Biomedical subjects
Publications and source records attributed to G L Cockerell.
A penumatic operated semiautomatic system was developed for the intrarectal instillation of solutions in the guinea pig. The apparatus permitted one person to inject large numbers of animals at considerable savings in time compared to manually operated syringe techniques. The procedure was shown to be both rapid and safe for administering solutions intrarectally in the guinea pig.
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This report provides a general overview of the pathobiology of neoplasia, and an update on the clinicopathological manifestations of lymphosarcoma, mastocytoma, histiocytoma, melanoma, sarcoid and circumanal gland tumors in domestic animals. Neoplasia represents a continuum of events from reversible hyperplasia to irreversible and pathological changes in tissue growth patterns. In some instances the causes of this disease process have been identified, but the etiology of the majority of naturally occurring neoplasms remain unknown. Surgical excision is the preferred treatment for tumors, but is often more beneficial when combined with chemotherapy, radiotherapy or immunotherapy. The successful diagnosis and management of neoplastic disease in domestic animals necessitates a thorough awareness of the clinical presentation and biologic behavior of specific tumors on the part of veterinarians who provide health care for these species.
Twelve cats were thymectomized at 5 weeks of age. Six of these cats were inoculated at 8 weeks of age and 6 at 4 months of age with the Rickard (R) strain of feline leukemia virus (FeLV), which produces a high incidence of thymic lymphosarcoma. Two groups of age-matched nonthymectomized cats were inoculated with the same FeLV-R stock. Thymectomy prior to FeLV infection had no influence on the induction of viremia or the incidence of lymphosarcoma. In the FeLV-inoculated nonthymectomized cats, lymphosarcoma developed in the thymus. In the thymectomized cats, lymphosarcoma developed in the intestine, mesenteric lymph nodes, and bone marrow, but the malignant lymphoblasts had surface markers characteristic of feline T lymphocytes. It was concluded that the presence of the thymus per se is not required for infection and oncogenesis by FeLV and that feline T lymphocytes may be transformed after peripheralization to other tissues.
Thymectomy of 5-week-old kittens was accomplished by left parasternal thoracotomy, ligation of the left internal thoracic artery, and removal of the thymus from the mediastinum by traction and blunt dissection. Thymectomy had no adverse clinical effects, and neither the response of peripheral blood lymphocytes to phytomitogens nor the proportions of circulating lymphocytes bearing T- or B-cell markers differed substantially between thymectomized cats and nonthymectomized control cats. Skin allograft rejection times of the thymectomized cats (3 weeks after operation) were slightly longer than those of littermate nonthymectomized controls. We conclude that removal of the thymus in preweanling kittens does not have important physiologic or immunologic consequences.
Soft tissue tumors containing a mixture of neoplastic fibrous tissue, cartilage, and bone have previously been classified as extraskeletal osteosarcomas in the dog. These tumors are often poorly differentiated, contain multiple neoplastic cell types, and might be more appropriately called mixed mesenchymal sarcomas. The present neoplasm caused clinical signs of stridorous respiration and dysphagia in a four and one-half year old dog. Four neoplastic cell types were demonstrated by light and electron microscopy.
Spent tissue culture medium from two continuous lymphoblastoid cell lines, FL-74 and CT45-S, expressing the T-lymphocyte receptor for guinea pig E and the B-lymphocyte receptor for EAC respectively were used to produce receptor-specific antisera. Anti-E receptor sera blocked E rosette formation on FL-74 cells, canine and feline lymphocytes and canine and feline thymocytes but not EAC rosette formation by CT45-S cells or canine and feline lymphocytes. Anti-EAC receptor sera blocked EAC rosette formation on CT45-S cells and canine or feline lymphocytes. Absorption of antisera will the appropriate lymphoblastoid cell line removed E or EAC-blocking activity. The results of this study suggest that similar methods may be used to produce lymphocyte subpopulation-specific antisera in other species including man.
The effect of serum from 12 cats with lymphosarcoma induced by feline leukemia virus (FeLV) on the response of normal cat peripheral blood lymphocytes to phytomitogen-induced blastogenesis was studied. The majority of FeLV sera, when tested at a concentration of 20% of the incubation medium, caused a 40 to 70% reduction in the mean blastogenic response to concanavalin A compared to the response obtained with a similar concentration of normal feline serum. Results with pokeweed mitogen were similar, but the depression in blastogenesis was less than with concanavalin A. Further studies showed that the blastogenic inhibitory activity of FeLV serum (a) was heat labile at 56 degrees for 30 min, (b) could not be overcome by greater concentrations of mitogens, (c) was proportional to the concentration of FeLV serum in the incubation medium, and (d) could not be demonstrated when lymphocytes were preincubated in FeLV serum followed by washing and reincubating in normal feline serum. The results suggested that a substance present in the serum of FeLV-infected cats contributes to altered immunological reactivity during leukemogenesis in the cat.
Erythrocyte rosette (ER) formation of equine peripheral blood lymphocytes (PBL) was characterized. Guinea pig and, to a lesser extent, human erythrocytes formed ER; cat, cow, dog, hamster, mouse, rat, and sheep erythrocytes showed negligible rosetting properties. Conditions of the assay were varied to determine which procedure allowed the largest percentage of rosette formation. The PBL from 20 normal horses were then assayed, averaging 38 +/- 2% ER. To characterize the erythrocyte receptor as being on T or B cells, equine thymocytes from 6 foals were assayed; the thymocytes formed an average of 66 +/- 5% ER. Mixed ER and erythrocyte-antibody-complement rosette assays showed no PBL which bound both ER and erythrocyte-antibody-complement rosettes. The PBL which was stimulated with phytohemagglutinin formed more rosettes (69 +/- 2%) than nonstimulated, control PBL (42 +/- 3%).
Membrane markers of feline T- and B-lymphocytes were identified for further investigation of leukemogenesis in the cat. Feline T-cells formed spontaneous erythrocyte rosettes with guinea pig (GPE) and rat erythrocytes (RE). The receptors for GPE and RE were separate entities and expressed independently on lymphoid cell membranes. The RE receptor appeared to be present only on more mature or differentiated T-cells, whereas the GPE receptor reacted with a broader population that included less differentiated T-cells. Feline B-cells bore a complement receptor that was detected by adherence of SE coated with antibody and complement. Malignant lymphoblasts obtained from thoracic fluid of cats with feline leukemia virus (FeLV)-induced thymic lymphosarcomas, as well as FL-74 cells (a FeLV-transformed feline lymphoblastoid cell line) expressed T-cell markers. These results provided definitive evidence for markers of feline T- and B-cells and identified an experimentally induced T-cell lymphosarcoma.
Mitogen-induced blast transformation of peripheral blood lymphocytes and quantitative changes in circulating T- and B-cells were studied serially in cats inoculated with feline leukemia virus (FeLV). Concanavalin A-induced blast transformation sharply declined beginning at 5 weeks post inoculation (Pl) in FeLV-infected cats when compared to age-matched uninfected control cats. Similar but less consistent changes were seen in responses to pokeweed mitogen-induced stimulation. In most infected kittens this defect persisted until they died from thymic lymphosarcoma, 15-24 weeks Pl. An early lymphopenia, due primarily to a decrease in circulating B-cells, occurred in infected cats 5-8 weeks Pl. Following a return of total and B-lymphocytes to control values, infected cats developed increased numbers of T-cells at 16 or more weeks Pl, which correlated with circulating lymphoblastic lymphocytes bearing T-cell markers. These results correlated neoplasia arising in a thymus-derived lymphocyte population with mitogenic hyporeactivity in the preneoplastic period and suggested that FeLV-induced immune alterations may be a necessary antecedent of leukemogenesis in the cat.
A temporal study is reported of the febrile responses, tissue bacterial contents, and serum concentration of the lysosomal enzymes, beta-glucuronidase and lysozyme, in nonimmune rats inoculated with virulent or attenuated strains of Francisella tularensis, and in immune rats challenged with either a high or low dose of virulent organisms. The level of serum beta-glucuronidase appears to be an indicator of hepatocyte damage, whereas serum lysozyme correlates with the appearance, frequency, and severity of pyogranulomatous lesions. Survival of nonimmune rats after a challenge with either virulent or attenuated organisms appears to depend on a balance between dose of bacterial inoculum, celerity of irreversible pathologic events, and the ability of the reticuloendothelial and immune systems to collaboratively mount a response to limit or prevent dissemination of the infection. In immune rats, infection of parenchymal hepatic cells does not occur after a low dose (10-4) virulent challenge. Infection of parenchymal hepatic cells, however, does occur in immunized rats when the challenge dose is sufficiently large (10-8) so as to overcome the capacity of the reticuloendothelial to clear opsonized organisms.
Serum and liver zinc concentration, amino acid uptake by liver, seromucoid content, and alpha2-macrofetoprotein production were measured in vaccinated as well as nonimmune rats exposed to either virulent (SCHU S4) or attenuated (LVS) strains of Francisella tularensi. It appears that liver damage (pyogranulomatous lesions) must occur before there is any alteration in the above variables. The presence of bacteria in the liver is not of itself sufficient to lead to the onset of systemic, induced metabolic sequelae (IMS). The occurrence of zinc redistribution in all instances of increased serum protein synthesis may imply a necessary relationship between these two sequelae. Amino acid redistribution does not appear to be linked to serum protein synthesis. An endogenous mediator of systemic IMS can be detected in tularemic rats by injection of the serum of these animals into healthy recipients. The occurrence of zinc redistribution and increased serum protein synthesis in some groups of rats in the absence of amino acids uptake by liver, as well as the apparent differential dose responsiveness of these responses, are suggestive of a multiplicity of endogenous mediators.
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A semiautomated microassay of blast transformation of feline lymphocytes was developed and used in a study of the response of normal cats to phytomitogen- and antigen-induced stimulation. Peripheral blood lymphocytes were isolated from defibrinated blood by ficolldiatrizoate gradient centrifugation and incubated at a concentration of 1 X 10(5) cells/culture. Blast transformation was measured by the incorporation of tritiated thymidine, to which the cells were exposed during the last 18 hours of incubation. Phytomitogens induced maximal transformation after 3 days' incubation. Greatest stimulation produced by 10 mug of concanavalin A (38- to 183-fold) followed by 4 mug of pokeweek mitogen (nine- to 51-fold), and finally phytohemagglutinin-P (three- to sixfold). Three of 4 cats sensitized to keyhole limpet hemocyanin responded when exposed to 50 mug of keyhole limpet hemocyanin in vitro, maximal transformation occurring after 4 days' incubation. Lymphocyte blast tranformation provides a convenient technique to assess lymphocyte function serially during experimentally induced immunologic alterations in the cat.
Pathogenesis of tularemia in nonimmune rats given (intraperitoneal inoculation) virulent strain (SCHU S4) or vaccinal strain (LVS) of Francisella tularensis and in immune rats given SCHU S4 is described. Both LVS and SCHU S4 caused pyogranulomas in liver and spleen of nonimmune rats. Nonimmune rats given 10(4) SCHU S4 organisms did not survive beyond 72 hours, but immune rats given challenge inoculum of 10(8) SCHU S4 organisms developed lesions and survived. Larger doses of LVS resulted in earlier onset of characteristic hepatitis and splenitis in nonimmune rats. Periportal lymphocytic infiltrates were present in the liver 48 hours after SCHU S4 challenge inoculation of immune rats and 96 hours after inoculation of LVS in nonimmune rats and were associated with intense macrophage aggregation. These changes indicate that the pathogenesis of tularemia is a result of the interdependency of the dose and virulence of the causative agent with the immune status of the host and that cellular immunity has a significant role in the response of the rat to tularemia.
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