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- and Cell-to-Cell Contact-Dependent Cytotoxicity of Allograft-Induced Macrophages Against Syngeneic Tumor Cells and Cell Lines: An Application of Allografting to Cancer Treatment1
*
Department of Physiology, Osaka Medical College, Daigakumachi, Takatsuki, Japan;
Central Research Institute, Nissin Food Products Co., Ltd., Noji-cho, Kusatsu-shi, Shiga, Japan; and
Department of Urology, Gifu University School of Medicine, Tsukasa-machi, Gifu, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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; 55–65% of bulk infiltrates), granulocytes
(20–25%), and lymphocytes (15–20%)) infiltrating into allografts,
but not into autografts, in C57BL/6 mice were cytotoxic against
syngeneic tumor cells and cell lines, whereas the cytotoxic activity
was hardly induced in allografted, IFN-
-/- C57BL/6
mice. Among the leukocytes, M were the major population of cytotoxic
cells; and the cytotoxic activity appeared to be cell-to-cell contact
dependent. When syngeneic tumor cells were s.c. injected into normal
C57BL/6 mice simultaneously with the M-rich population or
allogeneic, but not syngeneic, fibroblastic cells, tumor growth was
suppressed in a cell number-dependent manner, and tumor cells were
rejected either with a M:tumor ratio of about 30 or with an
allograft:tumor ratio of 
200. In the case of
IFN--/- C57BL/6 mice, however, the s.c. injection of
the allograft simultaneously with tumor cells had no effect on the
tumor growth. These results suggest that allograft or allograft-induced
M may be applicable for use in cancer treatment and that IFN-
induction by the allograft may be crucial for the
treatment. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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)3 activated in
vitro or in vivo to the tumoricidal state may fulfill these demanding
tasks (1, 2). In fact, gene transfer of monocyte chemoattractant
protein-1 to a rodent tumor cell line stimulated recruitment of
monocytes to tumors and inhibited tumor growth (3). It has also been
reported, however, that tumor-associated M either could promote the
growth of tumor cells (4) or were positively correlated with tumor
invasion and progression (5). Therefore, the successful or unsuccessful
eradication of M in tumor growth may depend either on the kind of
Ms infiltrating into tumors or on the stage of M activation.
In allografts, the rejection process that destroys the allogeneic cells
is inactive toward syngeneic cells, indicating that the leukocytes
infiltrating into allografts discriminate between self and nonself (6).
In the present study we examined whether the cells infiltrating into
allografts could be cytotoxic against syngeneic tumor cells and cell
lines in vitro and in vivo. The results indicated that among
leukocytes, M were the major population of cells cytotoxic against
syngeneic tumor cells and cell lines in an IFN-- and cell-to-cell
contact-dependent manner and that s.c. injected syngeneic tumor cells
were rejected by a simultaneous inoculation of the M-rich population
or of allograft cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Na251CrO4
(10.5 GBq/mg) was purchased from New England Nuclear (Boston, MA). RPMI
1640 medium was obtained from Nissui Seiyaku (Tokyo, Japan). FCS was
obtained from ICN Biomedicals (Costa Mesa, CA) and was used after heat
inactivation. Casein sodium was purchased from Wako Pure Chemicals
(Osaka, Japan). D-[
-methyl]Mannoside and
Con A were obtained from Sigma (St. Louis, MO). LPS (Escherichia
coli O55:B5) prepared by the Westphal method and Brewer
thioglycolate medium were products of Difco (Detroit, MI). IFN-,
penicillin, streptomycin, and L-glutamine were
obtained from Life Technologies (Gaithersburg, MD). Anti-TNF- Ab was
a product of Genzyme (Cambridge, MA). Anti-Thy-1.2 (53-2.1) Ab,
anti-NK-1.1 (PK136 or 3A4) Ab, biotin-labeled anti-IL-2R (7D4)
Ab, and PE-conjugated streptavidin were purchased from PharMingen (San
Diego, CA).
NG-monomethyl-L-arginine
(N-MMA) was obtained from Calbiochem (La Jolla, CA). All
other chemicals were of reagent grade.
Animals
Male specific pathogen-free C57BL/6 (B6)
(H-2b) mice, 7 wk old, were purchased from Japan
SLC (Hamamatsu, Japan). IFN--/- B6 mice were
donated by Dr. Y. Iwakura (Institute of Medical Science, University of
Tokyo, Tokyo, Japan) (7). In Con A blasts from IFN--/-
B6 mice, IFN- mRNA was not detected by RT-PCR analyses, whereas
IL-2, IL-4, and TNF- mRNAs were present at levels of expression
similar to those in normal (IFN-+/+)
B6 mice (8). After an s.c. inoculation of tumor
cells into normal or IFN--/- B6 mice, the
mice were maintained for several weeks in our animal facility under
specific pathogen-free conditions in an air-conditioned room (25
± 2°C; 50% humidity).
Tumor cells and cell lines
3-Methylcholanthrene-induced ascites-type fibrosarcoma (Meth A; H-2d) cells were provided by Dr. S. Muramatsu (Department of Zoology, Kyoto University Faculty of Science, Kyoto, Japan), and were maintained by routine i.p. injection of 3 x 106 cells into a syngeneic mouse strain (BALB/c; H-2d). EL-4 (lymphoma; H-2b), 3LL (lung carcinoma; H-2b), B16 (melanoma; H-2b), and CMT-93 (rectum carcinoma; H-2b) tumor cells, and NOR10 (H-2b), NCTC4093 (H-2b), and BALB/3T3 (H-2d) fibroblastic cell lines were purchased from American Type Culture Collection (Manassas, VA).
Cell preparations
Meth A cell-induced peritoneal exudate cells (PEC) were obtained
by peritoneal lavage on day 7 (or at various intervals) after an
i.p. transplantation of Meth A tumor cells (3 x
106 cells/mouse) to normal or
IFN--/- B6 mice as previously described
(8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). The M-rich (95% purity and 5% T lymphoblast
contamination) population was isolated from PEC by FACS (FACStar,
Becton Dickinson, Mountain View, CA) with the gate set in the forward
scattering/side scattering mode, as described previously (9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Skin
grafting and preparation of the cells infiltrating into the skin
graft-graft bed border were performed as described previously (19). The
grafts and the surrounding tissues of recipients were removed en bloc
and cut into small blocks with scissors. The blocks were digested with
0.15% protease/0.075% collagenase/0.001% DNase. All digested cells
were centrifuged, and a granulocyte-, lymphocyte-, or M-rich
population was sorted with the gate set in the forward scattering/side
scattering mode by FACS. The morphological characteristics of the cells
in each fraction were assessed by May-Giemsa stain. The cell number in
all the digested cells from skin autografts was approximately half that
in the case of skin allografts on days 5–9 after transplantation. PEC
including in vivo elicited Ms were collected by lavage of mice that
had received i.p. injection of 1 ml of 6% sodium casein or 2 ml of
Brewer thioglycolate medium (4 days before). In vitro activated M
were prepared by a further 8-h incubation of elicited M monolayers
with LPS (10 ng/ml) and IFN- (20 U/ml), and then the cells were
washed twice before the cytotoxic assay. Con A blasts were prepared by
stimulating spleen cells (108 cells) with 5
µg/ml of Con A for 48 h at 37°C in a 50-ml flask, washing them
twice with culture medium containing 0.3 mM
D-[-methyl]mannoside to avoid Con
A-dependent cytotoxicity, and washing them a third time with culture
medium. The viable Con A blasts were isolated by density gradient
centrifugation in sodium metrizoate/Ficoll (Otsuka Pharmaceutical,
Tokyo, Japan).
Complement-dependent cell lysis
Homogeneous (>99% purity, microscopically no other type of
cell in the M population (126 cells)) M were obtained after T
cell elimination from a M-rich population (prepared as described
above) by complement-dependent cell lysis with anti-Thy-1.2 Ab. The
cells (2 x 107 cells) in the M-rich
population were suspended in 500 µl of fresh medium, and then 16 µl
of anti-Thy-1.2 Ab and 160 µl of diluted Low-Tox-M rabbit
complement (Cederlane, Ontario, Canada) was added to the suspension.
The complement was reconstituted with 1 ml of cold distilled water and
was diluted (three times) with medium before use. The mixture was
incubated for 45 min at 37°C. To confirm that T cells had been
eliminated specifically from a M-rich population or bulk PEC, the Ab
plus complement-treated cells were stained with fluorescein-labeled
anti-Thy-1.2 Ab, and their surface Ag were analyzed by FCM. For the
in vitro specific elimination of NK or NKT cells from PEC, PEC were
incubated with anti-NK-1.1 Ab and complement.
Negative immunomagnetic selection of PEC
Sterile magnetic polymer beads (Dynabeads M-450, Dynal, Oslo, Norway) were supplied coated with covalently bound affinity-purified sheep anti-mouse IgG. Anti-NK-1.1 Ab-coated immunomagnetic beads were prepared as described previously (20). Washed mAb-coated beads (108 beads/2 ml) were added to bulk PEC (5 x 106 cells). The mixture of cells and beads was incubated 5 min at 4°C, and beads with any attached cells were removed magnetically. The supernatant was centrifuged, the pellet was resuspended in the culture medium, and then the cell number and the cytotoxic activity were determined.
FACS analysis
The expression of the IL-2R Ag on M with Con A blasts used as
a positive control was examined by FACS.
Cell number and viability
The cell number in the suspensions was determined with a hemocytometer after dilution of the cells in Turk’s solution. The viability of cells was determined by the trypan blue exclusion method.
Cytotoxicity assay
Target cells (106 cells) in 25 µl of culture medium were labeled with 25 µl (925 KBq) of Na251CrO4 at 37°C for 2 h, and effector cells (3 x 105 to 5 x 105 cells) in 200 µl of culture medium were mixed with 20 µl of 51Cr-labeled targets (104 cells). After an 18-h incubation, an aliquot of supernatant was removed from each well and assayed for released 51Cr in a Hewlett-Packard (Meriden, CT) gamma counter. Lysis of 51Cr-labeled targets in each well was quantified as the percent specific lysis, as described previously (21).
In vivo measurement of tumor growth
EL-4 (H-2b) or 3LL
(H-2b) tumor cells (104
cells/mouse) were s.c. injected simultaneously with an M
(H-2b)-rich population, or BALB/3T3
(H-2d) or NOR10 (H-2b)
fibroblastic cells into normal or IFN--/- B6
(H-2b) mice. At various intervals after the
treatment, the growth of these syngeneic tumor cells was determined by
measuring two diameters (perpendicular to each other) of the tumor with
Vernier calipers (22). The surface area of the tumor was previously
shown to correlate precisely with the tumor weight (23).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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against various kinds of syngeneic
tumor cells and cell lines
Bulk cells (M, 55–65%; granulocytes, 20–25%; lymphocytes,
15–20%) (11) infiltrating into allografts of Meth A tumor cells in B6
mice were cytotoxic against various kinds of syngeneic tumor (e.g.,
3LL, EL-4, B16, and CMT-93) cells and cell lines (e.g., NOR10 and
NCTC4093) with a 45–65% cytotoxic activity in an 18-h incubation
(Fig. 1
). Most of the activity was
retained after T cell elimination (Fig. 1A); and the
cytotoxic activity was not suppressed (3LL (103% of the cytotoxic
activity with control serum), B16 (133%), NCTC4093 (103%), and
NOR10 (123%)) by the addition of anti-CD3 Ab to the culture
medium. Furthermore, bulk allospecific CTLs that had been induced in
mixed lymphocyte cultures (B6 anti-BALB/c) were virtually inactive
toward syngeneic tumor cells (e.g., 0.5 ± 3.1 and 3.4 ±
2.1% (mean ± SD; n = 4) specific lysis for EL-4
cells and 3LL cells, respectively) and cell lines (e.g., 5.2 ±
3.0% (mean ± SD; n = 4) and 3.2 ± 2.0%
(mean ± SD; n = 4) specific lysis for NCTC4093
and NOR10 cells, respectively), indicating that T cells are not
involved in the cytotoxic activity of bulk PEC against syngeneic tumor
cells and cell lines. The granulocyte-rich population had no cytotoxic
activities against 3LL cells (0.2 ± 1.3% (mean ± SD;
n = 4) specific lysis) and NCTC4093 cells (0.5 ±
2.1% (mean ± SD; n = 4) specific lysis). In
addition, the cytotoxic cells were phenotypically
IL-2R- (Fig. 2)/NK-1.1-
(10)/Mac-1+ (19) by FCM, and neither the
cytotoxic activity nor the cell number changed significantly after
magnetic removal of cells attached to anti-NK-1.1 Ab-coated beads
from PEC or after the in vitro specific elimination of NK or NKT cells
from PEC with anti-NK-1.1 Ab and complement (Table I). These results taken together suggest
that the cytotoxic activities of PEC against syngeneic tumor cells and
cell lines appeared to be ascribable mainly to M, but not to T
cells, granulocytes, lymphokine-activated killer cells, or NK or NKT
cells.
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(60%), granulocytes (20%),
and lymphocytes (20%)) (19) infiltrating into the graft-graft bed
border of allografted BALB/c skin onto B6 mice were cytotoxic against
syngeneic tumor (e.g., 3LL) cells and cell lines (e.g., NCTC4093), and
most of the activity was recovered in M and not T cells (Fig. 1
B). By contrast, the M were inactive toward self Con A
blasts (0.1 ± 1.3% (mean ± SD; n = 8)
specific lysis) and autografts (2.0 ± 1.1% (mean ± SD;
n = 8) specific lysis) as previously described
(19). Distribution of cytotoxic activities against syngeneic tumor cells and cell lines in i.p. Meth A cell-treated or BALB/c skin-grafted B6 mice
When the cytotoxic activities against 3LL cells of lymphoid cells
in a variety of locations in i.p. Meth A cell-treated and untreated
mice were quantified, the cytotoxic activities were associated
exclusively with PEC of Meth A cell-treated mice and not with
peritoneal cells of control mice (Fig. 3,
left). Not only the cells in all lymphoid organs tested to
date but also peripheral mononuclear leukocytes of Meth A cell-treated
mice had little, if any, cytotoxic activity toward the targets.
Furthermore, casein- or thioglycolate-elicited inflammatory M were
totally inactive toward all these target cells (e.g., 0.2 ± 1.5
or 0.0 ± 1.2% (mean ± SD; n = 8) specific
lysis for 3LL cells). Similarly, the cytotoxic activities against 3LL
cells of cells in a variety of locations in BALB/c skin-grafted B6 mice
were distributed exclusively in the skin graft-graft bed border, but
not in the thymus, spleen, lymph node, bone marrow, or peripheral blood
(Fig. 3, right). By contrast, the bulk cells infiltrating
into autografts had no cytotoxic activity against these tumor cells and
cell lines at any time interval after transplantation (e.g., on day 6
after transplantation, 0.5 ± 1.1 and 0.8 ± 1.2% (mean
± SD; n = 8) specific lysis for 3LL and NCTC4093
cells, respectively).
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-mediated cytotoxicity against syngeneic tumor
cells and cell lines
When M isolated from tumor- or skin-allografted B6 mice were
cocultured with 3LL or NCTC4093 cells, the M exhibited high
cytotoxic activities against these targets, but they were totally inert
against 3LL and NCTC4093 cells in a Transwell consisting of two (upper
and lower) chambers with a cell-impermeable membrane (Table II). Although N-MMA, a NO
synthase inhibitor, completely inhibited NO release from the M
(58.3 ± 6.4 µM/18 h without inhibitor to 2.7 ± 1.3
µM/18 h with inhibitor), the inhibitor had no effect on the
M-mediated cytotoxic activity against 3LL and NCTC4093 cells. By
contrast, LPS/IFN--activated casein M were highly cytotoxic
(40.3 ± 4.2% specific lysis in an 18-h assay) against
NO-sensitive P815 cells even in a Transwell, and the cytotoxic activity
was completely suppressed by the addition of N-MMA
(0.0 ± 2.3%). Furthermore, in contrast to LPS/IFN--activated
casein-M, the allograft-induced M (AIM) did not release TNF-
(16), and the addition of anti-TNF- Ab did not affect the
AIM-mediated cytotoxic activities against 3LL and NCTC4093 cells.
LPS/IFN--activated casein-M, however, were cytotoxic (38.5
± 2.8% specific lysis in an 18-h assay) against TNF--sensitive
L929 cells even in a Transwell, and anti-TNF- Ab largely
(61%) inhibited the activity. These results indicated that in
contrast to other activated M, AIM exhibited cytotoxic activity
against syngeneic tumor cells and cell lines in a cell-to-cell
contact-dependent, soluble factor-independent manner.
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+/+) B6 mice (Fig. 4A). Thereafter, the cytotoxic
activities decreased, and almost no cytotoxicity remained against
syngeneic tumor cells and cell lines on day 17. By contrast, very low
cytotoxic activities of PEC against these syngeneic tumor cells and
cell lines were induced in Meth A cell-treated
IFN--/- B6 mice (Fig. 4B),
suggesting IFN--dependent cytotoxicity.
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To examine the in vivo cytotoxic effects of AIM on syngeneic tumor
cells, we performed the Winn assay with various AIM:tumor ratios (Table III). Subcutaneously injected 3LL lung
cancer cells (2 x 105 cells/mouse) grew
time dependently, and three of four animals with >30 mm diameter of
tumor mass died 1 mo after tumor transplantation. However, the
growth of 3LL cells was suppressed by a simultaneous inoculation of AIM
in a cell number-dependent manner, and in the presence of 2 x
106 cells in an AIM-rich population the tumor
cells were rejected without forming any tumor mass in the
transplantation site. Table IV shows
similar inhibitory effects of cells in the AIM-rich population on the
growth of EL-4 lymphoma cells. The growth was completely abrogated by
the simultaneous inoculation of AIM at an AIM:tumor ratio of
50.
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As it may sometimes be difficult to isolate AIM from tumor-bearing
patients, we next tried to induce AIM in the transplantation site of
syngeneic tumor cells (Fig. 5). 3LL cells
(2 x 105 cells/mouse) s.c. injected into B6
mice grew time dependently, and the tumor mass reached 16 mm diameter
on day 24 after transplantation. However, a simultaneous inoculation of
allogeneic (BALB/3T3; H-2d), but not syngeneic
(NOR10; H-2b), fibroblastic cells suppressed
tumor growth in a cell-number dependent manner and resulted in
rejection without forming any tumor mass in the transplantation site at
an allograft:tumor ratio of 200. In contrast, sonicated BALB/3T3
fibroblastic cells totally lost their inhibitory effect; and the
simultaneous inoculation of allogeneic BALB/3T3 fibroblastic cells with
3LL cells into IFN--/- B6 mice had virtually
no effect on tumor growth (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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recognize, phagocytose, and dispose of senescent RBC, damaged
cells, and foreign invaders (24). These continuous functions are
constitutive and therefore do not require external regulation. In
contrast, sporadic functions, such as participation in host defense
against chronic infections and cancer, require activation signals to
initiate the recruitment and activation of M to perform a
specific task. Once this task is completed, the cells can
revert to the nonactivated state (25). AIM fulfill these demanding
properties. 1) The cytotoxic activity against syngeneic tumor cells was
found only in the rejection site of allografted tumor or skin (Fig. 3).
2) Resident (Fig. 3) and casein- or thioglycolate-elicited inflammatory
(Table II) M were inactive toward syngeneic tumor cells or cell
lines. 3) AIM are a type of activated M (9, 10, 16, 17). 4) When
allografts were rejected, AIM reverted to the nonactivated state, and
the number of AIM was rapidly reduced in the rejection site (9, 10, 11, 12, 19)
(Fig. 4).
Among bulk infiltrates in allografts, T cells were found to be the
major producers of IFN- (8). Therefore, it is reasonable that, as
was shown in Fig. 1, the IFN--dependent cytotoxicity of cells in an
AIM-rich population against syngeneic tumor cells and cell lines was
significantly reduced after T cell elimination. Although IFN- was
essential for the induction of AIM-mediated cytotoxicity against
syngeneic tumor cells and cell lines (Figs. 4 and 5), IFN- alone was
insufficient to induce significant M-mediated antitumor activity
even in vitro, because resident or thioglycolate M activated by
IFN- in vitro had very low cytotoxic activity against tumor cells
(data not shown). Also in vivo, an s.c. injection of IFN- (0.05–5
µg in 0.2 ml of PBS) simultaneously with 3LL tumor cells was
ineffective on the tumor growth (unpublished data). The nature of the
additional factor(s) essential for the induction of AIM-mediated
cytotoxic activity against syngeneic tumor cells and cell lines remains
to be elucidated. Of particular interest, Hayashi (26) reported
recently that the inducibility of IFN- in cancer patients is a good
marker for the effectiveness of immunotherapy with bacillus
Calmette-Guérin cell wall skeleton.
It has been generally believed that CTLs recognize allografts as
nonself through the difference in the histocompatibility Ags and
destroy the allografts (27). Recent studies using
ß2-microglobulin, CD4, or CD8 knockout mice,
however, revealed that the main effector cells responsible for skin or
cardiac allograft rejection appear to be cells other than T or NK cells
(28, 29, 30, 31). We also reported that a novel type of activated M was the
major population of effector cells responsible for the rejection of
either i.p. allografted Meth A (H-2d)
fibrosarcoma cells in B6 (H-2b) mice (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) or
of allografted BALB/c (H-2d) skin on B6 mice
(19). The M were cytotoxic against allografts in a cell-to-cell
contact-dependent manner (11, 16). To determine whether the same
population of M could react with syngeneic tumor cells or cell lines
as well as with allografted Meth A tumor cells, we performed a series
of cold target inhibition assays. The cytotoxic activity of M
against 51Cr-labeled allograft (Meth A cells) was
inhibited by the addition of unlabeled H-2d, but
not H-2k or H-2b, Con A
blasts (11), whereas the cytotoxic activities of M against
51Cr-labeled 3LL and NCTC4093 cells were not
affected by the addition of cold H-2d,
H-2k, or H-2b Con A blasts
(our unpublished data).
The application of clinical allogeneic bone marrow transplantation has
expanded as a treatment modality for hematologic malignancies (32), and
it has been suggested that graft-vs-host disease is associated with an
antileukemic effect (33, 34). Some patients without graft-vs-host
disease, however, have remained free of leukemia 2–8 yr after bone
marrow transplantation, and recurrent leukemia has developed in other
patients with severe graft-vs-host disease (35). Furthermore, Champlin
et al. (36) demonstrated that bone marrow transplantation using donor
marrow depleted of CD8+ lymphocytes decreased the
incidence of a graft-vs-host disease without abrogating the
graft-vs-leukemia effect. In the present study we revealed that
host-derived AIM were cytotoxic not only against parenchymal tumor
(e.g., 3LL, CMT-93, and B16) cells and cell lines (e.g., NCTC4093 and
NOR10) but also against lymphoid tumor cells, including EL-4 lymphoma
cells. Therefore, it is plausible that the cytotoxicity of
recipient-derived M against the lymphoid tumor cells is a mechanism
responsible for the antileukemic effect following allogeneic bone
marrow transplantation and that it may be possible to make a
therapeutic application of AIM (or the inducer) to
leukemia.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ryotaro Yoshida, Department of Physiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki 569-8686, Japan. E-mail address:
3 Abbreviations used in this paper: M, macrophage; N-MMA, NG-monomethyl-L-arginine; Meth A, 3-methylcholanthrene-induced ascites-type fibrosarcoma; PEC, peritoneal exudate cells; AIM, allograft-induced macrophages.
Received for publication October 16, 1998. Accepted for publication April 12, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice, but not in TNF--/- mice. J. Immunol. 159:1418.[Abstract]
released from T cells is essential for induction of effector macrophages in the rejection site. J. Immunol. 160:6012. is the inducer of indoleamine 2,3-dioxygenase in allografted tumor cells undergoing rejection. J. Immunol. 145:1246.[Abstract]
and IL-1/ß in growth inhibition of an allografted tumor. J. Immunol. 151:2070.[Abstract]
-dependent expression of inducible nitric oxide synthase, interleukin-12, and interferon--inducing factor in macrophages elicited by allografted tumor cells. Biochem. Biophys. Res. Commun. 224:555.[Medline]
as a marker for the effective cancer immunotherapy with BCG-cell wall skeleton. Proc. Jpn. Acad. Ser B 70:205.
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, -Ab, +complement;
, +Ab, +complement.
, NOR10; 
,
NCTC4093.
, 3LL cells (3 x
104 cells/mouse) into B6 mice; •, 3LL cells plus
BALB/3T3 fibroblastic cells (6 x 106 cells/mouse)
into B6 mice;