Abstract
Because the viral promoter of the human immunodeficiency virus (HIV) does not function normally in mice, it has been difficult to develop a mouse model of AIDS. However, researchers at the University of Maryland have produced an HIV transgenic rat in which viral gene expression, changes in immune response, and disease development approximate that seen in man. These rats expressed an HIV-1 provirus with functional deletions of the gag and pol genes under the control of the viral long terminal repeat. Expression of viral RNA and protein was detected in lymphoid tissues. The delayed-type hypersensitivity response of the transgenic rats was significantly reduced in comparison with control animals. Transgenic rats developed clinical AIDS-like disease by five to nine months of age. Disease manifestations included wasting, interstitial pneumonia, endocarditis, nephropathy, skin ulcers, and focal gliosis. This rat model is likely to be extremely useful for studying AIDS pathogenesis and therapy.
Reid W, Sadowska M, Denaro F, Rao S, Foulke J, Hayes N, Jones O, Doodnauth, D, Davis H, Sill A, O'Driscoll P, Huso D, Fouts T, Lewis G, Hill M, Kamin-Lewis R, Wei C, Ray P, Gallo RC, Reitz M, Bryant J: An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. wzzip -rp Proc Natl Acad Sci USA
Prion diseases affect a variety of species, including cattle, sheep, and man. The infectious agent is believed to be a protein, the pathogenic prion (PrPSc), that replicates by altering the conformation of endogenous cellular proteins (PrPC) to convert them into new PrPSc prions. An international team of investigators has shown that recombinant antibodies that bind specifically to cell-surface PrPSc can dramatically reduce the formation of new PrPSc by prion-infected cells in vitro. The most effective antibody tested was able block new PrPSc formation completely and to stimulate degradation of previously formed PrPSc. Furthermore, prion-infected cells treated with this antibody were unable to transmit disease to mice when injected intracerebrally. These findings suggest that antibodies may be useful in preventing and treating prion diseases.
Peretz D, Williamson RA, Kaneko K, Vergara J, Leclerc E, Schmitt-Ulms G, Mehlhorn IR, Legname G, Wormald MR, Rudd PM, Dwek RA, Burton DR, Prusiner SB: Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. wzzip -rp Nature.
Endophytic fungi of tall fescue produce the toxin ergovaline, and endophytic fungi of perennial ryegrass produce lolitrem B. These toxins cause fescue foot and perennial ryegrass staggers, respectively. Quantitative assays for the two toxins are now available. Retrospective and prospective field cases studies and controlled barn studies showed that threshold ergovaline levels for fescue foot were 400–750 ppb in cattle and 500–800 ppb in sheep. Threshold levels of lolitrem B for ryegrass staggers in both species were 1800–2000 ppb. Lower environmental temperatures reduced the threshold dose of ergovaline for fescue foot. Overgrazing increased the likelihood of disease for both fescue foot and ryegrass staggers, since animals then ingested portions of the plants with the highest levels of toxin.
Tor-Agbidye J, Blythe LL, Craig AM: Correlation of endophyte toxins (ergovaline and lolitrem B) with clinical disease: fescue foot and perennial ryegrass staggers. wzzip -rp Vet Hum Toxicol
Investigators in Denmark have reported a precise and unbiased method for quantifying tumor metastasis to mouse lungs. Lungs containing metastatic tumor foci were fixed in paraformaldehyde, air-evacuated, treated with 20% sucrose, and frozen en bloc in OCT. Lungs were then cut into 2-mm parallel slabs and reembedded in OCT for sectioning. A total of five to eight sections of lung were examined per animal. Stereological measurements of metastatic tumor volume were performed by point counting and application of the Calvalieri principle. Metastasis volumes calculated in this way were highly reproducible and appeared to be a more precise quantitative measure of tumor metastasis than lung weight or number of surface metastases.
Nielsen BS, Lund LR, Christensen IJ, Johnsen M, Usher PA, Wulf-Andersen L, Frandsen TL, Dano K, Gundersen HJ: A precise and efficient stereological method for determining murine lung metastasis volumes. wzzip -rp Am J Pathol
In an attempt to develop an orthotopic preclinical model to study human kidney cancer, investigators characterized streptozotocin-induced murine renal cell carcinomas. These tumors were readily transplanted intrarenally into syngeneic animals. The tumors had several features that made them an attractive model for testing new therapies for human kidney cancer, including slow growth, propensity to undergo metastasis to the lung, and hypervascularity. Interestingly, these tumors shared a single specific karyotypic abnormality, thus these tumors may provide insight into the genetic changes that underlie renal cell carcinoma.
Gruys ME, Back TC, Subleski J, Wiltrout TA, Lee JK, Schmidt L, Watanabe M, Stanyon R, Ward JM, Wigginton JM, Wiltrout RH: Induction of transplantable mouse renal cell cancers by streptozotocin: in vivo growth, metastases, and angiogenic phenotype. wzzip -rp Cancer Res
Adenovirus vectors are frequently used to deliver exogenous genes into mammalian cells, both in vivo and in vitro. However, not all cell types express the Coxsackie and adenovirus receptor (CAR) molecule required for entry of the virus. Researchers in Sweden have produced transgenic mice that express CAR on the surfaces of many cell types. Cultured cells from these mice were highly susceptible to adenovirus-mediated gene delivery. Even lymphocytes and dendritic cells, which are usually resistant to adenovirus, were readily infected. Cells could also be infected in vivo, and some sites ordinarily refractory to adenovirus-mediated gene delivery, including the lung, lung alveolar macrophages, and capillary endothelium of the brain, could be infected. These mice and cells derived from these mice will allow efficient gene delivery to a wide variety of cell types.
Tallone T, Malin S, Samuelsson A, Wilbertz J, Miyahara M, Okamoto K, Poellinger L, Philipson L, Pettersson S: A mouse model for adenovirus gene delivery. wzzip -rp Proc Natl Acad Sci U S A