| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,§
*
Department of Immunology, Juntendo University, School of Medicine;
Department of Joint Disease and Rheumatism, Nippon Medical School;
Department of Immunology, National Children’s Medical Research Center;
§
CREST, Japan Science and Technology Corporation (JST), Tokyo, Japan; and
¶
Department of First Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
While the CD28-B7 interaction constitutes a predominant pathway
of T cell costimulation, some intact T cell responses in CD28-deficient
mice have suggested the presence of alternative pathways that
may be mediated by CD40 ligand
(CD40L)3 and CD44 on T cells
or heat-stable Ag on APCs (15, 16, 17, 18). CD40L is a type II membrane protein
belonging to the TNF family and predominantly expressed on
CD4+ T cells upon TCR stimulation. Its receptor CD40
belongs to the TNF receptor family and is expressed on B cells,
macrophages, and dendritic cells (DC) (19). Although the CD40-CD40L
interaction has been primarily implicated in the T-dependent humoral
immune responses, recent studies have revealed its important roles in
cellular immunity (20, 21). It has been reported that either CD40- or
CD40L-deficient mice could not resolve the Leishmania
major infection (22, 23, 24) and that administration of
anti-CD40L mAb could prevent acute graft-vs-host disease, cardiac
allograft rejection, and experimental allergic encephalomyelitis
(25, 26, 27). The CD40 stimulation has been demonstrated to induce the
production of proinflammatory cytokines such as TNF-
, IL-8, and
IL-12 from macrophages and DC (28, 29, 30, 31, 32, 33, 34, 35). It also augments the APC
activity of B cells, macrophages, and DC by up-regulating the
expression of B7 and other costimulatory molecules (36, 37, 38). A recent
report demonstrated critical involvement of the CD40-CD40L interaction
in induction of protective antitumor immunity by vaccination with
irradiated tumor cells (39). In addition, it has also recently been
demonstrated that transgenic expression of CD40L in some tumor cell
lines reduced their tumorigenicity and elicited protective immunity,
while the mechanism by which CD40L exerted the antitumor effect in vivo
has not been elucidated (40, 41).
In the present study, we compared the costimulatory mode of CD40L with that of B7 by characterizing the host responses to CD40L- or B7-transduced tumor cells. CD40L exhibited a potent antitumor effect, which was distinct from B7 and predominantly mediated by potentiation of host APC functions. Our results indicated that introduction of CD40L into tumor elicits more efficient antitumor response than that of B7.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Six- to eight-week-old female DBA/2 mice and C57BL/6 mice were purchased from SLC (Shizuoka, Japan). BALB/c nu/nu mice were purchased from Charles River Japan (Atsugi, Japan). These mice were used in accordance with the guidelines of the Committee on Animals of the Juntendo University School of Medicine.
Tumor cells and transfectants
Murine CD40L cDNA was prepared by RT-PCR from total RNA of anti-CD3-activated D10.G4 T cell clone by using an oligonucleotide corresponding to the first six codons as the 5' primer and to the last six codons as the 3' primer, according to the published sequence (42). The 5' and 3' primers were tagged with XhoI or NotI site, respectively. After XhoI and NotI digestion, the PCR product was subcloned into pBluescript II SK+ (Stratagene, La Jolla, CA), and nucleotide sequence was confirmed by sequencing. The CD40L cDNA was then transferred into XhoI and NotI sites of the BCMGSneo expression vector. A murine mastocytoma cell line P815 of DBA/2 origin and a murine melanoma cell line B16 of C57BL/6 origin were transfected with murine CD40L cDNA in BCMGSneo by electroporation as described (43). Stable transfectants were obtained by selection in 1 mg/ml G418 (Sigma, St. Louis, MO), and the cells expressing CD40L were isolated by flow cytometry. The mock P815 or mock B16 cells were derived similarly but transfected with the vector without insert. B7-1-P815 cells were prepared as described previously (43).
Immunofluorescence and flow cytometry
Cells were first preincubated with anti-Fc
R mAb
(2.4G2, PharMingen, San Diego, CA) to block nonspecific binding of mAb
to FcR and then incubated with either phycoerythrin-conjugated or
biotinylated mAb for 30 min at 4°C. Biotinylated mAbs were detected
with phycoerythrin-conjugated streptavidin (Becton Dickinson, San Jose,
CA). mAb against the following Ags were obtained from PharMingen: CD40L
(MR1), CD40 (HM40–3), B7-1 (1G10), B7-2 (GL1), ICAM-1 (3E2), MHC class
II (M5/114), and MHC class I (34-2-12). Murine CTLA-4 human Ig fusion
protein (CTLA4Ig) was generously provided by Dr. Peter Lane (Basel
Institute for Immunology, Basel, Switzerland). FITC-conjugated goat
anti-human IgG Fc (absorbed with mouse Ig) was purchased from
Caltag (South San Francisco, CA). The stained cells were analyzed on
FACScan (Becton Dickinson).
In vitro assay and ELISA
Peritoneal cells were isolated from DBA/2 mice and plated at 2 x 106 cells/well in RPMI 1640 containing 10% FBS, 1 mM L-glutamine, 0.05 mM 2-ME, and antibiotics. After a 2-h incubation at 37°C, plates were washed three times to remove nonadherent cells. Adherent cells (0.8–1.2 x 106/well, >90% CD11b+ as estimated by flow cytometry) were cocultured with mitomycin C-treated P815 or CD40L-P815 cells at the indicated numbers in the presence of 1 µg/ml anti-IL-10 (JES5–2A5) and 2 µg/ml Indomethacin. After 20 h, cell-free culture supernatants were subjected to IL-12 p70-specific ELISA according to the protocol recommended by the manufacturer (PharMingen). In some experiments, adherent peritoneal cells were cultured with 2 x 105 cells of P815 or CD40L-P815 for 24 h and stained with CTLA4Ig followed by FITC-conjugated anti-human IgG Fc to evaluate B7 levels.
Tumor growth and in vivo Ab treatment
P815, CD40L-P815, or B7-1-P815 cells (2 x 105/mouse) were s.c. inoculated into the shaved back of DBA/2 or BALB/c nu/nu mice in a 0.1-ml volume of PBS. In some experiments, CD40L-P815 (2 x 105 cells) were preincubated with 100 µg of anti-CD40L mAb in vitro before inoculation. Similarly, 1 x 105 cells of B16 or CD40L-B16 were inoculated into C57BL/6 mice as described above. The mice were monitored for tumor growth weekly, and tumor size was determined by measuring two perpendicular diameters with a caliper. Some mice that had rejected the primary inoculation of CD40L or B7-1 transfectants were then challenged with 2 x 105 parental P815 cells or 1 x 106 L5178Y cells at the distant sites on day 30 after the primary inoculation. In some experiments, 2 x 105 cells each of CD40L-P815 and parental P815 were simultaneously inoculated at the same or distant sites. The results are expressed as mean ± SD of five to ten mice in each group.
For in vivo depletion of T cells, mice were i.p. administered with 1 mg each of anti-CD4 (GK1.5) and/or anti-CD8 (53.6.72) mAbs 1 day before the tumor inoculation. For depleting NK cells, 500 µg of anti-asialo GM1 Ab (Yamasa, Chiba, Japan) was administered i.v. 1 day before the tumor inoculation. In preliminary experiments, depletion of the respective populations was confirmed up to 7 days after the treatment. To block the B7-CD28 interaction, 250 µg each of anti-B7-1 (RM80) and anti-B7-2 (PO3) mAbs (43, 44) were i.p. administered twice a week for 2 weeks starting at 1 day before the tumor inoculation. Endogenous IL-12 or IL-4 were neutralized by i.p. administration of 1 mg anti-IL-12 (C17.8, generously provided by Dr. G. Trinchieri, The Wistar Institute of Anatomy and Biology, Philadelphia, PA) or anti-IL-4 (11B11, PharMingen), respectively, twice a week for 2 weeks starting at day -1. In each experiment, equivalent an amount of rat IgG (Sigma) was administered as control and did not affect the tumor growth.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We transfected the murine CD40L cDNA into murine mastocytoma P815
cells that had not expressed CD40L. Stable transfectants
expressing high levels of murine CD40L (CD40L-P815) were identified by
FACS analysis (Fig. 1
). CD40L-P815 and
parental P815 cells expressed comparable levels of MHC class I and
ICAM-1 but did not express CD40, B7-1, or B7-2 (Fig. 1). We also
analyzed the expression of these molecules on B7-1-P815 cells and
obtained similar results except for the high expression of B7-1 (Fig. 1, and data not shown). No difference in the growth rate in vitro was
observed between CD40L-P815 or B7-1-P815 and the parental P815 cells
(data not shown).
|
It has been known that the stimulation of APC such as macrophages
or DC with CD40L leads to production of IL-12 and up-regulation of B7
molecules (28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38). To verify whether CD40L-P815 cells have such
abilities, we stimulated peritoneal macrophages from DBA/2 mice with
CD40L-P815 cells in vitro. As shown in Figure 2A, peritoneal macrophages
produced IL-12 p70 when cocultured with CD40L-P815 but not with
wild-type P815 cells. Up-regulation of B7 molecules by CD40L-P815 cells
was also observed when cocultured with CD40L-P815 (Fig. 2D)
but not with P815 cells (Fig. 2C). These stimulatory effects
of CD40L-P815 cells were abrogated by the addition of anti-CD40L
mAb (data not shown). These results indicated that CD40L on CD40L-P815
cells was functionally active in stimulating APC.
|
To examine the effect of CD40L on tumor growth in vivo, P815 or
CD40L-P815 cells were inoculated s.c. into syngenic DBA/2 mice.
B7-1-P815 cells were also inoculated for comparison. Although either
the parental P815 or mock P815 cells grew progressively and killed the
mice within 50 days, the CD40L-P815 cells were completely rejected
without forming a palpable tumor (Fig. 3A). CD40L-B16 cells, but not
parental B16 cells, were also rejected without transient growth in all
mice, similar to the rejection of CD40L-P815 cells (data not shown).
The rejection of CD40L-P815 was due to the local expression of CD40L,
since the CD40L-P815 cells that were pretreated with anti-CD40L mAb
in vitro before inoculation grew equivalently to the parental P815
cells (Fig. 3A). A similar rejection was also observed when
the CD40L-P815 cells were inoculated s.c. into BALB/c nu/nu
mice (Fig. 3B), suggesting that T cells were not essential
for the rejection. In contrast, inoculation of B7-1-P815 resulted in a
transient tumor growth followed by regression within 3 to 5 wk in DBA/2
mice (Fig. 3A) and no significant growth inhibition in
BALB/c nu/nu mice (Fig. 3B) These results
indicated that the introduction of CD40L exerted a potent antitumor
effect by apparently different mechanism from that exerted by the B7-1
introduction.
|
To determine the effector cells responsible for the
rejection of CD40L-P815 cells in DBA/2 mice, we performed in vivo cell
depletion experiments. Consistent with the observation in
nu/nu mice, the rejection of B7-1-P815 but not that of
CD40L-P815 was reversed by the depletion of T cells by anti-CD4 and
anti-CD8 mAbs (Fig. 3
C). Conversely, the rejection of
CD40L-P815 but not that of B7-1-P815 was reversed by the depletion of
NK cells by anti-asialo GM1 Ab (Fig. 3D). These results
indicated that not T cells but NK cells were primarily responsible for
the rejection of CD40L-P815, in contrast to B7-1-P815, whose rejection
was mediated by T cells. Since asialo GM1+ NK cells from
DBA/2 mice did not express CD40 on their surface as estimated by flow
cytometry (data not shown), a direct action of CD40L on NK cells seemed
unlikely. It has been known that the stimulation of macrophages or DC
with CD40L leads to production of IL-12 and up-regulation of B7
(22, 23, 24, 30, 31, 32, 33, 34, 35), both of which have been implicated in the activation
of NK cells. We then examined the contribution of these molecules by
administering the blocking mAbs. Administration of neutralizing
anti-IL-12 mAb, but not control mAb or anti-IL-4 mAb, abrogated
the rejection of CD40L-P815 (Fig. 3E). Administration of
anti-B7-1 and B7-2 mAbs did not affect the rejection of CD40L-P815,
while it abrogated the rejection of B7-1-P815 (Fig. 3F).
These results suggested that the rejection of CD40L-P815 was mediated
by NK cells that were activated by IL-12 from CD40L-stimulated host
APC. When parental P815 cells (2 x 105) were
coimplanted with the same number of CD40L-P815 cells at the same s.c.
site of nu/nu mice, tumor formation was suppressed, while
P815 cells grew well when implanted at a distant site from CD40L-P815
cells (Fig. 3G). This suggests that the NK cell-mediated
effect is locally limited but can also eradicate the bystander tumor
cells that do not express CD40L.
Primary rejection of CD40L-P815 elicits tumor-specific protective immunity
We performed tumor protection experiments to investigate if
CD40L-P815 can elicit protective immunity against subsequent challenge
with parental P815. DBA/2 mice that had rejected the CD40L-P815 cells
inoculated on day 0 were s.c. challenged with parental P815 cells or
DBA/2-derived T cell lymphoma L5178Y cells on day 30. As shown in
Figure 4A, parental P815
cells, but not L5178Y cells, were rejected by these recipients,
indicating the development of P815-specific protective immunity. In
contrast, such a protective immunity was not developed in BALB/c
nu/nu mice even though they still rejected the secondary
challenge with CD40L-P815 (Fig. 4B). Depletion of
CD4+, but not CD8+, T cells at the time of
primary CD40L-P815 inoculation consistently abrogated the protection,
indicating that CD4+ T cells were required for the
induction of protective immunity (Fig. 4C). Since the
immunized CD40L-P815 did not express MHC class II (Fig. 1), this
implied the contribution of host APC expressing MHC class II to the
development of protective immunity. We also performed the cell
depletion study at the time of secondary challenge with P815. Depletion
of CD8+ T cells, but not CD4+ T cells or NK
cells, abrogated the rejection of P815 cells (Fig. 4D),
indicating that the effector cells were CD8+ T cells, as
expected from the lack of MHC class II on P815 cells.
|
We next verified the systemic therapeutic effect of the CD40L
vaccination by inoculating CD40L-P815 and P815 cells simultaneously at
the distant sites on the back of a DBA/2 mouse. As shown in Figure 4E, P815 cells regressed after transient formation of tumor,
and this inhibition was abrogated by the depletion of CD4+
T cells. Such an inhibition on the distant P815 was not observed in
BALB/c nu/nu mice (Fig. 3G). These results
indicated that the T cell-mediated systemic immunity elicited by
CD40L-P815 was efficient for eradicating the wild-type tumors at
distant sites. The transient growth and subsequent regression of P815
cells observed in Figure 4E was very similar to those
observed with B7-1-P815 (Fig. 3A), both of which were
mediated by T cells. Elicitation of T cell immune responses generally
requires a costimulation by APC, but the CD40L-P815 cells lacked B7
(Fig. 1). We then examined the contribution of B7 on host APC.
Administration of the anti-B7-1 and B7-2 mAbs did not affect the
primary rejection of CD40L-P815 (Fig. 3F), but it did
abrogate the elicitation of protective immunity against subsequent
challenge with P815 (Fig. 4C). The anti-B7-1 and
anti-B7-2 treatment also abrogated the systemic inhibition of P815
cells, while sparing the rejection of CD40L-P815 (Fig. 4E).
These results indicated that the elicitation of T cell-mediated
systemic immunity by CD40L-P815 was dependent on B7 molecules that were
potentially up-regulated on host APC by CD40L.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In vivo depletion of lymphocyte subpopulations indicated that NK cells
were essential for the primary rejection of CD40L-P815 cells. However,
a direct activation of NK cells by CD40L was unlikely, since NK cells
did not express CD40, as estimated by flow cytometry, and the
CD40L-P815 cells did not exhibit increased susceptibility to NK cells
in vitro (data not shown). We then assumed an indirect mechanism for
the NK cell activation and found a critical contribution of endogenous
IL-12. This was also confirmed by the result that depletion of NK cells
or administration of anti-IL-12 mAb also abrogated the rejection of
CD40L-B16 cells (data not shown). It has been shown that
CD40L-stimulated macrophages and DC secrete not only IL-12 but also
TNF-, IL-8, and macrophage inflammatory protein (MIP)-1 (28, 29, 30, 31, 32, 33, 34, 35),
which might be responsible for NK cell infiltration at the site of
CD40L-P815 inoculation. It seems most likely that CD40L expressed on
tumor cells acted on dermal macrophages and/or epidermal Langerhans
cells to produce IL-12, which activated infiltrating NK cells to lyse
the tumor cells. This indirect activation scenario is consistent with
our observation that the NK cell-mediated effect was locally limited
but could also eliminate bystander tumor cells that did not express
CD40L (Fig. 2G). In our preliminary experiments, CD40L-P815
and P815 cells were equally susceptible to IL-12-activated NK cells in
vitro (data not shown). The bystander effect exerted by the CD40L
transfectants would be beneficial for eradicating a tumor mass by CD40L
gene transduction since only a part of tumor cells must be transduced.
A similar bystander effect has recently been reported by Grossmann et
al. (41). They demonstrated that expression of CD40L by less than 1.5%
of neuro-2a neuroblastoma cells suppressed the tumor growth, although
they did not address the contribution of NK cells or IL-12.
The primary rejection of CD40L-P815 cells was T cell independent, but it left CD8+ T cell-mediated protective immunity against subsequent challenge with wild-type P815 cells, which required CD4+ T cells and B7 for development. Although CD4+ T cells were required for the induction of protective immunity, P815 cells did not express class II MHC molecules, suggesting the importance of CD8+ T cells as effector cells. In fact, the protection was abrogated when the CD40L-P815-primed mice were depleted of CD8+ T cells at the time of challenge with wild-type P815 cells. These results suggest a scenario that host APC was stimulated by CD40L to up-regulate B7 and activated CD4+ T cells, which in turn help the development of CD8+ T cells. Requirement of CD4+ T cells for the generation of cytotoxic T cells against class II negative tumor was also recently reported by Ossendorp et al. (45). This T cell-mediated effect was systemic and could eradicate wild-type tumor at a distant site. Therefore, vaccination with the CD40L-transduced tumor cells would have a potential to eradicate multiple metastases systemically. A similar elicitation of T cell-mediated protective immunity by CD40L-transfected tumor cells has recently been reported by Dilloo et al. (40) and Grossmann et al (41). In the former case, up-regulation of B7 and MHC molecules was noted on the CD40+ tumor cells themselves and, in the latter case, in splenic APC, although they did not directly address the contribution of B7.
It may be worth noting that some reports have suggested a direct costimulatory effect of CD40L transfectants on human T cell activation (46). However, in our preliminary experiments, CD40L-P815 cells did not significantly costimulate the proliferation of anti-CD3-stimulated CD4+ T cells as compared with P815 cells (data not shown), arguing against the direct costimulatory effect of CD40L. It has been shown that CD40L stimulated macrophages and DC to up-regulate the expression of B7. Therefore, it seems likely that CD40L expressed on P815 cells acted on dermal macrophages and/or epidermal Langerhans cells to up-regulate B7. Then, these cells that took up the putative tumor Ag from the debris of CD40L-P815 cells migrated into the regional lymph node and activated the reactive T cells. Alternatively, CD40L-P815 cells might directly migrate into the regional lymph node where they activated host APC, since such a migration of P815 cells has been shown in a recent report (47). While we used poorly immunogenic P815 cells that did not spontaneously regress in syngenic host, it has been reported that the spontaneous rejection of highly immunogenic P815 variants was also dependent of B7 on host APC (48).
Our present results indicated a potent immunopotentiating effect of
CD40L that appeared to be predominantly mediated by activation of host
APC. It has been suggested by some reports that the CD40L molecules may
directly transmit a costimulatory signal into T cells (46, 49, 50).
However, such a pathway could not work in our present system, where
CD40L was expressed on immunogen. Therefore, our present results
further substantiate that the primary mode of CD40L action on cellular
immunity is to potentiate the APC functions, as also demonstrated in
other model systems (37, 38, 51, 52). The CD40 molecule belongs to the
TNF receptor family, and its cross-linking by trimeric CD40L activates
NF-
B, which leads to the production of proinflammatory cytokines, in
a similar way to that mediated by the TNF/TNF receptor interaction. The
pivotal roles of TNF in regulating both local innate immunity and
systemic acquired immunity have been well documented (53, 54).
Recently, a proinflammatory nature of CD40L in vivo has been
demonstrated (55). Our present results suggest that CD40L can also play
important roles in initiating innate immunity and eliciting acquired
immunity. While we used CD40L gene-transduced tumor cells in the
present model, infiltrating T cells would be a primary source of CD40L
in physiologic conditions. In such a situation, CD40L may act to
accelerate inflammatory reactions.
In conclusion, we demonstrated a potent APC-stimulating activity of CD40L in vivo, which not only is relevant to the costimulatory role of CD40L observed in transplantation and autoimmune disease models but also will be useful as a new strategy of immuno-gene therapy against tumors.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Atsuo Nakajima, Department of Immunology, Juntendo University School of Medicine, 2–1-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail address:
3 Abbreviations used in this paper: CD40L, CD40 ligand; DC, dendritic cell; CTLA4Ig, murine CTLA-4 human Ig fusion protein.
Received for publication February 6, 1998. Accepted for publication April 17, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production. Eur. J. Immunol. 26:1621.[Medline]
This article has been cited by other articles:
|
|
 |
|
  S Serba, J Schmidt, N Wentzensen, E Ryschich, and A Marten Transfection with CD40L induces tumour suppression by dendritic cell activation in an orthotopic mouse model of pancreatic adenocarcinoma Gut, March 1, 2008; 57(3): 344 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. N. Buhtoiarov, H. Lum, G. Berke, D. M. Paulnock, P. M. Sondel, and A. L. Rakhmilevich CD40 Ligation Activates Murine Macrophages via an IFN-{gamma}-Dependent Mechanism Resulting in Tumor Cell Destruction In Vitro J. Immunol., May 15, 2005; 174(10): 6013 - 6022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.A. Schey, P. Fields, J.B. Bartlett, I.A. Clarke, G. Ashan, R.D. Knight, M. Streetly, and A.G. Dalgleish Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma J. Clin. Oncol., August 15, 2004; 22(16): 3269 - 3276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Miyahira, H. Akiba, M. Katae, K. Kubota, S. Kobayashi, T. Takeuchi, A. Garcia-Sastre, Y. Fukuchi, K. Okumura, H. Yagita, et al. Cutting Edge: A Potent Adjuvant Effect of Ligand to Receptor Activator of NF-{kappa}B Gene for Inducing Antigen-Specific CD8+ T Cell Response by DNA and Viral Vector Vaccination J. Immunol., December 15, 2003; 171(12): 6344 - 6348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. T. van den Broeke, E. Daschbach, E. K. Thomas, G. Andringa, and J. A. Berzofsky Dendritic Cell-Induced Activation of Adaptive and Innate Antitumor Immunity J. Immunol., December 1, 2003; 171(11): 5842 - 5852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Younes and M. E. Kadin Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy J. Clin. Oncol., September 15, 2003; 21(18): 3526 - 3534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Friedlander, C. L. Delaune, J. M. Abadie, M. Toups, J. LaCour, L. Marrero, Q. Zhong, and J. K. Kolls Efficacy of CD40 Ligand Gene Therapy in Malignant Mesothelioma Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): 321 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tahara, K. Fujio, Y. Araki, K. Setoguchi, Y. Misaki, T. Kitamura, and K. Yamamoto Reconstitution of CD8+ T Cells by Retroviral Transfer of the TCR {alpha}{beta}-Chain Genes Isolated from a Clonally Expanded P815-Infiltrating Lymphocyte J. Immunol., August 15, 2003; 171(4): 2154 - 2160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Rieger and T. J. Kipps CpG Oligodeoxynucleotides Enhance the Capacity of Adenovirus-mediated CD154 Gene Transfer to Generate Effective B-Cell Lymphoma Vaccines Cancer Res., July 15, 2003; 63(14): 4128 - 4135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Keating, N. Chiorazzi, B. Messmer, R. N. Damle, S. L. Allen, K. R. Rai, M. Ferrarini, and T. J. Kipps Biology and Treatment of Chronic Lymphocytic Leukemia Hematology, January 1, 2003; 2003(1): 153 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Tutt, L. O'Brien, A. Hussain, G. R. Crowther, R. R. French, and M. J. Glennie T Cell Immunity to Lymphoma Following Treatment with Anti-CD40 Monoclonal Antibody J. Immunol., March 15, 2002; 168(6): 2720 - 2728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Futagawa, H. Akiba, T. Kodama, K. Takeda, Y. Hosoda, H. Yagita, and K. Okumura Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells Int. Immunol., March 1, 2002; 14(3): 275 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Suvas, V. Singh, S. Sahdev, H. Vohra, and J. N. Agrewala Distinct Role of CD80 and CD86 in the Regulation of the Activation of B Cell and B Cell Lymphoma J. Biol. Chem., March 1, 2002; 277(10): 7766 - 7775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. T. Nguyen, A. R. Elford, K. Murakami, K. M. Garza, S. P. Schoenberger, B. Odermatt, D. E. Speiser, and P. S. Ohashi Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance J. Exp. Med., February 11, 2002; 195(4): 423 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Gruber, D. C. Skelton, and D. B. Kohn Requirement for NK Cells in CD40 Ligand-Mediated Rejection of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Cells J. Immunol., January 1, 2002; 168(1): 73 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 X. Ma and L. J. Montaner Proinflammatory response and IL-12 expression in HIV-1 infection J. Leukoc. Biol., September 1, 2000; 68(3): 383 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pirtskhalaishvili, G. V. Shurin, A. Gambotto, C. Esche, M. Wahl, Z. R. Yurkovetsky, P. D. Robbins, and M. R. Shurin Transduction of Dendritic Cells with Bcl-xL Increases Their Resistance to Prostate Cancer-Induced Apoptosis and Antitumor Effect in Mice J. Immunol., August 15, 2000; 165(4): 1956 - 1964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zambello, L. Trentin, M. Facco, M. Siviero, S. Galvan, F. Piazza, A. Perin, C. Agostini, and G. Semenzato Analysis of TNF-receptor and ligand superfamily molecules in patients with lymphoproliferative disease of granular lymphocytes Blood, July 15, 2000; 96(2): 647 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kikuchi, M. A. S. Moore, and R. G. Crystal Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors Blood, July 1, 2000; 96(1): 91 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Braun, K. Chen, R. G. Foster, C. H. Kim, R. Hromas, M. H. Kaplan, H. E. Broxmeyer, and K. Cornetta The CC Chemokine CK{beta}-11/MIP-3{beta}/ELC/Exodus 3 Mediates Tumor Rejection of Murine Breast Cancer Cells Through NK Cells J. Immunol., April 15, 2000; 164(8): 4025 - 4031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chiodoni, P. Paglia, A. Stoppacciaro, M. Rodolfo, M. Parenza, and M. P. Colombo Dendritic Cells Infiltrating Tumors Cotransduced with Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf) and Cd40 Ligand Genes Take up and Present Endogenous Tumor-Associated Antigens, and Prime Naive Mice for a Cytotoxic T Lymphocyte Response J. Exp. Med., July 1, 1999; 190(1): 125 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Imaizumi, T. Kawabe, S. Ichiyama, H. Kikutani, H. Yagita, K. Shimokata, and Y. Hasegawa Enhancement of tumoricidal activity of alveolar macrophages via CD40-CD40 ligand interaction Am J Physiol Lung Cell Mol Physiol, July 1, 1999; 277(1): L49 - L57. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Soo Hoo, K. A. Lundeen, J. R. Kohrumel, N.-L. Pham, S. W. Brostoff, R. M. Bartholomew, and D. J. Carlo Tumor Cell Surface Expression of Granulocyte-Macrophage Colony-Stimulating Factor Elicits Antitumor Immunity and Protects from Tumor Challenge in the P815 Mouse Mastocytoma Tumor Model J. Immunol., June 15, 1999; 162(12): 7343 - 7349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chaussabel, F. Jacobs, J. de Jonge, M. de Veerman, Y. Carlier, K. Thielemans, M. Goldman, and B. Vray CD40 Ligation Prevents Trypanosoma cruzi Infection through Interleukin-12 Upregulation Infect. Immun., April 1, 1999; 67(4): 1929 - 1934. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
