Date of Award:

5-2003

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Biology

Committee Chair(s)

Edmund D. Brodie, Jr.

Committee

Edmund D. Brodie, Jr.

Committee

Dale L. Barnard

Committee

Robert W. Sidwell

Committee

Joseph K. K. Li

Committee

Daryll B. DeWald

Abstract

Aleutian disease of mink (AD) is an immunopathological disorder induced by persistent infection with AD virus. Many breeds of mink seem to have a high susceptibility to AD. Interestingly, the primary feature of AD in susceptible adult mink is a chronic, fatal immune complex-mediated glomerulonephritis comparable to that seen in human diseases such as systemic lupus erythematosus. Because of its comparative aspects to human diseases and the substantial economic loss to the fur industries in the world, classical AD and the nature of the virus has been studied extensively for three decades. Currently no therapies are available and vaccination has been a failure; the latter exacerbated the disease.

The hypothesis tested in this research was that the treatment of AD-infected mink with TGF-β1 and dehydroepiandrosterone (DHEA) inhibited or ameliorated the disease. The hypothesis was tested by evaluating the effects of TGF-β1 and epiandrostene-like compounds on the immune response of AD-infected animals on the normal physiological parameters of animals and by evaluating the effects of both compounds on virus loads.

The TGF-β1 study was designed to evaluate three different doses (200, 100 and 1 ng/kg) of recombinant human TGF-β1 and one dose (500 ng/kg) of TGF-β1 inhibitor at three different times (treated TGF-β1 2 weeks pre-, 8 hours post-, and 2 weeks post-virus inoculation) of administration relative to virus exposure. Animals were administered drug or placebo intravenously via the inguinal vein injection and animals were held to up to 9 months.

For the epiandrosterone study, five mink received 16 ng/kg HE2300 once per week, 17 animals received 16 ng/kg HE2300 three times per week, and five animals were injected with 16 ng/kg HE2500 three times per week. In addition, 17 animals received vehicle three times per week. All treatments were injected subcutaneously into the nape of the neck of the mink. Animals were held to up to 8 months.

Pathological analysis of various physical, physiological and immunological parameters in surviving mink treated with either immunomodulator (treated with TGF-β1 at 100 ng/kg and treated with HE2300 at 16 ng/kg three times per week) revealed that these parameters were near the levels measured for normal uninfected mink. In contrast, in untreated infected animals the measured virus pathology, and physiological and immunological parameters were significantly different from the untreated control animals. In a comparison of survival times, treated animals with either immunomodulator survived almost twice as long as untreated animals. A polymerase chain reaction (PCR) assay of lymph node tissue confirmed that AD-infected animals treated with either immunomodulator had significantly lower levels of virus DNA than untreated infected animals.

These findings support the hypothesis that TGF-β 1 and DHEA and its analogs may afford mink protection from chronic lethal AD.

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