Anti-Beta-Cell Immunity in Insulinopenic Diabetic Dogs

Abstract

Anti-islet immunity was studied in six spontaneously insulin-dependent diabetic (IDD) dogs, using mouse islets of Langerhans cells as targets, in vitro. Insulinopenia was demonstrated in all dogs by an i.v. glucose tolerance test. A significant lymphocytopenia was detected in the peripheral blood of this diabetic group. Pancreatic tissue from one of these animals was obtained shortly after death and the islets displayed a marked loss in beta cells without significant changes in the other types of islet cells. No insulitis was observed. Circulating mononuclear cells from the diabetic dogs induced an increased basal insulin (IRI) release from islet cells and a suppressed stimulated IRI release. Damage to or depth of beta cells may account for these findings. The stimulated IRI release was also suppressed when islets were incubated with the diabetic sera + complement, while the D-cell response to arginine was not altered, and the A-cell response was reduced but not abolished. A lysis of islet cells in the presence of IDD sera + complement was demonstrated by an increased release of 51Cr from labeled cells. These anomalies were observed neither when complement was heat-inactivated nor in the presence of control sera + complement. Canine IDD may be a new animal model for the study of anti-islet cellular and humoral immunities.

Anti-islet Cellular and Humoral Immunity, T-Cell Subsets, and Thymic Function in Type I Diabetes

“…22 The xenogenic origin of the target cells renders the mechanistic interpretation of the test less clear than desirable. 24 However, the results were remarkably consistent with previous studies in human patients, 19 and in diabetic dogs 11 and mice. 10 The cells responsible for the suppression of IRI release in vitro have been shown to be T-cells in diabetic patients 25 and in db/db mice.…”

“…We have found, as have others, 23 a T-cell (OKT3 + ) lymphopenia, affecting also the OKT4 + subset in long-standing, type I diabetes. This finding is reminiscent of the T-cell lymphopenia oberved in diabetic BB rats, 9 some insulin-dependent dogs, 11 and db/db mice, 15 albeit less clear-cut than in each of these animal models. In the diabetic db/db mice, the T-lymphopenia affects the suppressor-cytotoxic subset, with an increased LyVLy 2 ratio.…”

“…2 Similar abnormalities of the thymusdependent immune system, such as lymphocytopenia and/ or T-cell depletion, are noted in diabetic BB rats, 9 db/db mice, 10 and some insulinopenic diabetic dogs. 11 The involve-ment of T-cells in the disease pathogenesis is further suggested by the beneficial effects of antilymphocyte serum, 12 x-radiation, 12 and cyclosporin treatment. 1314 Lastly, a decrease in the production of the serum thymic factor (FTS or thymulin) was demonstrated in the db/db mice concomitantly with T-lymphocytopenia, T-cell imbalance, 15 and antiislet cellular and humoral immunity.…”

Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?

“…Other indirect evidence of autoimmunity in dogs was documented using mouse islets exposed to serum from diabetic dogs in vitro; the serum contained complement-fixing ICA that caused decreased stimulated insulin release and lysis of the islet cells (76). None of the minor autoantibodies in humans have been tested in dogs, and screening of an array of autoantigens may aid in picking out canine-unique or -specific autoantibodies.…”

“…Using mouse islets in vitro, canine mononuclear cells caused increased basal insulin release and decreased stimulated insulin release, suggesting possible β-cell damage and functional impairment (76). Peripheral blood T-cell proinflammatory responses to insulin were found in two of four diabetic dogs, quantified by IFN-γ production (68).…”