Antigenic determinants in type 1 diabetes mellitus. Review article.

Type 1 diabetes mellitus (IDDM) is a disease caused by the autoimmune destruction of insulin-producing pancreatic beta cells that takes place in genetically predisposed individuals. The results of the studies performed so far during the search for "the target antigen" in beta cell autoimmunity have indicated that, unlike many autoimmune disorders, type 1 diabetes appears to be the result of an autoimmune response to a multiplicity of autoantigens. Autoantibodies and autoreactive T lymphocytes reacting with islet target molecules of protein or glycolipid nature have been shown in the circulation of individuals and of animal models of type 1 diabetes (NOD mouse and BB rat) before and at the onset of the disease. In the present article we have reviewed the data available on the antigenic determinants in type 1 diabetes, with particular reference to those recognized by autoantibodies which represent the best available predictive marker of future disease development in large scale screening studies.

Natural killer cell activity in vasopressin-deficient rats (Brattleboro strain).

Several lines of evidence suggest that the neuropeptide vasopressin is involved in the regulation of the immune system. We explored this possibility by comparing the cytotoxic activity of natural killer (NK) cells in Brattleboro (DI) rats, which are homozygous for diabetes insipidus and lack vasopressin, and Long-Evans (LE) rats, the strain from which DI rats were derived. Additionally, we compared the effects of swim stress, morphine administration and vasopressin replacement on NK cell activity in these two strains. In DI rats, NK cell activity, determined by a standard 4-h chromium-release assay, was significantly higher than in LE rats. Both swim stress and morphine administration suppressed NK activity in DI and LE rats. There was no difference in the level of suppression between the two strains. Vasopressin replacement normalized water intake in DI rats, but had no significant effect on NK cell activity. DI rats exhibited lower plasma corticosterone levels, which were not elevated by vasopressin replacement. The results suggest that the lack of vasopressin in DI rats elevates baseline NK cell activity, probably via mechanisms that are secondary to the vasopressin deficiency (e.g. lower corticosterone levels). Neither vasopressin nor other hormones affected by vasopressin deficiency seem to be involved in the acute modulating effects of stress and morphine on NK cells.

Cytotoxic activity of sera from diabetic BB rats against BB rat islet--a functional study.

[3H] leucine incorporation into islet proteins, insulin secretion, hormone content (insulin, glucagon) and DNA synthesis were measured in cultured BB rat islets in a study to compare the effect of freshly prepared BB rat serum obtained from non-diabetic and newly diagnosed diabetic BB rats on islet functions. After exposure of isolated BB rat islet to a mixture of tissue culture medium and BB rat serum (1:1) for 24 hr, islet lysis was induced by 40% of the diabetic BB rat sera whereas the remaining 60% of diabetic BB rat sera tested did not influence islet functions as evidenced by insulin net production, glucose-induced insulin release and DNA synthesis measured in a subsequent culture period in TCM 199, 10 mmol/l glucose supplemented with 10% neonatal calf serum or short-term incubations. After exposure of islets to sera with anti-islet cytotoxicity the majority of islet cells were destroyed as indicated by a drastically reduced [3H] leucine incorporation into islet proteins and by a diminution of hormone and DNA content of islets. This toxicity against islets was overcome by heat treatment (58 degrees C, 30 min) of sera. The results indicate that heat-labile components in certain diabetic sera of BB rats can lyse the majority of islet cells in BB rat islets within 24 hr. Our assay may help to dissociate humoral and cellular components which cause the injury of beta cells and the onset of diabetes in BB rats.

The influence of T-lymphocyte precursor cells and thymus grafts on the cellular immunodeficiencies of the BB rat.

To determine whether abnormal T-lymphocyte precursor cells or an abnormal thymus is responsible for the immunologic deficiencies of spontaneously diabetic BB rats, thymus grafts or T-cell-depleted bone marrow cells were exchanged between diabetes-prone and non-diabetes-prone animals. Analysis of peripheral lymphocyte populations from these recipients with monoclonal antibodies, a fluorescence activated cell sorter, and mixed lymphocyte culture tests indicate that an abnormal thymus is not responsible for the immunodeficiency of BB rats, but that the defect resides within the lymphocyte precursor pool.

Time course of islet cell antibodies in diabetic and nondiabetic BB rats.

The BB rat develops a spontaneous type I diabetic syndrome with anti-islet autoimmunity. Sera from diabetic and nondiabetic BB rats (from diabetes-prone litters), nondiabetic BB rats (from low-risk lines), and nondiabetes-prone Sprague-Dawley rats were collected twice a week from age 40 days to 160 days. Sera were tested for: (1) complement-dependent toxicity to 51Cr-labeled islet cells in vitro; (2) immunoglobulin binding to RIN-5 F insulinoma cells; and (3) ability to selectively suppress insulin secretion from normal islets in vitro. All sera from rats that subsequently became diabetic or glucose-intolerant were toxic to islet cells from various rat strains in the presence of complement. They were toxic neither to hepatocytes nor to fibroblasts. The toxic potency was associated with the globulin fraction. It was, in most cases, maximal either before or immediately after the onset of the disease. Sera from the nondiabetes-susceptible BB rats and the rats which, in diabetes-prone litters, died too early to be classified tended toward greater toxicity to islets. Immunoglobulins from diabetic sera bound to RIN-5 F cells more than did the serum globulins from other groups, their maximal binding capacity occurring after the onset of diabetes. Furthermore, BB diabetic sera were capable of selectively inhibiting the insulin secretion from normal rat islets in vitro either in the presence or, in some cases, in the absence of complement. The A- and D-cell functions were not suppressed. The combination of such results suggests the presence of one or more antibodies capable of binding to beta cells, inhibiting their function, and inducing their lysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Type I diabetes of man and the BB rat: monoclonal antibody-defined T-cell abnormalities.

Both patients and BB rats with type I diabetes mellitus have demonstrated major T-cell abnormalities, the appearance of which precede the development of overt hyperglycemia. The BB rat experiences a profound T lymphocytopenia which appears to be a necessary antecedent but is not totally sufficient in itself for the development of diabetes. Meanwhile, patients exhibit an elevated percentage of circulating T cells bearing the Ia or Dr antigen. Daily prednisone administration selectively decreases Ia+ T cells, and antithymocyte globulin (ATGAM) plus prednisone has a long-lasting effect in suppressing OKT4+ T cells in patients with recent-onset type I diabetes.

Levels of immunoreactive dynorphin in brain and pituitary of Brattleboro rats.

The very potent opioid peptide, dynorphin, has recently been shown by radioimmunoassay and immunocytochemical techniques to be selectively concentrated in the pars nervosa of pituitary, suggesting a possible association of dynorphin with the neurohypophyseal hormones, vasopressin and oxytocin. In this study, we report that pituitary and brain contents of immunoreactive dynorphin in homozygote Brattleboro rats (unable to synthesize vasopressin) are similar to those in heterozygote animals and in normal Long-Evans rats. Thus, the syntheses of immunoreactive dynorphin and vasopressin in the hypothalamo-hypophyseal tract appear to be independently regulated.