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T N Fredrickson

Publications and source records attributed to T N Fredrickson.

107 records · Page 6Linked to original sources
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Non-Hodgkin lymphomas of mice.

Studies of lymphoid neoplasms occurring in normal or genetically engineered mice have revealed parallels and differences to non-Hodgkin lymphomas (NHL) of humans. Some mouse lymphomas have strong histologic similarities to the human NHL subsets including precursor B- and T-cell lymphoblastic, small lymphocytic, splenic marginal zone, and diffuse large-cell B-cell lymphomas (DLCL); whether molecular parallels also exist is under study. Others mouse types such as sIg+ lymphoblastic B-cell lymphoma have no histologic equivalent in human NHL even though they share molecular deregulation of BCL6 with human DLCL. Finally, Burkitt lymphoma does not appear to occur naturally in mice, but it can be induced with appropriately engineered transgenes.

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Thrombocytopenia in a retrovirally-induced murine erythroleukemia.

A variant strain of Rauscher leukemia virus (RLV-A) obtained from a transplantable murine monomyelocytic leukemia causes a disease characterized by frank anemia, wasting, hepatosplenomegaly and erythroblastosis. The involvement of platelets in this disease are reported here. The RLV-A induced a severe thrombocytopenia (25 percent of control level) at the terminal stage of disease. This thrombocytopenia was not associated with disseminated intravascular coagulopathy since the prothrombin times were always within normal limits. The partial thromboplastin time was elevated in the terminal stages of disease and was found to be associated with factor deficiencies, possibly owing to the presence of anti-factor antibodies, in the intrinsic coagulation pathway, especially factor VIII. Further, splenectomy did not abolish the thrombocytopenia, since splenectomized, virally infected animals also developed severe thrombocytopenia (29 percent of control levels). The ensuing splenomegaly during progression of disease was not the cause of the thrombocytopenia. A physiological response to the severe thrombocytopenia was the production of larger size platelets. At terminal stages of the disease, platelet volume increased to 4.2 mu 3 (normal is 3.0 mu 3). An increase in platelet volume was also observed in splenectomized, virally infected animals. Electron microscopy indicated that these circulating platelets contained c-type viral particles. Viral infection was associated with decreased life span of circulating platelets, as measured by 75Se-methionine at mid and terminal stages of the disease. Our results suggest that direct viral infection of platelets and/or megakaryocytes with subsequent cell lysis is a possible cause of the observed thrombocytopenia observed in RLVA-induced disease and may also occur in other retrovirally-induced diseases.

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Effects of intrarenal injection of nickel subsulfide in rodents.

After intrarenal (i.r.1 administration of 5 mg of nickel subsulfide (alpha Ni3S2) to Fischer rats, blood hematocrit became increased within one week and reached 76 +/- 1 percent at eight weeks (p less than 0.001 versus mean hematocrit of 46 +/- 1 percent in control rats). The alpha Ni3S2-induced erythrocytosis was attended by intense stimulation of erythropoiesis, with reticulocytosis, increased 59Fe-uptake into erythrocytes and erythroid hyperplasia in bone marrow and spleen. The half-life of 51Cr-labeled erythrocytes from alpha Ni3S2-treated rats was prolonged, consistent with increased proportion of circulating juvenile erythrocytes. Histological examination of rat kidneys after i.r. injection of alpha Ni3S2 showed mild inflmmation at one and two weeks. Dense black particles of alpha Ni3S2 were visible in histological sections of rat kidneys for eight weeks. 5'-Nucleotidase activity in rat kidney microsomes was inhibited at one to seven days after i.r. injection of alpha Ni3S2. Erythrocytosis did not occur in rats after (a) i.r. implantation of semi-permeable cellulose tubules containing alpha Ni3S2, (b) repeated i.m. injections of alpha Ni3S2, or (c) intrahepatic injection of alpha Ni3S2 after partial hepatectomy. Erythrocytosis did not occur in male BALB/c mice or ground squirrels after i.r. injection of alpha Ni3S2.

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Clonal outgrowths of T and B cells in SCID mice reconstituted with cells from mice with MAIDS.

Murine acquired immunodeficiency syndrome (MAIDS), induce in mice by a defective murine retrovirus (BM5def), is characterized by development of severe immunodeficiency and polyclonal lymphoid proliferation which progress to yield oligoclonal populations of T and B cells. Oligoclonal populations transferred to SCID mice grew as clonal CD4+ T cell or B cell lineage transplants having one or more unique clonal integrations of BM5def. In some cases, spleens of single donor mice were shown to contain both B cell and T cell lineage clones that could be transferred individually after separation and were clonally unrelated. Successful transplants were obtained from oligoclonal populations as early as 63 days after infection. Mouse strains both sensitive or moderately resistant to MAIDS yielded clonal transplants.

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In vivo murine tumor gene delivery and expression by systemic recombinant vaccinia virus encoding interleukin-1beta.

PURPOSE: This study investigates the feasibility of systemic gene delivery in a tumor-bearing host using a vaccinia virus-based in vivo gene delivery and expression system. METHODS: A recombinant vaccinia virus encoding human interleukin-1beta (hIL-1beta) was constructed with a strong synthetic vaccinia virus late promoter driving hIL-1beta gene expression. C57BL/6 mice bearing established subcutaneous pancreatic tumors were injected intravenously in a blinded, randomized fashion with different doses of either the recombinant vaccinia virus(vMJ601hIL-Ibeta), control vaccinia (wild-type or TK-deficient), or saline. Toxicity was assessed, serial tumor sizes were measured, and viral titers and the amount of hIL-1beta in tumor, liver, and spleen were determined. RESULTS: High viral titers (10(6) PFU/g) were detected in tumors for all three viruses on postinjection day 3, and tumor viral titers persisted at high levels until day 9. In contrast, viral titers were initially 104-fold lower in nontumor tissues and decreased to undetectable levels by day 9. vMJ60hIL-1beta was rapidly cleared from liver and spleen by day 3 (titer levels < 100 PFU/g), while tumor titer levels persisted at 8.5 x 10(6) PFU/g. hIL-1beta was measurable in three of three tumors from vMJ601hIL-1beta treated mice on postinjection day 3, one of three on day 6, and one of three on day 9; no hIL-1beta was detected in any other tumors or normal tissues. Wild-type vaccinia had no antitumor effects. Treatment with two different doses of vMJ601hIL-1beta resulted in a consistent and significant decrease in tumor size in repeatable experiments as compared to controls. Histologic analysis revealed tumor cell necrosis with a surrounding neutrophil infiltrate in the vMJ601hIL-1beta treated tumor. CONCLUSION: These data show that recombinant vaccinia virus encoding hIL-1beta given intravenously preferentially localizes and amplifies in tumor tissue, is rapidly cleared from liver and spleen, produces measurable hIL-1beta in tumor but not normal tissues, and inhibits growth of established solid tumors in mice. Recombinant vaccinia virus encoding therapeutic genes may be a practical, efficient vehicle for direct in vivo gene transfer and expression in the treatment of cancer.

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Characteristics of a murine gammaherpesvirus infection immunocompromised mice.

BACKGROUND-MATERIALS: Mice with normal or impaired immune function were studied for responses to intranasal infection with MHV68, a gammaherpesvirus that acutely infects lung epithelial cells and establishes latency in B cells. Infection of normal mice induced a vigorous pulmonary inflammatory response composed of T, B, and NK cells and macrophages and stimulated activation and proliferation of T and B cells in spleen. METHODS-RESULTS-CONCLUSIONS: Resolution of the infection was associated with induction of MHV68-specific antibodies, but virus-specific cytotoxic T cells were not detected. Mice inoculated with retroviruses that induce severe immunodeficiency unexpectedly cleared MHV68 from lung in the same time-frame as controls and failed to develop latency as determined by infectious center tests of spleen cells. In contrast, control of MHV68 infection in spleen and/or lung was impaired in mice deficient in CD4+ or CD8+ T cells or both T cell subsets, B cells, IFN-gamma, or inducible nitric oxide synthase (iNOS). Infection was uniformly lethal in nude and iNOS-deficient mice and killed one-third of IFN-gamma-deficient mice. These results indicate that resistance to MHV68 is markedly influenced by expression of IFN-gamma from T cells leading to induction of iNOS and generation of nitric oxide.

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