The thymus-dependent immune system in the pathogenesis of type 1 (insulin-dependent) diabetes mellitus. Animal model and human studies

The aim of the present study was to investigate the possible role of the thymus-dependent immune system in the disease mechanisms underlying type 1 (insulin-dependent) diabetes mellitus. Both animal experiments and human studies were carried out. Firstly, a brief historical review is given of the scientific progress within the aetiology and pathogenesis of diabetes mellitus during the last few decades. Mention is made summarily of some elements of the thymus-dependent immune system, and the athymic nude mouse is presented. Three diabetic animal models are reported, viz. two exogenously provoked diabetes models in mice, virus-induced diabetes and diabetes induced by streptozotocin, besides the spontaneously diabetic BB rat. Insofar as the mouse models are concerned, experiments were carried out on both nude mice and normal thymus-intact mice. Encephalomyocarditis virus was used in the virus model and could after inoculation be isolated in large quantities from nude mice as well as normal thymus-intact mice. Only the latter developed diabetes; the C57 mice in the form of glucose intolerance and the BALB/c/BOM mice in the form of elevation of the mean blood glucose values to about threefold normal level. The nude mice exhibited only a very short-lasting virus antibody formation, while in the thymus-intact mice it was possible, as might be expected, to demonstrate high titres of neutralizing virus antibodies for months after the virus inoculation. In the streptozotocin model, where the streptozotocin was administered by repeated small injections, the nude mice developed considerably milder diabetes than the thymus-intact mice. This survey includes other experiments using various forms of immunosuppression (thymectomy, irradiation, treatment with antilymphocyte serum), which together supply evidence that the thymus-dependent immune system is involved in the pathogenesis of diabetes in the two mouse models mentioned as well as in the spontaneously diabetic BB rat, regardless of the different aetiologies in the models. On this background, clinical immunological studies in patients with type 1 diabetes were carried out. Firstly, studies are reported of subpopulations of the peripheral lymphocytes which, after labelling with monoclonal antibodies, were investigated by means of flow-cytometry. The number of cytotoxic/suppressor T-lymphocytes was found to be reduced at the time of diagnosis of type 1 diabetes, but increasing towards normal levels five months later. The helper T-cells were found to be slightly increased at diagnosis as compared with the values in controls, whereas there were no differences in the total T-lymphocyte counts.(ABSTRACT TRUNCATED AT 400 WORDS)