Anti-Islet Immunity and Thymic Dysfunction in the Mutant Diabetic C57BL/ KsJ db/db Mouse

Abstract

Anti-islet immune reactions were studied in vitro in genetically diabetic homozygote C57BL/KsJ db/db mice, using murine islet cells as a target. Spleen lymphocytes inhibited insulin secretion by the islet cells. This inhibition was abolished when T-cells were eliminated by treatment with anti-Thy 1.2 monoclonal antibody in the presence of complement. Anti-islet complement-dependent antibody (CDA) and antibody-dependent cell cytotoxicity (ADCC) were also found in the sera of these mice. This anti-islet immunity was detectable as early as the tenth day of life and lasted throughout the entire life span of the animals. A significant lymphopenia was detected in thymus and spleen cell populations. None of these anomalies was found in control heterozygote mice. Thymic function was explored in the same mice by evaluating their serum thymic factor (FTS) levels using a rosette assay. The age-dependent decline of FTS levels was significantly accelerated in diabetic mice as compared with heterozygous littermates. Furthermore, FTS inhibitory immunoglobulins were detected in db/db mouse sera, which inactivated in vitro the biologic potency of synthetic FTS. Histologically, the thymus displayed an accelerated involution. It was shown by indirect immunofluorescence using anti-FTS monoclonal antibodies that the number of FTS+ cells was reduced in db/db mouse thymuses. Histologic study of the islets of Langerhans showed early signs of beta-cell hyperactivity and hypertrophy, followed by beta-cell rarefaction and profound dislocation of islet architecture. Insulitis was not detected.

Topical application of laminin-332 to diabetic mouse wounds

“…The db/db mice have an autosomal recessive mutation that results in defective leptin receptors in the hypothalamus. This defect leads to increased appetite, decreased energy expenditure, obesity and development of marked hyperglycemia that resembles human type 2 diabetes mellitus (8)(9)(10). This mouse also demonstrates delayed wound healing (7).…”

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

“…We used synthetic serum thymic factor (FTS) as a modulator of pancreatic islet cell damage. The physiological function of the thymus-derived serum thymic factor is induction of cell proliferation and stimulation in a manner similar to that of hormones (2,3,11,12,38). A previous report has shown that FTS prevents diabetes induced by alloxan or streptozotocin in rats (53), and in vivo administration of FTS prevents D-variant of Encephalomyocarditis virus-induced diabetes in BALB/cAJcl mice (30).…”

Experimental Models of Type-I Diabetes

“…It is followed by hypoinsulinemia when P-cell destruction occurs by 4-6 months of age. Islet hyperplasia is observed between 3 and 20 weeks of age, mainly due to P-cell hyper plasia [144], Evidence has been obtained indicating that anti-islet autoimmunity and thymic abnormalities are observed in the mice showing IDDM [144][145][146][147][148][149], Complement-de pendent antibody cytotoxicity [149], antibody-dependent cell-mediated cytotoxicity (ADCC) [154] and anti-islet autoreactive T lymphocytes [153] have all been demon strated in C57BL/KsJ db/db mice. More over, low levels of serum thymic factor 0,0011 presence of FTS inhibitory immuno globulins as well as an accelerated involution of the thymus have been reported in the same model [ 153].…”