Impaired immunological competence of spleen cells from neonatally thymectomized C57B1/6 young adult mice was apparent when these cells were tested in an in vitro graft-versus-host assay. Spleen cell inocula prepared from thymectomized mice did not induce enlargement of (C3H/eb x C57BI/6)F1 newborn spleen explants, whereas the same number of cells from intact donors consistently initiated splenomegaly. Spleen enlargement was observed, however, when the explants were challenged by cells from thymectomized donors in the presence of syngeneic thymus extract, indicating that the spleen cells in suspension attained immunological competence under the influence of a non-cellular component of the thymus. Immunocompetence was also evident when the cells from thymectomized donors were first incubated with thymus extract for 1 hr and subsequently tested for reactivity. Cells from the same thymectomized donor mice exposed in parallel to extracts from syngeneic spleen or mesenteric lymph node at an equivalent protein concentration did not initiate a graft-versus-host response. These experiments demonstrate that immune reactivity in the graft-versus-host response involves activation of lymphoid cells by a humoral factor of the thymus acting directly upon these cells.
By means of an assay of graft-versus-host activity some properties of the thymic humoral factor which confers immunocompetence upon lymphoid cells in vitro have been studied. Allogeneic and xenogeneic thymic preparations were found to activate lymphoid cells from neonatally thymectomized mice, enabling initiation of a graft-versus-host response. Thus, this thymus factor is apparently neither strain nor species specific. The active principle of calf thymus extracts was found to be in the supernatant after prolonged ultracentrifugation. When exhaustive dialysis and ultrafiltration through Diaflo membranes were performed, the active thymus agent was found to pass through both the dialysis sac and Diaflo UM-2 membranes. The molecule which confers immunocompetence upon lymphoid cells thus seems to be of molecular weight of an order of magnitude of 1000 or less. Dialyzed thymus preparations injected into neonatally thymectomized mice also restored the capacity of spleen cells of these mice to induce graft-versus-host activity. When injected into intact mice, thymus extract also increased the proportion of competent cells in the spleens of these animals, probably by activation of target cells originating outside the spleen.
The influence of neonatal thyniectomy on lung adenoma formation in mice was investigated. S W R and Swiss mice thymectomized at 3 days of age and given a single dose of 7,12-dimethylbenz (a) The role of the thymus in the development of immunologic competence of mammals has been well established. Thymectomy in the neonatal period of life induces a serious impairment of immunologic capacity, manifested as a deficiency in circulating antibodies (Miller et al., 1962;Good et al., 1962;Law et al., 1964), in delayedtype hypersensitivity (Jankovic et al., 1962), or in homograft rejection (Miller, 1961;Dalmasso et al., 1962), depending upon the test system employed, as well as upon the nature and extent of the antigenic stimulation. This immunologic deficit may also express itself in a higher sensitivity to viral challenge, which in the case of polyoma virus results in a higher incidence of tumors developing in thymectomized animals. Neonatally thymectomized rats (Vandeputte et al., 1963), hamsters (Defendi and Roosa, 1964) and mice (Miller et al., 1964;Mori et al., 1964; Law, 1965) have in fact been shown to be more susceptible to neoplastic induction by polyoma virus than intact controls.A logical step in the investigation of the significance of this immunologic deficit in the mechanism of carcinogenesis was to test the susceptibility of neonatally thymectomized mice vis-ic-vis chemical carcinogens, but the data collected so far are inconclusive and somewhat contradictory.In random-bred albino miceTeceiving skin paintings of benzpyrene (BP) twice weekly for 20 weeks, skin papillomas appeared earlier in thymectomized animals, while the regression rate of these tumors was lower than in the intact controls. At 40 weeks of age, however, the final tumor incidence was similar for both intact and thymectomized mice (Miller et al., 1963). C3H/Bi mice thymectomized, irradiated and inoculated subcutaneously with methylcholanthrene (MCA), showed a higher incidence of subcutaneous fibrosarcomas, which appeared earlier than in intact controls, particularly in the females. Parallel treatment with 3,4-9,10-dibenzanthracene (DBA) yielded less conclusive results (Defendi and Roosa, 1964).
Culture of epithelial cells from the thymus of mice was achieved in a medium modified to favor epithelial growth while inhibiting proliferation of fibroblasts. Epithelial cells were identified by the presence of desmosomes in electron microscopic preparations and by antibody to intermediate filaments containing keratin. Morphologically, the cells thus positively identified displayed two main patterns: carpets of large flat cells resembling paving stones which are confluent along the length of their membranes, and networks of cells interconnected by long cytoplasmic processes. These two types of cells were dominant in cultures derived from mice of all ages tested (newborn to nine months) but the relative proportion of each type appeared to change with the age of the donor mice and also with the concentrations of cortisone in the culture medium. Autoradiography revealed that the cultured cells were dividing, and that (in the presence of cortisone) the rate of DNA synthesis was decreased in a portion of the epithelial cells derived from mice in which thymic involution was already underway.
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