Biomedical subjects
Publications and source records attributed to S M Cotter.
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Five dogs with ostoegenic sarcoma were treated by surgical removal of the primary tumor and by adjuvant chemotherapy. Methotrexate at dosages of 3 to 6 g/m2 was used with leucovorin rescue. All dogs tolerated E g of methotrexate/m2 of body surface, but granulocytopenia precluded escalation beyond this dosage in 4 dogs. The rate and time of appearance of pulmonary metastases were not altered by treatment, with all dogs developing metastases at a median time of 4 months after amputation.
Ten post-weanling 4-month-old cats, designated "tracers", were placed in a feline leukemia cluster household to determine the efficiency of horizontal transmission of feline leukemia virus (FeLV). The tracer cats were confirmed as negative for prior exposure to FeLV. Following the placement in the leukemia cluster environment, the tracer cats were serologically monitored at intervals of 3-6 weeks for a total period of 1 year. The tests employed included the detection of FeLV using fixed-cell immunofluorescence and the detection and titration of antibody to : (1) the feline oncornavirus-associated cell membrane antigen (FOCMA), as detected by membrane immunofluorescence; (2) viable FeLV, using serum neutralization; (3) virion core protein p30, using radioimmunoprecipitation; and (4) virion glycoprotein gp70, using radioimmunoprecipitation. All of the tracers had evidence of horizontal infection by FeLV, by several criteria. Seven of the 10 had virus that could be isolated from plasma. All of these 7 developed a terminal illness within 18 months; 3 developed aplastic anemia, 3 infectious peritonitis, and 1 lymphoma. The remaining 3 were negative for FeLV by both virus isolation and fixed-cell immunofluorescence. These 3 did, however, develop high antibody titers by all four criteria and they remained healthy throughout the examination period. These results clearly indicate that unprotected pros-weanling cats brought into a leukemia exposure household environment have a high risk of becoming infected with FeLV. Furthermore, a large proportion of the cats are at risk for development of persistent viremia and FeLV-related diseases.
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The feline leukemia virus (FeLV) was discovered in 1964 in a cluster of cats with lymphosarcoma. The observed clustering of cases of feline lymphosarcoma suggested that FeLV was an infectious agent for cats. The development of a simple immunofluorescent test for FeLV permitted a seroepidemiological study to be undertaken on the distribution of the virus in cats living in their natural environment. Over 2000 cats were tested, and the results showed conclusively that FeLV is an infectious agent for cats. This finding has now been independently confirmed using three different test procedures. After the infectious nature of FeLV was discovered, a simple FeLV test and removal program was devised to control the spread of the virus in the natural environment. The spread of FeLV was controlled in 45 households by removing the FeLV-infected cats, while in 25 households, where the infected cats were left in contact with the uninfected cats, 12% of the uninfected cats became infected. The ultimate control of FeLV awaits the development of an effective FeLV vaccine, which now seems feasible since we have already experimentally immunized some cats with attenuated FeLV. Although FeLV is infectious for cats there is no evidence that FeLV can infect humans.
Cats represent an unusually valuable model for studying the role of the immune response to leukemia, lymphoma, and other mesodermal neoplasms. The agents that cause spontaneous feline leukemias, lymphomas, and fibrosarcomas, the feline leukemia and sarcoma viruses, are well characterized. A specific tumor cell membrane antigen, designated the feline oncornavirus-associated cell membrane antigen (FOCMA) has also been described. Feline leukemia and feline sarcoma viruses are antigenically indistinguishable, and FOCMA is common for both. Both laboratory-induced and spontaneous feline leukemias, lymphomas, and fibrosarcomas are available for study. A clear correlation has been shown between the resistance of cats to development of lethal tumors following inoculation of feline sarcoma virus and the presence of high humoral antibody titers to FOCMA. The geometric mean antibody titer to FOCMA for cats that resisted growth of fibrosarcomas was more than 20-fold higher than the mean for cats that succumbed to lethally progressing tumors. Cats with induced or spontaneous leukemia or lymphoma also have either no detectable FOCMA antibody or very low levels. Conversely, some cats resist development of leukemia or lymphoma following natural exposure to feline leukemia virus in leukemia cluster households, and these cats have high FOCMA antibody titers. These results support the concept of a natural immunosurveillance mechanism against leukemia or lymphoma development in an outbred mammalian species.
When compared to their housemates that subsequently developed leukemia, cats that remained healthy had five-to tenfold higher (geometric mean) humoral antibody titers to the feline oncornavirus-associated cell membrane antigen. This is compatible with the application of the immunosurveillance hypothesis to the natural development of leukemia in an outbred mammalian species.
Two hundred fifty Boston cats with disorders such as lymphosarcoma, myeloproliferative disease, anemia, glomerulonephritis, pregnancy abnormalities, feline infectious peritonitis, toxoplasmosis, and various bacterial infections were examined for feline leukemia virus (FeLV) by immunofluorescence. Antibody titers against feline oncornavirus-associated cell membrane antigen (FOCMA) were tested in 133 of these cats. The tests for FeLV and FOCMA antibody were also conducted among healthy cats not known to have been exposed to FeLV, as well as among healthy cats from households where FeLV was known to be present. Most of the cats with lymphosarcoma and the other aforementioned disorders were infected with FeLV and low FOCMA antibody titers. Healthy cats known to have been exposed to FeLV were often viremic, but those that remained healthy were able to develop high FOCMA antibody titers. Healthy cats without known prior exposure to FeLV were unlikely to be viremic but often had detectable FOCMA antibody titers, indicating that some exposure occurs under natural conditions in the Boston area. The association of FeLV with infections other than lymphosarcoma was assumed to be caused by the immunosuppresive effect of FeLV, thus allowing development of disease.
Healthy feline leukemia virus (FeLV)-infected cats from leukemia cluster environments were followed for up to 23 months for development of disease and evidence of alteration in the hemogram. The incidence of disease development in FeLV-postive cats was more than fivefold higher than the incidence for FeLV-negative cats. Ten cases of leukemia developed in 69 infected cats, whereas one case of leukemia occurred in 59 uninfected cats. The incidence for development of diseases other than leukemia was 30.4 percent for FeLV-infected cats as opposed to 6.8 per cent for uninfected cats. This could be a result of the immunosuppressive effects of FeLV. Felv-infected cats had no evidence of subclinical anemia. Mean packed cell volumes and total leukocyte counts were about the same for infected and uninfected animals. The only variation seen in healthy FeLV-infected cats was a decreased mean lymphocyte count. The difference between mean lymphocyte count for FeLV-infected and uninfected animals was significant at the 0.999 level. These findings suggest that the incubation period for feline leukemia may be very prolonged under natural conditions and that an increased susceptibility to unrelated infectious diseases exists during this period. This increased susceptibility was apparently not associated with anemia or depressed total leukocyte counts.
Feline leukemia is an infectious disease caused by a horizontally transmitted virus. Infection of animals or cultured cells with feline oncornaviruses results in the expression of a specific cell membrane antigen, feline oncornavirus-associated cell membrane antigen (FOCMA). The humoral antibody response to FOCMA is directly correlated with tumor progression. The measurement of this antibody is a useful tool for determining virus exposure. Using this procedure it was determined that cats living in leukemia "cluster" households as well as cats used as contact controls in virus injection experiments have a risk of infection of 90% or higher.
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Antibody titers to the feline oncornavirusassociated cell membrane antigen (FOCMA) were determined for 447 healthy cats from laboratory colony and household environments. Only 2.7 percent of 221 cats from colony environments were antibody positive as compared to 50.4 percent of 256 cats from household environments. Incidence of FOCMA antibody and geometric mean antibody titer for pet cats from New York City representing single cat apartment habitats were substantially lower than values for unscreened cats from the Boston, Glasgow, and Detroit suburban environments. Geometric mean antibody titer for young adults in the Boston population was significantly higher than titers for kittens or aged cats. This may be due to greater mobility resulting in increased exposure to other cats. In contrast to the high frequency of FOCMA antibody positivity in pet-cat populations, less than 2 percent of the same groups were positive for virus group-specific antigen in peripheral blood leukocytes and platelets. This was interpreted as an indication that many more cats became infected with feline leukemia virus under natural conditions that the number developing persistent virus infection and/or clinical leukemia.
Serum samples from 182 healthy cats residing in environments known to have a natural exposure to feline leukemia virus (FeLV) were examined for the presence of antibody to the feline oncornavirus-associated cell membrane antigen. The number included 138 cats from leukemia-"cluster" households. Such cats previously showed greatly increased frequencies of FeLV infection, as determined by the virus group-specific antigen (gasa) in peripheral blood leukocytes and platelets. The geometric mean antibody titer for all 182 cats with known exposure to FeLV was 4.69, more than four times higher than the mean titer for healthy pet cats from the same geographic areas but with no known FeLV exposure. About 92 percent of the cats in exposure environments were positive for FeLV gsa or feline oncornavirus-associated cell membrane antigen (FOCMA) antibody, and gsa-positive cats had lower FOCMA antibody geometric mean titers than gsa-negative cats. In the exposure environments, no differences were seen for cats of different sexes, but a higher geometric mean antibody titer was observed for cats 5 years and over when compared to younger groups. These results prove that previous reports of increased incidences of leukemia in cluster households were not due to chance alone, but rather to increased infection rates of cats in the FeLV environment. Also, they suggest that horizontal transmission of FeLV is highly efficient under crowded conditions, and that most cats naturally exposed to virus elicit an active immune response.
Cats with naturally occurring leukemia and lymphoma had low or negative humoral antibody titers to the feline oncornavirus-associated cell membrane antigen (FOCMA). Geographic differences were seen in the relative frequencies of various forms of lymphoproliferative neoplasms. Lymphatic leukemia and thymic lymphoma were most common in Boston, whereas alimentary lymphoma was most frequent in Glasgow. No significant differences were found in geometric mean FOCMA antibody titers for the various forms of leukemia-lymphoma or for feline leukemia virus (FeLV)-positive as compared to FeLV-negative cats. Approximately 70% of 76 Boston cats with nonregenerative anemias were FeLV gs antigen (gsa) positive; this was similar to the percentage with leukemia-lymphoma from the same population that was positive. Fifty-five to 62% of the Boston cats with other infectious diseases, such as peritonitis and septicemia, were gsa positive. We postulate that this is due to a predisposition to infectious diseases by the immunosuppressive action of FeLV. Young cats from the Boston population that developed lymphoma, infectious peritonitis, and certain other diseases were more likely to be FeLV gsa positive than older cats with the same diseases.
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