Download Specific Antigenicity of Tumors and

[CANCER RESEARCH 33, 1598 1603, July 1973]
Specific Antigenicity of Tumors and Immunological Tolerance in
the Rat Induced by Friend, Gross, and Rauscher Viruses1
H. Kobayashi, N. Kuzumaki, E. Gotohda, IM. Takeichi, F. Sendo, M. Hosokawa, and T. Kodama
Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan
SUMMARY
Several lines of rat tumors grew only in Friend, Gross,
and Rauscher virus-tolerant rats that had received injec
tions of each of these viruses at birth. When the tumors
were transplanted into the virus-tolerant rats that had
received injections of the other types of murine leukemia
virus, they grew initially, and then regressed. Tumors
did not grow in normal rats. The same is true in the methylcholanthrene-induced tumors that had been given injections
of murine leukemia viruses. It was deduced from these re
sults that the transplantation antigen of tumor cells that
were induced by infection with Friend, Gross, and Rauscher
viruses may contain an antigen common to all three vi
ruses and also an antigen that is individually specific, and
that the host's immunological tolerance (induced by the
neonatal injection of either Friend, Gross, or Rauscher
virus) may consist of the tolerance common to all three
viruses and, also, of the tolerance that is individually spe
cific.
INTRODUCTION
Much remains to be studied about the relationship of
the transplantation antigens that are induced by Friend,
Gross, Rauscher, and other MLV. We previously reported
that Friend virus-induced tumors that developed in rats
given injections of Friend virus at birth grew only in the
Friend virus-conditioned and -tolerant rats, and that they
did not grow in syngeneic normal adult rats (6). In this
study we attempted to determine whether the same result
can be extensively observed in the tumors induced by Gross
and Rauscher viruses. We also attempted to reveal the re
lationship of the transplantation antigen to the tumors in
duced by Friend, Gross, and Rauscher viruses that devel
oped after the tumors were transplanted into virus-tolerant
rats that had received injections of MLV at birth.
MATERIALS
AND METHODS
Friend Virus. Ten years have passed in our laboratory
'This work was supported in part by a research grant for cancer re
search from the Ministry of Education of Japan.
2The abbreviations used are: MLV, murine leukemia virus: WKA/Mk.
Wistar-King-Aptekman.
Received July 25, 1972; accepted March 19, 1973.
1598
since the initiation of serial passages of the Friend virus.
The virus was recovered [by a modification of the method
of Chenaille et al. (1)] from the enlarged spleen of Friend
leukemia dd/Om mice.
Gross Virus. A rat-adapted strain of Gross virus was
used. The Gross virus was kindly supplied by Dr. K.
Yokoro, Hiroshima University, Hiroshima, Japan. It was
previously sent by Dr. H. Okano, Kyushu University,
Fukuoka, Japan, who initially received the virus from
Dr. J. Furth, Columbia University, New York, N. Y. The
Gross virus was recovered from the enlarged thymus of
WKA/Mk rats given injections of Gross virus at birth by
the same method used with the Friend virus.
Rauscher Virus. Rauscher virus was sent by Dr. K.
Yokoro, Hiroshima University, Hiroshima, Japan. Re
covery of this virus was similar to that of Friend virus.
Normal Rats. Inbred WKA/Mk rats were used. They
were bred in the Experimental Animal Center by Dr. S.
Makino and Dr. M. Sasaki, Faculty of Science, Hokkaido
University, Sapporo, Japan. Skin transplantation suc
ceeded in all cases.
Tolerant Rats. Adult WKA/Mk rats that had been
given i.p. and s.c. injections of undiluted murine leukemia
virus within 48 hr after birth were used as tolerant rats.
Friend and Rauscher virus-tolerant (2- to 3-monthold adult) rats received neonatal injections of Friend and
Rauscher virus, and the treatment for both groups was the
same. Gross virus-tolerant rats were only 1 to 2 months old
and received injections of Gross virus at birth.
Tumors. WFT tumors were established from the en
larged spleen of WKA/Mk rats approximately 200 days
after the neonatal injection of Friend virus and were
maintained in Friend virus-tolerant rats. WGT tumors
were established from the thymus of WKA/Mk rats 2 to
3 months after the neonatal injection of Gross virus; these
were maintained in Gross virus-tolerant rats. WRT tumors
were established from the spleen of WKA/Mk rats ap
proximately 200 days after the neonatal injection of
Rauscher virus and were maintained in Rauscher virustolerant rats. Morphological studies of the WFT, WGT,
and WRT tumors have already been described (10). Thir
teen lines of WFT, 10 lines of WGT, and 3 lines of WRT
tumors are now available in both the solid and ascites
forms. The tumors used for the experiments had been
transplanted for less than 15 generations, except for the
WFT-3 tumor, which was transplanted for less than 35
generations. As the control tumor, Sato lung cancer in
duced by 4-nitroquinoline-/V-oxide in Donryu rats, was
CANCER RESEARCH VOL. 33
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Friend, Gross, and Rauscher Tumors in Rats
sent by Dr. S. Oboshi, National Cancer Center, Tokyo, gressed. A total of 424 of the 434 Friend virus-tolerant
Japan, and FMT-15, induced by methylcholanthrene in rats (97.7%) died of tumor growth; only 3 of the 168
Fischer rats, was sent by Dr. M. Aizawa, Department of normal rats (1.8%) died of tumor growth, and the re
Pathology, Hokkaido University School of Medicine, mainder survived more than 3 months without tumor de
Sapporo, Japan. The LFT-2 tumor was induced by Friend velopment.
Lethal Growth of Gross Virus-induced Tumors (WGT).
virus in Long-Evans rats. The LFT-2 tumor was maintained
in Friend virus-tolerant Long-Evans rats. All tumors were When 10 lines of Gross virus-induced primary tumors
(WGT), all successfully established as transplantable
usually maintained in the ascites form.
Artificial Infection with MLV. Methylcholanthrene- lines, were transplanted i.p. into Gross virus-tolerant
induced ascites tumor KMT-17 of the WKA/Mk rat was rats, all lines thrived and, in nearly all cases, killed the
artificially infected with MLV's. For the virus infection, host. In contrast, the WGT line did not grow well in
the KMT-17 tumor was transplanted i.p. into tolerant normal rats and, in all cases (even if they grew initially),
rats that had received injections of Friend, Gross, or the tumors later regressed. With all 10 lines of WGT, 98
Rauscher virus after the tumor was mixed with the virus of the 101 Gross virus-tolerant rats (97%) died of tumor
at transplantation. After transplantation of the tumor for growth, but none of the 50 normal rats died of tumor
1 to 2 generations, the success of the artificial infection growth (Table 2). General results of the transplantation of
WGT appear quite similar to the results of WFT trans
of the virus and the subsequent appearance of a new anti
plantation.
gen on the cell surface were proved by electron micro
Lethal Growth of Rauscher Virus-induced Tumors
scopy, cytotoxicity test, and immunofiuorescence (8,
(WRT).
When 3 lines of Rauscher virus-induced tumors
14, 16).
were transplanted into Rauscher virus-tolerant rats,
the tumors thrived and killed the host in all 59 cases. In
RESULTS
contrast, none of the 48 normal rats were killed (Table 3).
It was therefore concluded that all lines of tumors induced
Lethal Growth of Friend Virus-induced Tumors (WFT).
in rats by Friend, Gross, and Rauscher viruses thrive
Thirteen lines of Friend virus-induced tumors (each con only in virus-tolerant rats given injections of the cor
sisting of 10' to 10" cells) were transplanted i.p. into
responding virus at birth, and that they do not grow or
Friend virus-tolerant and normal WKA/Mk rats (Table 1). thrive in normal rats.
All WFT lines grew well, and they killed the Friend virusGrowth Pattern of Each MI. V-induced Tumor. Two
tolerant rats; however, in normal rats they either did not lines of WFT and 3 lines each of WGT and WRT were
grow at all or, even if they grew initially, they later re- transplanted into each type of tolerant rat. As shown in
Table 4, both WFT-3 and WFT-13 tumors thrived and
killed all of the Friend virus-tolerant rats, but they did
Tablel
not thrive in the Gross and Rauscher virus-tolerant rats,
Lethal growth of Friend virus-induced tumors inoculated i.p. in Friend
except for some lethal tumors in the Rauscher virusvirus-tolerant and normal WKA/Mk rats
tolerant rats.
rats"WFT-1WFT-2WFT-3WFT-4WFT-5WFT-6WFT-7WFT-8WFT-9WFTFriend virus-tolerant
)lLeinai
-i !.
Table 2
innormal
growths
Lethal growth of Gross virus-induced tumors inoculated i.p. in Gross
rats/no.
virus-tolerant and normal WKA/Mk rats
tested3/380/53"0/260/90/40/30/50/40/263/168(1.8%)
tested128/129113/11384/8425/259/129/97/1311/1113/132/22/22/219/19424/434(97.7%)Meansurvival(days)33.210.219.520.052.
rats"WGT-1WGT-2WGT-3WGT-4WGT-5WGT-6WGT-7WGT-8WGT-9WGTGross virus-tolerant
atk.tlLethal
y21.825.435.024.3e36.0e28.5e21.0e18.21
innormal
growths
rats/no.
tested8/924/2515/1531/314/44/52/22/24/44/498/101(97%)Me
tested0/20/150/140/130/2
10WFT11WFT12WFT13TotalLethalgrowths/no.
10Total,Lethalgrowths/no.
" Given injections of Friend virus at birth.
" Regression of the tumor is observed after the initial growth. WFT-2N,
obtained as a variant of WFT-2, grew lethally in all of the 141 normal
rats (9).
e Inoculated s.c.
JULY
1Given injections of Gross virus at birth.
6 Inoculated s.c
1973
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1599
Kobayashi et al.
leukemia virus that induced the tolerance were then trans
planted. For example, after the immunization of Gross
virus-tolerant rats with WFT-13 and WRT-2 tumors, the
WGT-4 tumor was transplanted. As a control, WGT-4 was
rats"Lethalgrowths/no.
virus-tolerant
transplanted into unimmunized Gross virus-tolerant rats,
and these were compared with each other (Table 5). No
innormal
signs of a breakdown of immunological tolerance were ob
rats/no.
tested34/3414/1411/1159/59(100%)Meansurvival(days)18.818.222.8Lethalgrowths
tested0/40/240/200/48(0%)
served, from the viewpoint of survival days or transplantability,
or from the growth curve of the tumor. This may
WRT-1WRT-2WRT-3TotalRauscher
indicate the specificity and comparative stability of the im
munological tolerances induced by MLV in rats.
Lethal Growth of Methylcholanthrene-induced KMT17 Tumor Artificially Infected with MLV's. For repro
duction of the experimental results obtained above, a
'Given injections of Rauscher virus at birth.
methylcholanthrene-induced
KMT-17 tumor that de
veloped apart from the MLV in the WKA/M k rat was
artificially infected with Friend, Gross, and Rauscher vi
WGT-2, WGT-3 and WGT-4 tumors thrived and killed ruses. The virus-infected tumor was then transplanted
the Gross virus-tolerant rats, whereas they did not thrive or into each strain of virus-tolerant rats or into normal rats.
kill either Friend or Rauscher virus-tolerant rats, even Friend virus-infected KMT-17 (FV-KMT-17)
grew
after considerable growth of the local tumors was ob
and killed only Friend virus-tolerant rats, and Gross
virus-infected KMT-17 (GV-KMT-17) grew and killed
served.
There were similar findings with the WRT tumors. only Gross virus-tolerant rats. FV-KMT-17 did not kill
WRT-1, WRT-2, and WRT-3 thrived and killed Rauscher Gross or Rauscher virus-tolerant rats, in which the tumor
virus-tolerant rats but did not grow or kill the Gross grew initially and later regressed. GV-KMT-17 did not
virus-tolerant rats. However, when the WRT tumors kill Friend or Rauscher virus-tolerant rats, in which the
were inoculated into Friend virus-tolerant rats, the tumor grew initially and later regressed. However,
WRT-1 and WRT-3 tumors (in particular) killed the host, Rauscher virus-infected KMT-17 (RV-KMT-17) grew and
with tumor development at the site of transplantation, but killed Rauscher virus-tolerant rats and also some of the
when WRT-2 was inoculated s.c. into Friend virus-tolerant
Friend virus-tolerant rats (Table 6). These findings indicate
rats, the tumor regressed after the initial growth (40 x 40 that leukemia virus-infected tumors thrived in tolerant
mm) at the inoculation site. However, in 11 of 14 cases,
the tumor metastasized and appeared again in the lymph
Table 4
nodes and organs in the abdominal cavity nearly 2
Lethal
growth
of
each
murine
leukemia
virus-induced tumor inoculated
months after the 1st inoculation.
s.c. in tolerant WKA/Mk rats given injections (at birth) of each murine
The average pattern of the growth curves of WFT-13,
leukemia virus
WGT-2, and WRT-2 tumors in each virus-tolerant rat is
Lethal growths in tolerant rats/
shown in Chart 1. Although all tumors regressed after
no. tested
temporary growth, the maximum size of the tumors
differed with each tumor type and in each type of rat.
For example, while the WGT-2 grew in Rauscher virus- TumorFriend
virus84/84"
virus0/3
virus2/50/6
tolerant rats to a maximum size of only 20 x 20 mm, it
virus-induced
grew to a maximum size of 30 x 30 mm in Friend virusWFT-3
tolerant rats. Similarly, the WRT-2 grew to a maximum
19/19°Gross 0/11Rauscher
WFT-13Friend
size of approximately 20 x 20 mm in Gross virus-tolerant
rats. However, in Friend virus-tolerant rats, it grew to a
103/103
0/14
2/11
Total
maximum size of more than 40 x 40 mm and regressed;
virus-induced
occasionally it killed the host by metastasis. In short, Gross
24/25"
WGT-2
0/12
0/2
Friend virus-tolerant rats were more tolerant to the growth
15/15"
WGT-3
0/8
0/2
of these tumors than either Gross or Rauscher virus-tol
31/31°
WGT-4
0/6
0/2
erant rats, and normal rats are least tolerant to all 3 (WFT,
70/71
0/26
0/6
Total
WGT, and WRT) types.
Specificity of Immunological Tolerance of Rats Given Rauscher virus-induced
34/34"
Neonatal Injections of MLV. Attempts were made to
WRT-1
9/10
0/3
14/14"
WRT-2
determine whether the immunological tolerance induced
11/14
0/1
11/11"
by the MLV's could be broken down after the regression
WRT-3
0/4
9/10
of the tumors induced by the other types of MLV. Re
29/34
59/59
Total
0/8
peated immunizations with live tumor cells of the different
'The
same
results
were
presented
in
Tables
1,
2,
and
3.
types were performed s.c. and tumors induced by the same
Table 3
Lethal growth of Rauscher virus-induced tumors inoculated i.p. in
Rauscher virus-tolerant and normal WKA /Mk rats
1600
CANCER RESEARCH VOL. 33
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Friend, Gross, and Rauscher Tumors in Rats
Friend
Rauscher
Gross tolerant
tolerant
tolerant
Normal
l'
u
WFT-13 5
30
CO
K
20
H
IQ
40
WGT-2
10
40
30
WRT-2
20
10
weeks
1234
weeks
after inoculation
Chart I. Growth curve of various MLV-induced tumors inoculated s.c. in tolerant WKA/Mk rats given injections (at birth) of other MLV's (a,
metastatic growth of the WRT-2 killed the Friend virus-tolerant rat later).
weeks
weeks
Table 5
Speciflcily of immunological tolerance of WKA/Mk rats given injections of MLV at birth
MLV-induced tumors were transplanted in correspondingly tolerant rats that had been immunized with live tumors induced
by other types of MLV.
growths in tolerant
testedImmunized3/3
rats/no,
withGross Rat
virus-tolerant
WRT-3Friend
virus-tolerant
WRT-2Rauscher
virus-tolerant
Immunized
immunized2/2
withWGT-4
WFT-13, WRT-2
WFT-13,
(20.0)"
WGT-4WFT-13 2/2(13.0)4/4(30.0)
WGT-2, WGT-2
WGT-3
WGT-4. WGT-4
LFT-2
WGT-3,
WFT-13
WFT-13
WFT-13
WFT-13WRT-2
4/4 (30.7)
5/5(28.5)
I/I (41.0)
I/I
(35.0)1/2
WFT-13, WGT-3. 4
WGT-2, WGT-4, WFT-13
WGT-4LFT-2
WRT-2
WRT-2WRT-3
(30.0)
3/3 (22.0)
I/I
(25.0)1/1
WGT-3, WFT-13
WGT-4, WFT-13Challenged"
WRT-3
WRT-3Lethal
(27.0)I/I
(27.0)
2/2 (26.0)Not
(20.0)28/28
(31.5)3/3(25.3)4/4(40.5)
" Challenged s.c. 1 to 3 weeks after the final immunization.
*Numbers in parentheses, mean survival (days).
JULY 1973
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1601
Kobayashi et al.
Table 6
Lethal growth of methylcholanthrene-induced KMT-17 tumor cells (IO6)
artificially infected with Friend, Gross, and Kauscher virus in
tolerant WKA /Mk rats
developed or chemically induced tumors became un
able to grow in syngeneic normal rats or primary autoch
thonous rats after they were artificially infected with the
Friend virus, and that the Friend virus-infected tumors
grew only in Friend virus-tolerant rats or immunosuppres
testedGross
in tolerant rats/no,
sive rats (5, 8, 15). The above findings are similar in nature
and may be termed "xenogenization of tumors," which is
growths
in
virusvirusvirusnormal
defined as the immunological regression of tumors without
tolerant
tolerant
tolerant
rats/no,
the aid of previous immunization in the host. In this report
DonorFV-KMT-17"GV-KMT-17"RV-KMT-I7CLethalFriend
rats3/30/62/30/4"growths
rats0/912/120/2Rauscher
rats0/40/24/43/3"Lethal
tested0/430/90/6
it was clarified that xenogenization of rat tumors may be
produced by infection with Gross and Rauscher viruses
as well as with Friend virus. There was no difference be
tween each of the murine leukemia virus-induced tumors
with regard to their ability to produce xenogenization of
" KMT-17 cells artificially infected with Friend virus were inoculated
tumors in rats.
:.
Concerning the transplantation antigens of the tumors
6KMT-17 cells artificially infected with Gross virus were inoculated
induced
by Friend, Gross, and Rauscher viruses, it is
c.
' KMT-17 cell artificially infected with Rauscher virus were inoculated
probable that an antigen common to all and (also) an in
c.
dividually specific antigen may exist in each tumor. It is
" A small number of RV-KMT-17 cells (IO4) were inoculated.
also probable that a tolerance common to all and an in
dividually specific tolerance may exist in tolerant rats.
rats induced by the corresponding leukemia virus but This is because both virus-induced tumors and tumors
did not thrive in tolerant rats induced by different types of artificially infected with the virus can grow lethally in
leukemia virus, there were no lethal effects, with the excep
tolerant rats induced by the corresponding virus and not
tion of some cases of RV-KMT-17 in Friend virus-tolerant
grow in normal adult rats and also because the tumors grow
temporarily and eventually regress in tolerant rats induced
rats. They did not thrive in normal adult rats. These re
by different types of MLV, which result may not be due to
sults are similar to those obtained in the previous exper
iments with the MLV-induced tumors WFT, WGT, and the nonspecific immunosuppression of the host.
Antigenic similarities between Friend and Rauscher
WRT.
viruses have been noted (12). However, this does not
Transplantation of Allogeneic Tumors in Tolerant WKA/
Mk Rats. In order to determine the immunosuppressive mean a complete correspondence of the transplantation
effects of MLV's in the tolerant host, we transplanted al- antigen, as was indicated in our experiments. Although
the Rauscher virus-induced tumors or the tumors ar
logeneic tumors (such as Sato lung cancer in Donryu
rats and FMT-15 in Fischer strain rats) s.c. into Friend,
tificially infected with Rauscher virus grew and eventually
Gross, and Rauscher virus-tolerant WKA/Mk rats, and killed most of the Friend virus-tolerant rats, the growth
the growth rates of the tumors in tolerant and normal rats pattern in these rats was evidently different from that in
Rauscher virus-tolerant rats. Moreover, the Friend
were compared (Table 7). In tolerant rats, both allogeneic
tumors showed the same transplantation rate and growth virus-induced tumors or the tumors artificially infected
with Friend virus regressed in Rauscher virus-tolerant rats.
curves as in normal rats. It was therefore assumed that
the growth of MLV-induced tumors in each strain of Therefore, it may be concluded that the transplantation
virus-tolerant rats (as shown in the preceding experiments)
antigen induced by Friend virus seems to possess the
Rauscher-specific transplantation antigen as a part of it,
may depend entirely upon the specific immunological tol
and that most of the Rauscher virus-specific transplan
erance of the host toward the specific transplantation
antigen of each tumor and may not depend upon the tation antigen may be involved in the Friend virus-spenonspecific suppression of immunological reactivity of the
host. The healthy existence of cellular immunity, as tested
Table 7
by allogeneic skin transplantation, delayed-type hypersenLethal growth of allogeneic tumors inoculated s.c. into tolerant and
sitivity of 2,5 dinitrochlorobenzene, and graft-versusnormal WKA/Mk rals
host reaction, in Friend and Gross virus-tolerant rats is
described in a manuscript being prepared (N. Takeichi,
Lethal growths in
testedAllogeneic
tolerant rats/no,
N. Kuzumaki, and H. Kobayashi. Immune Responses
growths in
of the Rat Inoculated with Friend and Gross Viruses at
normal
Birth, in preparation).
virus0/2Lethal rats0/5
virus0/10"
tumorsSato
DISCUSSION
It has been reported that Friend virus-induced tumors
grew only in Friend virus-tolerant rats and did not grow in
normal adult rats (6). We also reported that spontaneously
1602
lung cancer"
FMT-15"Friend
0/2Grossvirus0/10/2Rauscher
0/2
"4-Nitroquinoline /V-oxide-induced lung cancers were transplanted
in Donryu rats; 5 x IO5cells were used.
* Methylcholanthrene-induced tumors were transplanted in Fischer
rats; 1 x IO7cells were used.
CANCER RESEARCH VOL. 33
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Friend, Gross, and Rauscher Tumors in Rats
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group, so that the Gross virus-specific transplantation an
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Morphological Studies of Tumors in Rats Induced by Murine Leu
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Friend
Rauscher
Chart 2. Relations of transplantation antigen and immunological tol
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1603
Specific Antigenicity of Tumors and Immunological Tolerance in
the Rat Induced by Friend, Gross, and Rauscher Viruses
H. Kobayashi, N. Kuzumaki, E. Gotohda, et al.
Cancer Res 1973;33:1598-1603.
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