immunology of spontaneous mammary carcinomas in mice iv...

CANCER RESEARCH 26, 929-934,May 10661

Immunology of Spontaneous Mammary Carcinomas in MiceIV. Association of the Mammary Tumor Virus with theImmunogenicity of C3H Nodules and Tumors1

DAVID H. LAVRIN,' PHYLLIS B. BLAIR, AND DAVID W. WEISS

Department of Bacteriology and Immunology, and Cancer Research Genetics Laboratory, University of California, Berkeley, California

Summary

Experiments were conducted to test the hypothesis that atleast part of the immunogenicity of spontaneous mammarycarcinomas and preneoplastic hyperplastic alveolar nodulesresides in antigens possessed or induced by the mammary tumorvirus (MTV).

Outgrowths of 2 recently isolated C3H nodules grew well in theMTV-infected C3H animals, but developed not at all, or only toa very limited extent, in adult MTV-free C3Hf hosts. Experiencewith either nodular tissue afforded protection to many of theC3Hf animals against subsequent challenge with implants of amammary carcinoma originating from 1 of the outgrowths. Incontrast, C3H mice accrued no such protection from noduleimmunization.

Infection of C3Hf mice with MTV at birth by foster-nursingon a C3H mother rendered these animals (designated C3Hf/f .C3H) receptive to the growth of the nodular tissues. In addition, C3Hf/f.C3H hosts could not be immunized effectivelyagainst tumor challenge by exposure to the nodular outgrowths.The immunogenicity of C3H preneoplastic and neoplasticmammary tissues for C3Hf mice cannot be explained, therefore,on the basis of any residual heterozygosis of normal isoantigeniccomposition. Instead, the present findings support the hypothesisthat antigens associated with the presence of the MTV play aprominent role in the immunogenicity of C3H mammary tumorsand nodules.

Introduction

In the preceding communication (8) it was reported thatoutgrowths of hyperplastic alveolar nodules (HAN, or "nodule")

originating in C3H mice infected with the mammary tumorvirus (MTV) appear to be immunogenic in isogenic MTV-freeC3Hf hosts. The hypothesis was advanced that at least part of

1This work was supported by Research Cirants E-292 and E-344from the American Cancer Society, Inc., AI-2309 and CA-05388from the NIH, and by Cancer Research Funds of the Universityof California.

2 Damon Runyon Memorial Postdoctoral Fellow, 19G3-19G5.

Received for publication August 18, 1965; revised November 19,1965.

the immunogenicity of spontaneous mammary carcinomas andnodules of C3H mice resides in antigens possessed or induced bythe mammary tumor virus (MTV). A number of predictionsfollow from this supposition. Experiments were designed to testtheir validity, and thereby to accumulate evidence for or againstthe hypothesis.

An immediate prediction arising from the hypothesis is thatmice infected early in life with MTV should prove to be lessreactive against isogenic preneoplastic and neoplastic tissuesinfected with the virus than uninfected animals of the samegenotype. This expectation derives from the well-documentedobservation that continuous exposure to antigens, especiallyantigens first introduced early in life, induces a state of immunologie unresponsiveness or lowered responsiveness (3, 14, 18).It should follow, therefore, that the growth of C3H nodules andtumors encounters less impediment in adult C3H hosts, whichare infected with MTV, than in uninfected C3Hf mice (10, 13),and that they induce a greater degree of immunity in the latteragainst a 2nd experience with the tissues. In addition, infectionof C3Hf mice with MTV early in life would be expected to reducetheir reactivity against C3H nodules and tumors to the level ofthe C3H animals. The recent finding of Morton that amongreciprocal FI hybrid mice, those infected neonatally with MTVby nursing on infected mothers are less resistant as adults toimplants of infected mammary tumors has, indeed, been explained by the author on the basis of the phenomenon of specifically induced immunologie unresponsiveness (9).

If these expectations could be shown to hold true, and if thepossibility that infection with MTV reduces immunologieresponsiveness in a general, nonspecific manner can be excluded,then the role of antigens associated with the presence of the MTVin the immunogenicity of preneoplastic and neoplastic mammarytissues of the mouse would be strongly supported. Such findingswould also indicate that the antigens are already expressed beforethere is any morphologic indication of the activities of thistumorigenic virus.

The present communication reports the results of experimentswhich confirm these expectations.

Materials and Methods

The materials and methods employed have already beendescribed in the preceding communication (8), and only a briefsupplementary description is required here.

MAY 1966 929

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D. H. Lavrin, P. B. Blair, and D. W. Weiss

Animals used as nodule outgrowth and tumor hosts were of themutually isogenic C3H lines: C3H, infected with the MTV, andC3Hf, free of the biologically active MTV [but infected with arelated agent recently named "NIV" (11)]. In addition, C3Hfanimals foster-nursed from birth on MTV-infected C3H motherswere employed in Experiment 3. These animals are designatedC3Hf/f.C3H. Foster-nursed and normal C3Hf mice used inExperiment 3 came from randomly selected litters in the samegeneration of the C3Hf line.

The 2 C3H HAN outgrowths described in the present experiments are the same tissues, 1 fast growing and 1 slow growing,which were used previously (8). They were in the 3rd-6th trans

plant generation in the currently reported experiments.The mammary adenocarcinoma was the same tumor, origi

nating from the fast-growing nodular outgrowth, which was usedto ascertain the antitumor immunogenicity of C3H HANoutgrowth tissue in C3Hf hosts in the preceding study (8). Thetumor was now in the 2nd-4th transplant generations.

Nodule implants were approximately 0.1 cu mm in size. Theirgrowth was ascertained by examination of the stained wholemounts of the mammary fat pads. The relative fat pad areasoccupied by the implanted outgrowths were estimated visuallyand expressed as % occupancy; complete occupancy of the fatpad area lying between the inguinal and dorsal lymph nodes wasdenned as 100%.

Significance of differences in tumor incidences were determined by the x2 test (15).

Results

TRANSPLANTATION OF C3H HAN OUTGROWTHS INTO C3H,

C3Hf, AND C3Hf/f.C3H HOSTS (IMMUNIZINGTRANSPLANTS).Groups of mice of the following ages were implanted with one orthe other of the 2 C3H nodular outgrowths: 3-6 weeks, 10-15weeks, and 30-36 weeks. Each host received an implant in bothinguinal No. 4 mammary fat pads. Normal mammary parenchyma had Ix-en removed from the pads of most of the animals at3 weeks of age (7) ("cleared" hosts), but some mice had not beensubjected to the clearing operation ("intact" hosts).

EXPERIMENT1. C3H and C3Hf mice received implants of theslow-growing nodular outgrowth. After 10 weeks, the inguinal fatpads containing the outgrowths were removed and prepared forexamination.

EXPERIMENT2. C3H and C3Hf mice received implants of thefast-growing nodular outgrowth. Since development of thisoutgrowth is considerably more rapid, growth in this experimentwas permitted for 5 weeks only, after which the inguinal fat padswere removed and examined.

EXPERIMENT3. C3Hf and C3Hf/f.C3H mice were implantedwith samples of the fast-growing nodular outgrowth. Nodulargrowth was permitted for 6 weeks before removal of the inguinalfat pads for study.

The relative areas of the fat pads which were occupied by theoutgrowths were estimated, and some of the tissues were examined histologically. The extent of proliferation of the nodularimplants in the various groups is summarized in Table 1.

As can be seen from Table 1, development of the outgrowths inC3Hf hosts occurred only in animals which were 3-6 weeks oldat the time of nodule outgrowth implantation; growth failed to

TABLE 1

GHOWTHOF C3H NODULAROUTGROWTHSIN C3Hf, C3HANDC3Hf/f.C3H HOSTS

Each host animal received nodular implants in both inguinalmammary fat pads (see the text for details).

EXPERIMENTANDTISSUE1.

Slow-growingC3HHANoutgrowth2.

Fast-growingC3HHANoutgrowth3.

Fast-growingC3HHANoutgrowthAGE

OFHOSTATIMPLANTA

TION(wk)310-1530-363-610-1530-3615STATE

OFFATPADClearedIntactClearedIntactClearedIntactClearedIntactClearedIntactClearedIntactClearedHOST

ANIMALSC3H

hostsNo.

offat

pads144101210206861887t

fatpadsfilled

(median)75558035<5505535203720C3Hf/f.C3H

hosts2250C3Hf

hostsNo.

offat

pads14610916610826%fatpadsfilled

(median)4232<5<55550<55<5

take place in adult C3Hf mice. This is in agreement with theinitial findings reported in the preceding paper (8). In C3Hanimals, on the other hand, nodular growth occurred in hosts ofall ages. Furthermore, nodular implants grew considerably in thefat pads of the adult C3Hf/f.C3H mice. These C3Hf/f.C3Hanimals thus resemble C3H rather than C3Hf mice in supportingnodular growth in the adult host.

Growth of nodular outgrowth tissue is usually found to beinhibited by the presence of normal mammary parenchyma inthe host fat pad (7), and in the present experiment very littlegrowth occurred when the slow-growing nodular outgrowth wastransplanted into the intact fat pads of adult C3H mice. Thefast-growing nodular outgrowth, on the other hand, was notinhibited by the presence of the normal parenchyma.

As reported in the previous communication (8), evidence ofC3Hf host reactivity against both C3H nodular outgrowths wasfound in many of the whole mount pads examined. Grossi}*,thisreactivity was expressed by interference with the typical nodularstructure of the outgrowths.3 Histologie examination of outgrowths from C3Hf hosts of any age revealed necrosis and muchlymphocytic infiltration around the nodular tissue; this reaction

3Figs. 1 and 3 presented in the preceding communication (8)illustrate the appearance of a commonly manifested atypicalgrowth pattern of C3H nodular tissue in C3Hf hosts. Figs. 2 and4 illustrate the appearance of the same nodular tissue in C3Hhosts.

930 CANCER RESEARCH VOL. 26



Immunology of Mammary Carcinomas. IV

TABLE 2TUMOR INCIDENCE IN C3Hf, C3H, AND C3Hf/f.C3H MICE AFTER IMMUNIZATIONWITH

C3H NODULAR (HAN) OUTGROWTHAND CHALLENGE WITH C3H TUMOR"

EXPERIMENT123Control12Control3HOSTAN'lUALSC3HfC3HfC3HfC3HfC3HC3HC3HC3Hf/f.C3HIMMUNIZINGHANSlowFastFastNoneSlowFastNoneFastNO.

WITH TCMOHS/TOTAL No. OFMICE0Immunized

animalsImmunized

when young(3-6 wk); challenged at 10-15

wk6/109/118/911/12Immunized

asadultsImmunized

at10-15 wk; chal

lenged at18-24wk0/53/55/13'5/57/710/10Immunized

at30-36wk; chal

lenged at37-48wk0/30/62/4"3/3\.

minimum/,-, 1animalsChallenged

at8-16wk12/18*12/12Challenged

at36-37wk12/13

" See the text for details.'' Incidence of tumors at 11 or 12 weeks after tumor challenge implantation.' All the tumors in this group were less than 10 x 10 mm at termination.d At least half of the tumors in each of these groups were less than 10 x 10 mm at termination.

was most pronounced in animals which had received the implants in adult life. In contrast, only very limited lymphocyticinfiltration was observed around the nodular outgrowths in C3Hhosts.3 Details of the histologie appearance of these outgrowths,and of the behavior of the fast-growing nodular outgrowth in

intact fat pads, will be the subject of a later communication(Lavrin, Dunn, and DeOme, unpublished data).

TRANSPLANTATION OF C3H MAMMARYTUMOR TISSUE INTO HOSTS

PREVIOUSLY IMMUNIZED WITH IMPLANTS OF C3H NODULAR

OUTGROWTH.Two weeks after removal of the inguinal fat padscontaining the nodular outgrowths, each mouse received ans.c. implant in the right thoracic region of a tumor fragment froma mammary tumor which had arisen from the fast-growing

nodular tissue. In addition, control C3H and C3Hf mice whichhad not been immunized previously with nodular implants werealso challenged with the tumor. Tumor growth was observed for11-12 weeks, and tumor incidence and size at termination were

recorded. Some of the mice died shortly after tumor implantation, for reasons not related to the tumor challenge; these animalsare excluded from the data on tumor development.

Tumor incidence is recorded in Table 2, and summarized inTable 3. Progressive growth of the immunizing nodular implantswas not found to be necessary for the development of heightenedtumor resistance. Cleared and intact hosts are therefore combined for purposes of presentation and calculation in Tables 2 and

3.C3H mice developed a high incidence of tumors regardless of

whether they had received implants of the C3H nodular outgrowths when young (90% incidence) or adult (89%), or had notbeen immunized (96%). More tumors developed among C3Hmice immunized when young than among C3Hf animals immu-

TABLE 3

INCIDENCE OF A CHALLENGE TUMOR OF C3H ORIGINIMMUNIZEDAND NONIMMUNIZEDC3Hf, C3H, AND

C3Hf/f.C3H MICE (SUMMARIZEDDATA)"

HOSTANIMALSC3HfC3HC3Hf/f.C3HMICE

IMMUNIZEDWHENYOUNGXo.

withtumors/

total No.ofmice15/2119/21%with

tumors7190MICE

IMMUNIZEDWHENADULTNo.

withtumors/total No.ofmice8/3217/1910/10%with

tumors2589100NON-IMMUNIZEDMICENo.

withtumors/

total No.ofmice12/1824/25%

withtumors6796

" Incidence at 11 or 12 weeks after tumor implantation (see

the text for details).

nized when young (90% vs. 71%), but the difference was notsignificant. However, among the groups immunized in adulthood,significantly fewer tumors developed among C3Hf than amongC3H mice (8/32 vs. 17/19, or 25% vs. 89%, P <0.005). Inaddition, significantly fewer nonimmunized adult C3Hf animalsthan nonimmunized adult C3H mice developed tumors (12/18vs. 24/25, or 67% vs. 96%, P<0.05). Furthermore, adultC3Hf mice immunized with the C3H nodular outgrowthsdeveloped significantly fewer tumors than nonimmunized C3Hfadults (8/32 vs. 12/18, or 25% vs. 67%, P<0.01). The tumorincidence in C3Hf/f.C3H animals immunized when adult(100%) resembled the incidence among adult immunized C3Hmice (89%) rather than the incidence among adult immunizedC3Hf hosts (25%).

MAY 1966 931




TABLE 4SIZE OF TUMORSIN IMMUNIZEDANDNONIMMUNIZEDHOSTS

11-12 WEEKSAFTEIÃ•CHALLENGEIMPLANTATION"

HOSTANIMALSC3HfC3HC3Hf/f.C3HMICE

IMMUNIZEDWEENYOUNGNo.

oftumors<

10x10mm33No.oftumors>

iox10mm1216MICE

IMMUNIZEDWHENADULTNo.

oftumors<

10X10mm533No.

oftumors>

10X10mm3147NONIMMUNIZED

MICENo.

oftumors<

10X10mm81No.

oftumors>

10X10mm423

" See Table 3 for tumor incidence data.

It is also seen from Table 2 that immunization with eithernodular outgrowth evoked resistance against challenge with thetumor.

Among the 32 C3Hf mice immunized in adult life, the 8 animalswhich permitted growth of the challenge tumor implants werealso distinguished by their support of some degree of growth,albeit of a very limited extent, of the immunizing nodular tissue.This apparent correlation parallels similar observations reportedand discussed in the preceding communication (8).

At the termination of the experiments 11-12 weeks aftertumor challenge, most of the tumors were at least 10 x 10 mm(bisecting diameters). However, as can be seen in Table 4,tumor size was limited in the C3Hf hosts either not immunized orelse immunized with nodular tissue when adult. Thus, at least70% of the tumors were large in the C3H and C3Hf/f.C3Hhosts, and also in the C3Hf hosts exposed to C3H nodular outgrowth when young. In contrast, only 3 of the 8 tumors developing in C3Hf mice immunized when adults were as large as 10 x 10mm (38%), and only 4 of the 12 tumors developing in nonimmu-nized adult C3Hf hosts were at least 10 x 10 mm (33%). Thesedata have not teen subjected to statistical analysis because of thesmall size of the groups. However, it is to be noted that the 2groups which exhibit significantly less tumor incidence are alsothe 2 groups in which most of the tumors failed to reach 10 x 10mm by termination of the experiments.

Discussion

The experiments described in this communication representthe initial findings in a series of studies designed to ascertainwhether the specific immunogenicity of preneoplastic andneoplastic mammary tissues of mice infected with the MTVresides, at least in part, in antigens possessed by the virion orproduced as a result of the virus-host interaction. The results ofthe present experiments suggest an affirmative answer to thisquestion.

Outgrowths of 2 C3H nodules evoked in C3Hf but not inC3H hosts cellular reactions usually associated with thosemanifested against implants of antigenically foreign tissue.These reactions were considerably more pronounced in adult thanin young C3Hf animals, the outgrowths failing even to exhibitappreciable growth in the former. Infection of C3Hf mice withMTV at birth, by means of foster-nursing on a C3H mother(C3Hf/f .C3H), rendered them as receptive to the C3H nodules

as C3H hosts themselves. In addition, many C3Hf animals couldbe protected against challenge with a C3H mammary carcinomaby means of exposure in adult life to C3H nodular tissue, evenwhen this tissue failed to initiate growth, whereas C3H andC3Hf/f. C3H animals derived no such protection. Implants of thetumor appeared to grow more rapidly in C3H mice, whetherimmunized or not, than in unimmunized C3Hf adults or in thosefew among the C3Hf animals immunized as adults which permitted development of the challenge tumors. Treatment ofC3Hf animals with C3H nodular tissue at 3 weeks of age, whenthe mouse's immunologie reactivity is still not yet fully de

veloped, not only failed to bestow heightened tumor resistance,but in fact resulted in more rapid growth of the challengetumors.

The only satisfactory interpretation which presents itself forthese observations is the following: An important antigen, orantigens, responsible for the specific immunogenicity of C3Hpreneoplastic and neoplastic mammary tissues is determined bythe presence of the MTV. This antigen is present on the surfaceof the infected target cells, and the immune reactions against itdamage or destroy these cells. The antigen may be already expressed shortly after infection with MTV, at a time when specificimmunologie unresponsiveness can still be induced very readilyin the mouse by contact with an antigen, and hence mice infectedwith MTV at birth through the mother's milk become unrespon

sive to it Consequently, C3H mice fail to react against implantsof C3H nodular tissue, and do not acquire heightened tumorresistance as a result of the nodule experience. In contrast, adultC3Hf mice do react against C3H HAN implants, and deriveheightened tumor resistance from the contact, because the immunizing and challenge tissues contain antigen to which they hadnot been exposed in early life, and to which they can thereforerespond immunologically. Experimental introduction of MTVinto C3Hf animals at birth renders them specifically tolerant,and prevents their effective immunization in adulthood.

This hypothesis rests on the assumption that infection withMTV does not reduce immunologie competence in a broad, nonspecific manner. That MTV infection does not, in fact, impairgeneral immunologie unresponsiveness has been ascertained bycareful comparisons of the immunogenicity of several antigens(sheep red blood cells, bovine serum albumin, and salmonellagroup-specific antigens) and skin homografts in C3H and C3Hf,and HALB/c and BALBA'.fC3H mice (Weiss and Bonhag, and

Uezfulian, Blair, and Weiss, unpublished data).The present observation that immunization with one nodule

outgrowth line can confer heightened resistance to challenge witha tumor arising from another nodule further supports the supposition that MTV-associated antigenicity plays an importantrole in mammary tumor immunology.

The fact that infection of C3Hf animals with MTV at birthrenders them nonreactive (within the limits of detectability ofsuch reactions inherent in the techniques here employed) toMTV-infected nodular and tumor tissue also provides further,conclusive evidence against the possibility that any theoreticalheterozygosis of isoantigenic characteristics between the C3Hand C3Hf lines could account for the immunizing ability of theC3H tissues in C3Hf hosts.

It was reported in the preceding communication that a C3Hfnodular outgrowth grew well in adult C3Hf hosts, and failed to




Immunology of Mammary Carcinomas. IV

confer heightened resistance against challenge with a tumorarising in that outgrowth (8). It was suggested that the apparentnonimmunogenicity of this tissue could have arisen from the factthat it had been serially transplanted for 10 generations. It isequally possible, however, to ascribe its nonimmunogenicity tothe fact that the donor tissue contained no (known) virus notpossessed by the hosts. An investigation of the behavior of otherC3Hf nodules in C3Hf mice is in progress, as is an examination ofthe immunogenicity of mammary tissues infected with the C3Hfagent, NIV (11), in BALB/c mice, which are not infected witheither MTV or NIV.

If the immunogenicity of spontaneous mammary tumors does,indeed, reside largely in MTV-associated antigens, the previouslyreported heightened reactivity of MTV-free C3H/2 hosts toMTV-free C3Hf-derived tumors induced by a previous experiencewith those tumors (17) might seem surprising. Two explanationssuggest themselves, however. For one, an adult tumor experience,followed by treatment with immunologie activators and/orkilled tumor tissue, could well break, at least partially, a state ofimmunologie unresponsiveness directed towards antigens specifically associated with the non-MTV viral antigen (NIV) of C3Hfand C3H/2 animals; such a breaking of states of immunologieunresponsiveness by hyperimmunization with the same or withclosely related antigens has been demonstrated in other systems(6, 16). For the other, it is entirely possible that in addition to themajor antigens possessed or induced by MTV and NIV, theremay be non-virus-associated antigens developing in neoplastic,and perhaps even already in preneoplastic, tissues. Eitherexplanation might apply to the findings of Attia (1) that heightened resistance and susceptibility to tumor isografts can beinduced by previous tumor experience in strain A mice, which areinfected with the MTV. The observation that the resistanceacquired by C3H/2 mice against tumors of C3Hf nodular originis, on the whole, weaker (17) than that induced in C3H/2 animalsby C3H tumors (2) is also compatible with either explanation.

A question which then presents itself is: Why were normalC3H/2 mammary tissues found incapable in previous experiments of eliciting a significant degree of tumor resistance orenhancement in C3H/2 hosts against C3Hf tumors (17), andwhy was there a similar failure of C3Hf and C3H/2 normal mammary gland preparations to immunize against C3H tumors (2)?After all, both C3Hf and C3H/2 animals are infected with NIV,and it is known that NIV and MTV share common antigenicdeterminants (4, 5). There are several possible answers: The content of virus-associated antigens may be less in normal than inneoplastic tissues. It is also conceivable that virus-associatedantigens may be incomplete in nonneoplastic tissue. Thus, it isknown, for example, that the normal mammary glands of C3Hanimals possess the biologic activity ascribed to MTV, i.e.,tumorigenic ability, but the discrete viral particles thought to bethe MTV cannot usually be found in such tissue (12).

Several studies are in progress to test further the hypothesisthat antigens possessed or induced by the MTV are involvedprominently hi the immunogenicity of MTV-infected mammarynodules and tumors. One line of experimentation is to repeat thepresently reported findings in the MTV-free C3H/2 line (Lavrin,unpublished data). Another is to ascertain whether MTV-infectednormal mammary tissue also encounters host reactions in un-infected animals. A 3rd is to explore further the immunizing

efficacy of normal mammary tissue derived from young, MTV-infected females (Dezfulian, Blair, and Weiss, and Lavrin,Dezfulian, and Weiss, unpublished data). The results of thesestudies, which provide further support for the hypothesis, willbe reported in succeeding communications.

Acknowledgments

The authors wish to express their appreciation to Dr. K. B.DeOme for his continuous interest and for his many valuablesuggestions, and to Mrs. Patricia Leslie, Miss Irene Sun, and Mrs.L. Fissoti Webber for skillful technical assistance.

References

1. Attia, M. A. Enhancement of a Spontaneous Tumor in theStrain of Origin following Vaccination with a Tumor Membrane Fraction. Proc. Am. Assoc. Cancer Res., 4' 3, 19IÃŒ3.

2. Attia, M. A., DeOme, K. B., and Weiss, D. W. Immunologyof Spontaneous Mammary Carcinomas in Mice. II. Resistanceto a Rapidly and a Slowly Developing Tumor. Cancer Res.,25: 451-57, 1965.

3. Billingham, R. E., Brent, L., and Medawar, P. B. QuantitativeStudies on Tissue Transplantation Immunity. III. ActivelyAcquired Tolerance. Phil. Trans. Roy. Soc. London, Ser. B,239: 357-414, 195Ã¶.

4. Blair, P. B. Immunology of the Mouse Mammary Tumor Virus(MTV) : Development of Methods of Assay. In: W. J. BÃ¼rdette(ed.), Viruses Inducing Cancer, Implications for Therapy.Proceedings of the Workshop on Prospects for Control ofViral-Induced Tumors by Immunologie Methods and Chemotherapy, National Advisory Cancer Council, Bethesda, June,19G5.Salt Lake City: University of Utah Press, in press.

5. Blair, P. B., and Weiss, D. W. Immunology of the MouseMammary Tumor Virus (MTV): Comparison of MTV withthe Agent Found in C3Hf/Crgl Mice. J. Nati. Cancer Inst.,in press.

6. Cinader, B. Acquired Tolerance, AutoantÂ¡bodies,and Cancer.Can. Med. Assoc. J., 86: 1161-65, 1962.

7. Faulkin, L. J., Jr., and DeOme, K. B. Regulation of Growthand Spacing of Gland Elements in the Mammary Fat Pad ofthe C3H Mouse. J. Nati. Cancer Inst., fy: 953-69, I960.

8. Lavrin, D. H., Blair, P. B., and Weiss, D. W. Immunology ofSpontaneous Mammary Carcinomas in Mice. III. Immunogenicity of C3H Preneoplastic Hyperplastic Alveolar Nodulesin C3H/f Hosts. Cancer Res., 26: 293-303, 1966.

9. Morton, D. L. Acquired Immunological Tolerance to Spontaneous Mammary Adenocarcinomas following NeonatalInfection with Mammary Tumor Agent (MTA). Proc. Am.Assoc. Cancer Res., B: 46, 1964.

10. Nandi, S., and Bern, H. A. Relation between Mammary-GlandResponses to Lactogenic Hormone Combinations and TumorSusceptibility in Various Strains of Mice. J. Nati. CancerInst., 24: 907-31, 1960.

11. Nandi, S., and DeOme, K. B. An Interference PhenomenonAssociated with Resistance to Infection from Mouse MammaryTumor Virus. Ibid., 35: 299-308, 1965.

12. Pitelka, D. R., Bern, H. A., Nandi, S., and DeOme, K. B. Onthe Significance of Virus-Like Particles in Mammary Tissuesof C3Hf Mice. Ibid., S3: 867-85, 1964.

13. Pitelka, D. R., DeOme, K. B., and Bern, H. A. ViruslikeParticles in Precancerous Hyperplastic Mammary Tissues ofC3H and C3Hf Mice. Ibid., 25: 753-77, 1960.

14. Smith, R. T., and Bridges, R. A. Immunological Unresponsive-

MAY 1966 933




ness in Rabbits Produced by Neonatal Injection of Defined 17. Weiss, D. W., Faulkin, L. J., Jr., and DeOme, K. B. Acquisi-Antigens. J. Exptl. Med., 108: 227-50, 1958. tion of Heightened Resistance and Susceptibility to Spon-

15. Tate, M. W., and Clelland, R. C. Nonparametric and Shortcut taneous Mouse Mammary Carcinomas in the Original Host.Statistics, pp. 84-87. Danville, 111.: Interstate Printers and Cancer Res., $4: 732-41, 1964.Publishers, 1957. 18. Weiss, D. W., and Main, O. The Effect of Pre- and Neo-natally

16. Weigle, W. O. The Immune Response of Rabbits Tolerant to Injected Diphtheria Toxoid on the Homologous Responsive-Bovine Serum Albumin to the Injection of Other Heterologous ness of Young Guinea Pigsâ€”A Preliminary Report. Immunol-Serum Albumins. J. Exptl. Med., 114: 111-25, 1961. ogy, B: 333-39, 1962.




1966;26:929-934. Cancer Res David H. Lavrin, Phyllis B. Blair and David W. Weiss Immunogenicity of C3H Nodules and TumorsAssociation of the Mammary Tumor Virus with the Immunology of Spontaneous Mammary Carcinomas in Mice: IV.

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