Immune Response to Leukemia Virus and Tumor-Associated Antigens in Cats'

[CANCER RESEARCH 36, 640-645, February 1976]

Immune Response to Leukemia Virus and Tumor-associated Antigens in Cats'

M. Essex, 2"3 A. Sliski, W. D. Hardy, Jr., 3 and S. M. Cotter

Department of Microbiology, Harvard University School of Public Health, Boston, Massachusetts 02115 [M. E., A. S., S. M. C.], and Sloan-Kettering Institute for Cancer Research, New York, New York 10021 [W. D. H.]

Summary leukemia and/or lymphoma. Oncornaviruses have been identified in numerous other outbred mammalian species, Cats represent an unusually valuable model for studying but oncogenicity by the particles has been difficult to dem- the role of the immune response to leukemia, lymphoma, onstrate (13). Highly oncogenic oncornaviruses have been and other mesodermal neoplasms. The agents that cause found in inbred laboratory mouse strains, but evidence is spontaneous feline leukemias, lymphomas, and fibrosarco- lacking that the same viruses cause spontaneous tumors in mas, the feline leukemia and sarcoma viruses, are well wild mice. characterized. A specific tumor cell membrane antigen, Our purpose here is to examine the role of the immune designated the feline oncornavirus-associated cell mem- response in the development and progression of leukemia brane antigen (FOCMA) has also been described. Feline and lymphoma in cats and to speculate about what signifi- leukemia and feline sarcoma viruses are antigenically indis- cance this may have concerning a role for the immune tinguishable, and FOCMA is common for both. Both labora- response in the development of lymphoid tumors of man. It tory-induced and spontaneous feline leukemias, lympho- is therefore necessary first to consider the natural history of mas, and fibrosarcomas are available for study. A clear lymphoid neoplasia of cats. Several features of the feline correlation has been shown between the resistance of cats disease appear to make it an appropriate model for the to development of lethal tumors following inoculation of study of lymphoid neoplasia of children. Cats are outbred feline sarcoma virus and the presence of high humoral like man, and leukemia occurs in all breeds with no evident antibody titers to FOCMA. The geometric mean antibody genetic predisposition. An early age peak is seen in feline titer to FOCMA for cats that resisted growth of fibrosarco- leukemia (13, 16, 42), similar to the peaks seen for acute mas was more than 20-fold higher than the mean for cats leukemia and Burkitt's lymphoma of children. Cats develop that succumbed to lethally progressing tumors. Cats with both true lymphoid leukemia, with primary involvement of induced or spontaneous leukemia or lymphoma also have the blood and bone marrow, and localized lymphoma (13, either no detectable FOCMA antibody or very low levels. 16). The histopathology of feline lymphoma is similar to that Conversely, some cats resist development of leukemia or for any rapidly growing lymphoid tumor such as Burkitt's lymphoma following natural exposure to feline leukemia lymphoma (60). virus in leukemia cluster households, and these cats have A possible disadvantage of the model is that feline leuke- high FOCMA antibody titers. These results support the con- mia and lymphoma are caused by horizontally transmissi- cept of a natural immunosurveillance mechanism against ble agents that replicate in a productive fashion in most cats leukemia or lymphoma development in an outbred mamma- with tumors, since comparable agents have not been found lian species. in acute leukemia of man. On the other hand, the seroepide- miology of FeLV 4 appears similar to that of the Epstein-Barr virus, which is horizontally transmitted and which many Introduction believe will eventually be accepted as the cause of Burkitt's lymphoma (36, 45). Serological tests for evaluating the host Evidence that convincingly supports a viral etiology for immune response to both the etiological agent and the most spontaneous human lymphoid tumors has not been altered tumor cell are available for feline leukemia and obtained. Despite this, substantial evidence indicates that lymphoma 4 (13, 22, 23, 32, 34, 58). The opportunity to use both oncornaviruses and herpesviruses can cause sponta- such procedures for the study of individuals with either neous lymphoproliferative tumors in certain animal species. laboratory-induced or spontaneous tumors known to be In at least 2 species, the chicken and the cat, horizontally caused by the same agents is unusual. Furthermore, transmitted oncornaviruses cause spontaneous lymphoid healthy cats at high risk for development of leukemia, which were known to be exposed to FeLV under natural condi- ' Presented at the symposium "Immunological Control of Virus-associated Tumors in Man: Prospects and Problems," April 7 to 9, 1975, Bethesda, tions, are also available for study (8, 9, 13, 14, 17-19, 31, Md. This work was supported by grants from the National Cancer Institute 34). (CA-13885, CA-08748), the Anna Fuller Fund, the Jane Coffin Childs Fund for Whether immunosurveillance of developing malignant Medical Research, the National and Massuchusetts Branches of the Ameri- can Cancer Society, the Cancer Research Institute, and the Oliver S. and cell clones occurs under natural conditions is an issue that Jennie R. Donaldson Charitable Trust. Presenter. 4 The abbreviations used are: FeLV, feline leukemia virus; FOCMA, feline 3 Scholar of the Leukemia Society of America. oncornavirus-associated cell membrane antigen; FeSV, feline sarcoma virus.

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is central to tumor immunology (46). Several observations hosts (40). If they are immunogenic, the question still re- support this concept. A substantially increased risk for tu- mains of whether the autochthonous immune response to mor development occurs in organ-transplant patients and the determinants can result in cytostasis or cytolysis of others subjected to therapy with immunosuppressive drugs tumor cells. In most instances where immunogenicity to the (54). A similar increase in tumor risk occurs in patients with virus core "group-specific" (gs) antigens has been de- the rare inherited immunological deficiency diseases (29), tected, it has been associated with a non-complement-fix- and this is not due to an increased susceptibility of cells to ing humoral response, which is not correlated with tumor the transforming effects of oncogenic agents (44). In labora- development or progressions (52, 59). tory animals the administration of immunosuppressive The issue of antigens in the virus particle that result in drugs results in increased incidences of tumor develop- virus neutralization seems simple by comparison. The gp70 ment, shorter latent periods, and increased rates of metas- is the primary virion envelope antigen, and antiserum to this tasis (2, 35, 37). An observation that is in apparent conflict component results in virus inactivation (4, 61). Antiserum to with the immunosurveillance concept is the lack of in- core proteins is ineffective because such a reaction cannot creased risk for tumor development in nude (thymusless) occur without disruption of the envelope. mice (56, 63). We proposed the term feline oncornavirus-associated cell membrane antigen (FOCMA) for the specific reactivity found at the surface of FeLV-infected cells. FOCMA does Cell Membrane Antigens not cross-react to any significant degree with similar antigens induced by other oncornaviruses, including those in- The antigen systems to be considered for an analysis of duced by the endogenous oncornaviruses of cats (6, 12, 13, the immune response to feline leukemia can be operation- 20, 24, 53). The target cell most commonly used for detec- ally grouped into 2 categories: those found at the surface of tion of feline antibody to the FOCMA antigen by either the infected and/or transformed cells, and those that make membrane fluorescence or cytotoxicity tests is the FI 74 up the virion particle. The main proteins that make up the culture of feline lymphoma cells (12, 13, 22, 23). This cell virion particle are listed by molecular weight as p30, p15, produces FeLV of all 3 of the virus subgroups that have p12, and pl0 of the virus core. Considerable evidence sug- been described in cats (57). The virus subgroups are each gests that the 3 major virion proteins, gp70, p30, and p15, antigenically distinct on the basis of their virus envelope can also be detected on the membranes of infected cells. In antigens. The presence of the virus core antigens on the the case of gp70, it is logical to expect some degree of surface of the FI 74 cell must also be considered. detection, because oncornavirus particles bud from the cell membrane, and the gp70 is at the surface of the virus particle (4). The detection of p30 and p15 at the cell mem- Experimentally Induced Tumors brane might not be as readily expected, however, because they appear to be internal virus proteins (4). In the case of Antibody to FOCMA was first detected in cats that had p30, this has been demonstrated on cells replicating either been given laboratory inoculations of FeSV (21, 22, 24). feline or murine oncornaviruses using antisera from rabbits Both the animals that developed tumors that subsequently hyperimmunized with either disrupted virus or the p30 frac- regressed and those that showed no palpable tumors at all tion (65). had significant levels of humoral antibody to FOCMA (Table An antigenic activity that appears to be the Friend-Molo- 1). Of 41 "regressor" or "no tumor" animals, all developed ney-Rauscher cell surface antigen has also been found in titers of 4 or higher. More than two-thirds had titers of 16 or disrupted virus particles (25). In this case it appears to higher and four-fifths had titers of 8 or higher. The geomet- represent the p15 fraction (62). It is unlikely, however, that ric mean antibody titer for this group was more than 20-fold the Friend-Moloney-Rauscher cell surface antigen is a sin- higher than the geometric mean for cats that developed gle cross-reacting entity that always occurs as the predomi- progressing tumors. Of 57 cats that developed rapidly pro- nant antigenic activity on infected cells. The degree of gressing fatal tumors only one-half had any detectable anti- cross-reactivity between Friend, Moloney, and Rauscher body to FOCMA, and only 1 cat had a titer of 8 or higher. tumor cells varies widely with different sera and different A strong correlation was also seen between the presence serological procedures (7, 64). of maternally transmitted FOCMA antibody in the serum of In addition to virus core and envelope proteins, it is at neonatal kittens and their ability to resist doses of FeSV that least theoretically possible that antigenic determinants that would otherwise be lethal (21, 24). Although protection are not virion structural proteins are also found at the sur- against tumor development in the kittens was regularly asso- face of infected and/or transformed cells. These could in- ciated with the presence of passively acquired FOCMA anti- clude depressed embryonic antigens (12, 41) as well as body, whether or not virus-neutralizing antibody was also virus-directed non-virion antigens that might or might not present in the same kittens was not determined. It is thus be tumor specific (12, 47). possible that neutralization of FeSV inoculum by virus-neu- A question that still remains concerning the virus core tralizing antibody, if it was also present, could have been components (especially p30) at the cell surface is whether responsible for preventing tumor induction. or not they are immunogenic in the autologous host natu- Both virus-neutralizing and FOCMA antibody levels have rally exposed to that virus. Such virus core antigens have been determined for many of the regressor and progressor generally been considered nonimmunogenic in autologous cats listed in Table 1. The presence of significant titers of

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Table 1 Antibody titers to FOCMA in cats treated by injections of FeSV

Geomet- No. with de- ric tectable anti- No. with titers No. with titers No. with titers mean ti- Tumor status body ->4 ---8 ->16 ter

Progressor 29/57 (51)" 13/57 (23) 1/57 (2) 1/57 (2) 0.87 Regressor or no tumor 41/41 (100) 41/41 (100) 33/41 (80) 28/41 (68) 20.30 developed

" Numbers in parentheses, percentage.

Table 2 Antibody titers to FOCMA in healthy cats or cats with spontaneous leukemia, lymphoma, or nonregenerative anemia

No. with detecta- No. with titers Geometric Health status ble antibody NO. with titers ->4 No. with titers ->8 1> 16 mean titer

Lymphoid leukemia" 23/45 (51)b 7/45 (16) 1/45 (2) 0/45 (0) 0.77 Lymphoma" 14/44 (32) 2/44 (5) 0/44 (0) 0/44 (0) 0.34 Anemia" 35/81 (43) 8/81 (10) 3/81 (4) 2/81 (2) 0.63 Healthy exposed 113/138 (82) 94/138 (68) 68/138 (49) 43/138 (31) 5.77 FeLV positive 53/66 (80) 42/66 (64) 24/66 (36) 9/66 (14) 3.51 FeLV negative 61/72 (85) 52/72 (72) 44/72 (61) 34/72 (47) 8.81 Healthy, presumably unexpo- 3/120 (3) 1/120 (1) 1/120 (1) 1/120 (1) 0.04 sed ~

" Collected at the Angell Memorial Animal Hospital, Boston, Mass. Numbers in parentheses, percentage. " Collected at previously identified leukemia-lymphoma cluster households in the Boston area where several FeLV- positive neoplastic cats were known to have resided. See Refs. 8, 9, 18, and 19. ,t Specific-pathogen-free or "minimal disease status" cats maintained in experimental colonies. virus-neutralizing antibody was not correlated with either relationship occurred under natural conditions. In an at- FOCMA antibody titers or tumor progression (59). Cats that tempt to answer this question, 2 major groups of cats were had undergone sarcoma regression were no more likely to studied serologically: (a) those that developed spontaneous have significant levels of free virus neutralizing-antibody leukemia or lymphoma; and (b) those that were known to be than those with progressing tumors. This is compatible with exposed to FeLV under natural conditions and that were independent observations showing that cats frequently still healthy. have significant levels of infectious FeSV persisting in the Cats that develop spontaneous lymphoid neoplasia or blood after regression of FeSV-induced sarcomas has oc- nonregenerative anemia all have low or negative humoral curred (1). antibody levels to the FOCMA antigen (10, 13, 14, 16) (Table Although a lower number of animals that were injected 2). Anemia is included with this group because it has been with FeLV were available for study, the same trend was shown to be caused by FeLV under experimental conditions observed (12-14). Those that developed clinical leukemia (38), and a high percentage of the spontaneous nonregener- had either no detectable FOCMA antibody or very low lev- ative anemias occur in FeLV-infected cats (10, 16, 27, 34). els, while those that remained healthy after receiving the The geometric mean antibody titer was only 0.77 in cats same virus doses had high FOCMA antibody titers. with spontaneous lymphoid leukemia and only 0.34 in cats Since FeLV is known to be spread efficiently in a horizon- with lymphoma. Only 9 of 89 cats with lymphoid neoplasia tal fashion under both laboratory and field conditions (13, had titers of 4 or higher and only 1 had a titer of 8 or higher. 15, 19, 23, 31,34), we determined FOCMA antibody titers for The low levels of FOCMA antibody were found in lymphopro- healthy cats that were contact exposed to FeLV or FeSV liferative disease irrespective of such factors as pathologi- cagemates in the laboratory (17). Of 20 such cats that re- cal form, geographical location, whether or not the cat was mained healthy without developing tumors, 18 developed viremic with FeLV, age at the time of diagnosis, or breed FOCMA antibody titers ranging up to 128. The geometric (10, 16). These results indicated that the immune status of mean for all 20 was 8.11. cats with spontaneous lymphoproliferative neoplasia was the same as that for cats with laboratory-induced progres- Immune Surveillance Under Field Conditions sive sarcoma or leukemia, at least in respect to the apparent Although evidence for an association between an efficient poor humoral antibody response to FOCMA. immune response to FOCMA and protection from tumor To determine the serological status of cats that remained growth under laboratory conditions was quite convincing, it healthy despite being constantly exposed to FeLV, we con- was still necessary to determine whether the same type of centrated the study on about 140 cats in 2 leukemia-lym-

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phoma cluster households. In one of these houses 11 cases B-cell functions have been shown to be correlated with of lymphoid leukemia had occurred over a 39-month period tumor regression or prevention in some systems, however, among a population-at-risk of 35 (8, 9, 19). In the other including the Moloney oncornavirus-induced fibrosarcoma house, between 140 and 150 cats had resided over an 18- of mice (48, 49) and malignant melanoma of man (50). It is month period, during which time 10 cases of lymphoma possible that the humoral antibody activity regularly corre- were recorded (18, 19). lated with regression or tumor prevention in the feline sys- The possibility that other cases had also occurred could tem may merely be paralleling the activity of the cell-me- not be eliminated because several cats died of unknown diated immune response. It is clear, however, that the causes when an autopsy was not possible. FeLV could be FOCMA antibody is not acting as a blocker for cell-mediated detected in most of the cases of leukemia and lymphoma in immunity. The possibility that FOCMA antibody can either each of the houses, and one-third to one-half of the healthy act alone (with complement) to inhibit or lyse tumor cells or cats were also FeLV-positive, as determined by the pres- facilitate cytotoxicity by immune effector cells must be con- ence of gs antigen in circulating leukocytes and platelets (8, sidered. 18, 19). Another obvious question concerns the nature of the Because of evidence that both laboratory-inoculated and antigenic determinant to which the FOCMA antibody of naturally infected cats excrete FeLV in oral and nasal excre- regressor cats is directed. In reference to the apparent tions (28, 43), it seemed safe to assume that more of the cats virus-negative leukemias of man, it would be interesting to in these 2 houses were regularly exposed to FeLV. know whether the FOCMA determinant is also a virion struc- Serological examination of the healthy cats in these 2 tural component and, if so, whether it is present only at the houses indicated that 82% had detectable FOCMA antibody. cell membrane and immunogenic when complete virus is Since virus-positive cats were more likely to be antibody also being produced. Our observations on the lack of corre- negative, 92% of all the cats had either detectable virus or lation with FOCMA antibody and virus-neutralizing antibody detectable FOCMA antibody, or both. The geometric mean suggest that it is not a component of the virion envelope. FOCMA antibody titer for the FeLV-negative healthy cats in Since we know that p15 and p30 can be expressed at the the 2 houses was 8.81. This is 10- to 20-fold higher than the cell surface, the possibility that the regression-related geometric mean titers for cats with either spontaneous or FOCMA antibody of cats is directed to either or both of the induced leukemia, or induced fibrosarcoma that progresses antigens must remain open. Equally likely, however, is the to kill the host. possibility that FOCMA might include a true tumor antigen The serological status of cats in these high-exposure determinant, one which would not necessarily also be a environments was followed in a prospective sense at inter- virion structural component but would represent the deter- vals of 3 to 4 months for up to 2 years. During this time 14 minant which is immunogenic in cats that resist tumor de- previously healthy cats developed leukemia or lymphoma. velopment. Of those that developed such diseases, none had FOCMA antibody titers higher than 4 for up to 5 months prior to Role of Immunosuppression leukemia development, and the geometric mean titer for cats that subsequently developed leukemia or lymphoma As mentioned earlier, immunosuppression greatly in- was 5- to 10-fold lower than the mean for healthy cats living creases the risk for development of lymphoproliferative neo- in the same environments. plasms in both man and lower animals. Since the Friend It was clear that FeLV-negative cats with high FOCMA and Moloney leukemia viruses are known to be immunosup- antibody titers represent the group at lowest risk for tumor pressive under laboratory conditions (11,51), it is logical to development. Even cats that are FeLV positive do not ap- ask whether the same phenomenon occurs in cats following pear to have an increased risk for tumor development if natural exposure to FeLV. Perryman et al. have shown that their FOCMA antibody titers remain high. Cats in the latter cats inoculated with the Rickard strain of FeLV are also category are negative for free virus-neutralizing antibody immunosuppressed while incubating leukemia (55). Several (30). On the other hand, cats that test as FeLV positive and reports have also described premature atrophy of the thy- have FOCMA antibody titers of less than 4 over a 3- to 4- mus in both induced and spontaneous leukemia or lym- month period are at greatly increased risk for tumor develop- phoma of cats (3, 39). Additionally, a higher-than-expected ment. As far as these 2 cluster households are concerned, number of cats with at least 1 particular nonneoplastic about one-half of the cats in this category will die from disease, infectious peritonitis, were observed to be concur- leukemia or another disease within a 2-year period after 1st rently infected wth FeLV (33). detection. With this background, we decided to test cats presenting When all the above results are taken together, it is difficult with nonneoplastic infectious diseases at the Angell Memo- to escape the conclusion that immunosurveillance is opera- rial Animal Hospital for evidence of FeLV infection (10, 16). tive against feline leukemia under natural conditions and Most cases examined were either hemobartonellosis, infec- that FOCMA is the target of the immunosurveillance mech- tious peritonitis, septicemia, pneumonia, cystitis, or stoma- anism. Several key questions concerning this response still titis. Of 110 cats with these diseases, 64, or 58%, were also remain to be answered, however. One concern is the possi- infected with FeLV, and less than 2% of the healthy cats in ble role of thymus-derived T-cell or classical cell-mediated the same environment were FeLV positive (10, 13). Healthy immunity, since many tumor immunologists feel that T-cell cats in the 2 leukemia cluster households mentioned above functions are generally most important. were also studied for the development of these infectious

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1976 American Association for Cancer Research. M. Essex et al. diseases. It was determined that FeLV-positive healthy cats 16. Essex, M., Cotter, S. M., Hardy, W. D., Jr., Hess, P., Jarrett, W., Jarrett, O., Mackey, L., Laird, H., Perryman, L., Olsen, R. G., and Yohn, D. S. had a 5-fold increased risk for the development of non- Feline Oncornavirus-Associated Cell Membrane Antigen. IV. Antibody neoplastic diseases when compared to FeLV-negative cats Titers in Cats with Induced and Naturally Occurring Leukemia and Other from the same houses. Despite the fact that FeLV-positive Diseases. J. Natl. Cancer Inst., 55: 463-467, 1975. 17. Essex, M., Hardy, W. D., Jr., Cotter, S. M., and Jakowski, R. M. Immune healthy cats had hematocrit values that were indistinguisha- Response of Healthy and Leukemic Cats to the Feline Oncornavirus- ble from those for FeLV-negative cats, the mean absolute Associated Cell Membrane Antigen (FOCMA). In: Y. Ito and R. M. lymphocyte count for healthy FeLV-positive cats was se- Dutcher (eds.), Comparative Leukemia Research 1973, pp. 431-436. Tokyo: University of Tokyo Press, 1974. verely depressed when compared to FeLV-negative cats 18. Essex, M., Hardy, W. D., Jr., Cotter, S. M., Jakowski, R. M., and Sliski, A. from the same environments (18). These observations sug- Naturally Occurring Persistent Feline Oncornavirus Infections in the Absence of Disease. Infect. Immunity, 11: 470-476, 1975. gest that immunosuppression by FeLV occurs under natural 19. Essex, M., Jakowski, R. M., Hardy, W. D., Jr., Cotter, S. M., Hess, P., and conditions and that healthy cats that are incubating leuke- Sliski, A. Feline Oncornavirus-associated Cell Membrane Antigen. II1. mia are at a high risk for development of other infectious Antibody Titers in Cats from Leukemia Cluster Households. J. Natl. Cancer Inst., 54: 637-641, 1975. diseases. 20. Essex, M., Klein, G., Deinhardt, F., Wolfe, L., Hardy, W. D., Jr., Theilen, Since more than one-half of the cases of random Boston G., and Pearson, L. Induction of the Feline Oncornavirus-Associated Cell cats with severe nonneoplastic infectious diseases were Membrane Antigen in Human Cells. Nature New Biol., 238: 187-189, 1972. found to be infected with FeLV, the possibility must be 21. Essex, M., Klein, G., Snyder, S. P., and Harrold, J. B. Antibody to Feline considered that FeLV kills more cats by predisposing to Oncornavirus-Associated Cell Membrane Antigen in Neonatal Cats. In- tern. J. Cancer, 8: 384-390, 1971. these other diseases than by inducing leukemia. It is also 22. Essex, M., Klein, G., Snyder, S. P., and Harrold, J. B. Feline Sarcoma possible that extensive variation exists among cats in their Virus (FSV)Induced Tumors: Correlation between Humoral Antibody and general immune responsiveness and that poor responders Tumor Regression. Nature, 233: 195-196, 1971. 23. Essex, M., and Snyder, S. P. Feline Oncornavirus-Associated Cell Mem- have increased sensitivity to persistent infections with both brane Antigen. I. Serologic Studies with Kittens Exposed to Cell-Free FeLV and other infectious organisms. Nevertheless, if some Materials from Various Feline Fibrosarcomas. J. Natl. Cancer Inst., 51: forms of leukemia in man are eventually shown to be caused 1007-1012, 1973. 24. Essex, M., Snyder, S. P., and Klein, G. Relationship between Humoral by oncornaviruses (5, 26), the question of whether these Antibodies and the Failure to Develop Progressive Tumors in Cats In- same agents also act as immunosuppressants, even in indi- jected with Feline Sarcoma Virus. In: R. M. Dutcher and L. Chieco- Bianchi (eds.), Unifying Concepts of Leukemia, pp. 771-777. Basel: S. viduals that have not developed leukemia, must also be Karger AG, 1973. add ressed. 25. Friedman, M., Lilly, F., and Nathenson, S. G. Cell Surface Antigen Induced by Friend Murine Leukemia Virus is also in the Virion. J. Virol., 14: 1126-1131,1974. References 26. Gallagher, R. E., and Gallo, R. C. Type C RNA Tumor Virus Isolated from Cultured Human Acute Myelogenous Leukemia Cells. Science, 187: 350- 353, 1975. 1. Aldrich, C. D., and Pedersen, N. C. Persistent Viremia after Regression of 27. Gardner, M. B., Rasheed, S., Rongey, R. W., Charman, H. P., Alena, B., Primary Virus-Induced Feline Fibrosarcomas. Am. J. Vet. Res., 35: 1383- Gilden, R. V., and Huebner, R. J. Natural Expression of Feline Type-C 1388, 1974. Virus Genomes. Prevalence of Detectable FeLV and RD-114 gs Antigen, 2. Allison, A. C., and Law, L. W. Effects of Antilymphocyte Serum on Virus Type-C Particles and Infectious Virus in Postnatal and Fetal Cats. Intern. Oncogenesis. Proc. Soc. Exptl. Biol. Med., 127: 207-212, 1968. J. Cancer, 14: 95-105, 1974. 3. Anderson, L. J., Jarrett, W. F. H., Jarrett, O., and Laird, H. M. Leukemia 28. Gardner, M. B., Rongey, R. W., Johnson, E. Y., DeJournett, R., and Virus Infection of Kittens; Mortality Associated with Atrophy of the Thy- Huebner, R. J. C-Type Tumor Virus Particles in Salivary Tissue of Domes- mus and Lymphoid Depletion. J. Natl. Cancer Inst., 47: 807-817, 1971. tic Cats. J. Natl. Cancer Inst., 47: 561-568, 1971. 4. Bauer, H. Virion and Tumor Cell Antigens of C-Type RNA Tumor Viruses. 29. Gatti, R. A. and Good, R. A. Occurrence of Malignancy in Immunodefi- Advan. Cancer Res., 20: 275-341,1974. ciency Diseases--A Literature Review. Cancer, 28: 89-98, 1971. 5. Baxt, W., Yates, J. W., Wallace, H. J., Jr., Holland, J. F., and Spiegelman, 30. Hardy, W. D., Jr. Immunology of Oncornaviruses. Vet. Clin. North Am., 4: S. Leukemia-Specific DNA Sequences in Leukocytes of the Leukemic 133-146, 1974. Member of Identical Twins. Proc. Natl. Acad. Sci. U. S., 70: 2629-2632, 31. Hardy, W. D., Jr., Hess, P. W., Essex, M., Cotter, S., McClelland, A. J., 1973. and MacEwen, G. Horizontal Transmission of Feline Leukemia Virus in 6. Boone, C. W., Church, E. C., and McAIlister, R. Testing by the "Paired- Cats. In: Y. Ito and R. M. Dutcher (eds.), Comparative Leukemia Re- Label" Antibody Binding Technique for Feline Leukemia Virus-Induced search 1973, pp. 105-111. Tokyo: University of Tokyo Press, 1974. Cell Surface Antigens (FeLV-CSA) on the Surface of Human Rhabdomy- 32. Hardy, W. D., Jr., Hirshaut, Y., and Hess, P. Detection of the Feline osarcoma Cells Releasing RD 114 Virus. Virology, 55: 157-163, 1973. Leukemia Virus and Other Mammalian Oncornaviruses by Immunofluo- 7. Cerny, J., and Essex, M. Membrane Antigens of Murine Leukemia Cells. rescence. In: R. M. Dutcher and L. Chieco-Bianchi (eds.), Unifying Nature, 251: 742-744, 1974. Concepts of Leukemia, pp. 778-799, Basel: S. Karger AG, 1973. 8. Cotter, S. M., Essex, M., and Hardy, W. D., Jr. Serological Studies of 33. Hardy, W. D., Jr., and Hurvitz, A. I. Feline Infectious Peritonitis: Experi- Normal and Leukemic Cats in a Multiple-Case Leukemia Cluster. Cancer mental Studies. J. Am. Vet. Med. Assoc., 158: 994-1001, 1971. Res., 34: 1061-1069, 1974. 34. Hardy, W. D., Jr., Old, L. J., Hess, P. W., Essex, M., and Cotter, S. 9. Cotter, S. M., Gilmore, C. E., and Rollins, C. Multiple Cases of Feline Horizontal Transmission of Feline Leukemia Virus. Nature, 244: 266-269, Leukemia and Feline Infectious Peritonitis in a Household. J. Am. Vet. 1973. Med. Assoc., 162: 1054-1058, 1973. 35. Hellman, K., Hawkins, R. I., and Whitecross, S. Antilymphocyte Serum 10. Cotter, S. M., Hardy, W. D., Jr., and Essex, M. The Association of the and Tumor Dissemination. Brit. Med. J., 2: 533-535, 1968. 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M. Essex, A. Sliski, W. D. Hardy, Jr., et al.

Cancer Res 1976;36:640-645.

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