Biomedical subjects
E F Wheelock
Publications and source records attributed to E F Wheelock.
Identification of macrophage-mediated cytolytic activity as a tumor suppressive mechanism during maintenance of the L5178Y-tumor dormant state in DBA/2 mice.
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Plagiarism and freedom of information laws.
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The effect of particle size on the immunodepressive properties of silica.
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Factors affecting responses to murine oncogenic viral infections.
Silica specifically kills macrophages in vitro, and in vivo has been used as a method of determining the possible immunological or other roles of macrophages in a number of viral infections. In experiments reported here, injection of 30 or 50 mg silica i.p. increased the severity of the oncogenic effects of the murine sarcoma virus (MSV) and Friend virus (FV) in BALB/c mice. Unlike Herpes simplex and Coxsackie B-3 infections, however, passive transfer of adult macrophages to suckling mice did not protect the latter against MSV. In mice injected with silica, histological evidence of the compensatory proliferation of macrophages suggests that precursors of these cells may act as target cells for the virus and that this may override any immunosuppressive response effected by the silica. In addition, there was a considerable enhancing effect on the erythroproliferative response to both MSV and FV by injection of saline 5 h before the virus, and indeed to FV after only a simple abdominal needle puncture. We attributed this to the lymphopenic immunodepressive effects of stress, and our data may explain previously published findings of augmented oncogenic responses in mice after "normal" serum injections. Newborn BALB/c (FV-1b) mice were susceptible to N-tropic FV, but developed resistance by 29 days of age. Antithymocyte serum (ATS) but not silica injections or adult thymectomy ablated this resistance. C57BL (FV-2r) mice were completely resistant to FV; however, those receiving FV and ATS developed late-onset leukaemia histologically characteristic of that produced by the helper component of the FV complex.
Effect of serum from mice with dormant Friend leukemia viral infections on synthesis and modulation of erythroleukemia cell surface gp70.
Serum of mice with dormant Friend virus infections modulates the expression of cell surface antigens on Friend virus-transformed cells (FLC-745 cells). By radioimmunoassay, the modulated antigen was identified as virion gp70 of Friend leukemia virus. After two days of culture in medium containing 5% serum from mice with dormant Friend virus infections, the modulated cells expressed about 50% less surface gp70 than non-modulated cells cultured in 5% normal mouse serum. After 9 days in culture, the modulated cells expressed no surface gp70; however, these cells contained the same amount of internal gp70 as nonmodulated cells, indicating that gp70 was synthesized during the modulation period. Both modulated and nonmodulated cells grew equally well during the 9 days of culture. These results indicate that the effects of modulation of Friend virus-coded cell surface antigens are restricted to the cell surface.
In vivo lysis of L5178Y cells in the establishment of the tumor-dormant state in DBA/2 mice.
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The tumor dormant state. Quantitation of L5178Y cells and host immune responses during the establishment and course of dormancy in syngeneic DBA/2 mice.
Subcutaneous implantation of DBA/2-derived L5178Y cells into DBA/2 mice followed 10 d later by nodule excision protected 100% of mice from the rapid outgrowth of an intraperitoneal challenge of L5178Y cells given 7 d postexcision. Challenged mice remained clinically normal for 48--250 d before onset of an ultimately fatal tumor outgrowth. The numbers of L5178Y cells in the peritoneal cavity increased logarithmically for 4 d after challenge and then declined to low but detectable levels which persisted throughout the clinically normal period. Cells active in 18-h in vitro cytolytic assays against 51Cr-labeled L5178Y target cells were found in the peritoneal cavity. The effector cells were determined to be Thy1.2 positive. Their activity was tumor specific and reached peak levels 4 d after tumor challenge and then gradually declined to undectable levels during the following 70 d. Tumor emergence occurred most frequently during the period when CMC activity was no longer demonstrable in the remaining clinically normal mice. A transient peak of low level cytophilic antitumor antibody was detected about 30 d after tumor cell challenge. The temporal associations between the numbers of tumor cells and the levels of cell-mediated lysis against L5178Y cells indicate the importance of the cell-mediated cytolysis response in limiting initial tumor outgrowth and suggest its role as one of the factors responsible for long-term tumor suppression during tumor dormancy.
The tumor dormant state. Comparison of L5178Y cells used to establish dormancy with those that emerge after its termination.
The tumor dormant state established in L5178Y immunized and challenged mice is characterized by a prolonged period of clinical normalcy followed by rapid tumor outgrowth. The tumor cells which emerged after termination of the tumor dormant state had abnormal marker chromosomes identical to those in the L5178Y cells used in the original challenge inoculum, indicating that the emergent tumor cells were progeny of the challenge inoculum. Original and emergent L5178Y cells had equivalent in vivo growth rates, when inoculated into normal DBA/2 mice. The emergent L5178Y cells were less susceptible than original cells to in vitro lysis by tumor dormant PC. Original and emergent L5178Y cells expressed common tumor-associated target antigens for cytolytic effector cells. Both modulation and masking of these target antigens were ruled out as mechanisms for decreased susceptibility to cell-mediated cytolysis. Immunofluorescence revealed heterogeneity in tumor-associated antigen expression within both original and emergent cell populations, with a decreased intensity of staining in the emergent population. Both populations were equally susceptible to lysis by alloimmune cells, alloantiserum, and anti-Thy 1.2 serum, but emergent cells were less susceptible to lysis by serum directed against L5178Y TAA. Quantitative absorption revealed that the emergent L5178Y cells expressed eightfold less serologically detectable TAA than the original cells. These findings indicate that the host immune response developing during establishment of the tumor dormant state selects a stable tumor cell subpopulation which expresses decreased amounts of surface tumor-associated target antigens.
Group-specific cytolytic antibody directed against the major glycoprotein (gp70) of murine leukemia viruses in serum of mice with dormant FLV infections.
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Susceptibility of Friend virus antigen-modulated erythroleukemic cells to lysis by T lymphocytes from mice with dormant Friend virus infections.
Spleen cells from DBA/2 mice with dormant Friend leukemia virus (FLV) infections or from mice immunized with x-irradiated FLC-745 erythroleukemic cells are not cytolytic for FLC-745 cells when tested directly, but acquire cytolytic activity in vitro by cultivation with x-irradiated FLC-745 cells. Spleen cells cultured from normal mice do not acquire such cytolytic activity. Cytolytic activity resides in the T lymphocyte population. Alloantiserum, but not antisera against FLV-virion polypeptides, inhibited the lysis of FLC-745 cells by cytolytic T lymphocytes. To understand further the role of cellular and humoral immune anti-FLV responses in mice with dormant FLV-infections, in vitro experiments were conducted that mimicked the in vivo FLV-specific immune environment of these mice. We found that FLV-immune serum from mice with dormant FLV-infections modulated FLV-antigen expression on the surfaces of FLC-745 cells without affecting their susceptibility to lysis by cytolytic T lymphocytes. These results suggest that cytolytic T lymphocyte restrain the outgrowth of FLV-antigen-modulated erythroleukemic cells in mice with dormant FLV infections and that the targets for cell-mediated lysis may be H-2d-associated antigens.
A new method for quantitation of cell-mediated immunity in the mouse.
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Tumour-dormant states established with L5178Y lymphoma cells in immunised syngeneic murine hosts.
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Antigenic modulation of Friend virus erythroleukemic cells in vitro by serum from mice with dormant erythroleukemia.
Friend leukemia virus (FLV) erythroleukemic cells cultured in medium containing FLV-immune serum from dormant FLV-infected mice undergo modulation of FLV cell surface antigens. Modulation was determined by an increased resistance to FLV antibody-mediated complement-dependent lysis and was associated temporally with the capping of FLV-immune complexes at the cell surface. Modulated cells regained their susceptibility to FLV antibody-mediated complement-dependent lysis when transferred to medium containing normal mouse serum. After 48 h of culture in FLV-immune serum, 26% of the FLV erythroleukemic cells were devoid of FLV cell surface antigens as demonstrated by immunofluoresence. Antigenic modulation occurred to a greater extent in cells maintained in logarithmic growth than in cells in GO or resting phase. FLV-antigenic modulation is discussed as a possible mechanism by which antibody induces and maintains FLV-transformed cells in a dormant state.
Progressive inhibition of T-cell function preceding clinical signs of cytomegalovirus infection in mice.
Groups of mice that received a predominantly lethal or a nonlethal dose of murine cytomegalovirus (CMV) were studied prospectively to correlate clinical observations with detection of virus in spleen cells and with the response of spleen cells to the thymus-derived (T-) cell mitogen concanavalin A (con A). In both groups of mice, virus was virtually cleared from spleen cells by day 8 after infection. Depression of the spleen cell response to con A preceded clinical signs of infection, was more severe in the lethally infected group, and improved as clinical signs cleared in the few surviving mice. Serum from infected mice depressed the response of uninfected spleen cells to con A. These findings support the hypothesis that clinical illness and death from CMV infection of mice are a consequence of events that follow the depression of T-cell function by CMV. This depression is at least partially mediated by a humoral mechanism.
Role of viremia in the suppression of T-cell function during murine cytomegalovirus infection.
The suppression of T-cell deoxyribonucleic acid (DNA) synthesis by serum from mice acutely with murine cytomegalovirus (MCMV) was investigated. Spleen cells from uninfected mice were exposed to concanavalin A in the presence of serum taken from mice at various times after infection with MCMV. The capacity of the serum to suppress DNA synthesis first appeared at day 3 postinfection and was associated with free infectious virus. Addition of MCMV to serum from uninfected mice also suppressed DNA synthesis. Ultracentrifugation of serum from mice acutely infected with MCMV removed most of the virus and aborgated the inhibition of DNA synthesis. However, in two of four experiments, serum from mice in weeks 4 and 5 postinfection did not contain infectious MCMB but did suppress. Therefore, it appears that MCMV itself can suppress DNA synthesis of T cells; however, this may not be the exclusive mechanism of suppression exerted by serum from MCMB-infected mice.
Influence of immune stimulators on viral leukemogenesis.
Injection of RNA, extracted from statolon by the SDS-phenol method, into FLV-infected mice 24 hours before SRBC immunization restored the immune response to SRBC to normal levels. Leukemosuppression was observed in 50% of the RNA-treated FLV-infected mice. These RNA-treated mice were clinically normal 25 days after infection, whereas all untreated infected mice developed erythroleukemia. Furthermore, all RNA-treated mice with suppressed erythroleukemia produced antibody which was cytotoxic for Friend leukemia cells. Our studies, and studies by others, indicate that the immunostimulatory and leukemosuppressive principle in statolon appears to be a dsRNA.
Discussion paper: humoral immune responses to tumor-associated antigens.
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