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R A Cuthbertson

Publications and source records attributed to R A Cuthbertson.

32 records · Page 2Linked to original sources
PubMed1987

Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage.

Transgenic mice carrying the murine granulocyte-macrophage colony stimulating factor (GM-CSF) gene expressed from a retroviral promoter exhibit elevated levels of GM-CSF in the serum, urine, peritoneal cavity, and eye. The eyes of transgenic mice are opaque, contain accumulations of macrophages, and develop retinal damage. Similarly, lesions containing macrophages develop in striated muscle. The mice also display an accumulation of large, often multinucleate, activated macrophages in the peritoneal and pleural cavities. The transgene is transcribed in peritoneal cells, as well as in eyes and infiltrated striated muscle. A high proportion of transgenic mice die with muscle wasting when aged 2-4 months, possibly because of macrophage activation resulting from the high levels of GM-CSF.

Animals↗
PubMed1986

Low-dose immunosuppression may unmask type I diabetes mellitus by specific inactivation of suppressor cells.

Type I diabetes mellitus is strongly genetically linked to the major histocompatibility complex but relatively few potentially susceptible people, who are presumably frequently exposed to appropriate triggering factors (e.g. viral illness, environmental agents), develop overt disease. It is possible that some such individuals show latent disease (e.g. islet cell antibodies and perhaps local pancreatic pathology) that does not progress. On the basis of animal data and some clinical evidence we speculate that latent disease is controlled by suppressor cells. We suggest that physiological immunosuppression (e.g. with glucocorticoids) may selectively inactivate such T suppressor cells. Such immunomodulation may allow further islet cell destruction to occur and repeated episodes could eventually produce diabetes. Such episodes of altered immunoregulation may be due to intercurrent viral illness, stress, or therapy with low doses of immunosuppressive agents.

Animals↗
PubMed1986

A comparison of portal versus systemic venous drainage in murine foetal pancreatic islet transplantation.

We have compared the efficiency of foetal islet graft growth and function in renal subcapsular (systemic drainage) and splenic (portal drainage) sites. Age-matched female BALB/c streptozotocin (STZ)-diabetic mice were grafted either under the left renal capsule or on to the hilar surface of the spleen with one half of a syngeneic 17-day gestation foetal pancreas which had been in organ culture for 2 weeks. Gain in body weight, return to normoglycaemia and to normal glycosylated haemoglobin levels were not significantly different between the two groups. However, when an intraperitoneal arginine challenge was performed the portally grafted mice showed more normal responses than the systemically grafted mice. Although still not normal after the arginine challenge, mean blood glucose values were lower and serum insulin values higher in the spleen grafted animals than in the renal subcapsular graft group. The total amount of insulin was assayed by extraction of both the graft and the pancreas of each animal. The amount of insulin in the grafts from the spleen was not significantly different from those in the renal subcapsular site. We conclude that the efficiency of a graft draining into the portal circulation is greater than an equivalent sized graft draining systemically when a maximal challenge is applied.

Animals↗
PubMed1986

Anatomy of the mouse retina. Capillary basement membrane thickness.

Transmission electron microscopy of ultrathin sections was used to measure mouse retinal capillary basement membrane thickness (BMT). BMT increases predictably with age from 50 +/- 9 nm at 6 weeks to 154 +/- 27 nm at 20 months, but is not affected by strain or sex. There is an effect of retinal site, however, with BMT increasing with the radial distance from the optic nerve, 41 +/- 4 nm (center), 54 +/- 5 nm (mid-zone), and 64 +/- 6 nm (periphery). The layer of retina from which capillaries were taken had no effect on BMT, and the inner and outer BMT maintained a consistent ratio, even at different ages.

Animals↗
PubMed1986

Anatomy of the mouse retina. Endothelial cell-pericyte ratio and capillary distribution.

A technique is described for preparing whole retinal vascular digests using distilled water and DNase. This produces a more satisfactory preparation of the mouse retinal vascular bed than "trypsin digestion." Nonetheless, the calculation of endothelial cell/pericyte (E/P) ratios based on cell counts from digest preparations has poor reproducibility due to the inability to unequivocally identify at least 25% of the cells in conventionally stained (PAS and hematoxylin) preparations. A more accurate and reproducible means of assessing this ratio uses 1 micron sections of plastic-embedded sections of retina. No effect of age, sex, strain, or area of sampling was found. Capillaries were in three specific bands, centered on the nerve fiber layer, the junction of inner plexiform and inner nuclear layers, and the outer plexiform layers.

Animals↗
PubMedDate not supplied

Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration.

Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 microg (9-10 microCi) in 50 microl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.

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