials and Methods. All mice were
then challenged with 1 x 106 live parental TS/A cells
as indicated above. In all experiments, tumor growth and survival were
followed as a measure of the protective immunity induced by the various
vaccines, and tumor measurements were performed for