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Studies on the immunopathogenesis of insulin-dependent diabetes mellitus induced in the rat by thymectomy and irradiation

Stumbles, Philip (1994) Studies on the immunopathogenesis of insulin-dependent diabetes mellitus induced in the rat by thymectomy and irradiation. PhD thesis, Murdoch University.

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This study describes the immunological and pathophysiological features of a diabetic syndrome induced in inbred rats by a combination of thymectomy and irradiation (Tx-X), a procedure known to alter immune function and regulation.

The syndrome was characterized clinically by hyperglycaemia, insulinopaenia, ketoacidosis and polyuria. Onset of the disease was rapid and fatal unless daily insulin therapy was initiated immediately. Acutely diabetic animals had pancreatic lesions largely confined to the islets of Langerhans, where atrophy was typically observed. Lmmunohistochemical studies clearly demonstrated that the atrophic change was due to selective destruction of the B cells of the islets, leading to collapse of these structures. lnsulitis was also observed in some diabetic rats, particularly those with less acute disease and also occasionally in nondiabetic Tx-X animals, indicating that a sub-clinical form of the disease may occur. Acute diabetic animals developed autoantibodies to islet cells as detected by immunofluorescence, and to a 64kDa islet protein as detected by immunoprecipitation. A large proportion of Tx-X animals also developed a lymphocytic infiltration of thyroid glands and autoantibodies to thyroid components.

The incidence of diabetes ranged from 11 to 62 percent (mean 34 percent). Incidence levels were slightly elevated in males and induction of disease was strain related, but did not depend upon the RT1 u MHC haplotype as does the spontaneous diabetes of BB rats. Incidence and onset of the disease were variable between groups of animals and could be modulated by altering the hygienic background of the animal, implicating a role for environmental factor(s) in disease pathogenesis. Inhibition of disease by reconstituting Tx-X rats with normal lymphocytes, transfer of disease to naive recipients using diabetic lymphoid cells and demonstration of abnormalities in cell mediated and humeral immunity provided strong evidence supporting an autoimmune pathogenesis for this syndrome.

In conclusion, the Tx-X-induced diabetic syndrome in rats has been shown to bear many features of the human diabetic condition (IDDM) and thus provides further evidence supporting a role for autoimmune mechanisms in the pathogenesis of this major human disease. Finally, it is proposed that this model should provide a valuable adjunct to existing animal models for studying factors influencing the development of this disease and in assessing potential prophylactic or therapeutic regimes.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Supervisor(s): Penhale, William
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