thymosin and Diabetes-Mellitus--Type-1

Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 trans-molecules composed of α and β chains from DQ2 and DQ8 express unique β-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis- and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

Topics: Adolescent; B-Lymphocytes; Diabetes Mellitus, Type 1; Epitopes, B-Lymphocyte; Genetic Predisposition to Disease; Heterozygote; HLA-DQ Antigens; Homozygote; Humans; Insulin; Islets of Langerhans; Male; Protein Binding; Syndecans; T-Lymphocytes; Thymosin

In most studies the activity of suppressor T cells and the percentage of suppressor/cytotoxic T-lymphocyte subsets in type 1 diabetes have been found to be altered. To determine whether thymosin and insulin in vitro have a role in improving or normalizing these abnormalities, PBMC from 28 patients with type 1 diabetes of various durations were treated with thymosin or insulin and the activity and the percentage of suppressor T cells were detected by using the method of ConA-induced suppressor T cells and WuT8 (suppressor/cytotoxic) monoclonal antibody respectively. Both thymosin and insulin were found to have ability to improve and normalize the ConA-induced suppressor cell activity and the percentage of WuT8 cells in diabetic patients. Data have shown that the lower the activity and the percentage of suppressor T cells, the more intense the effects of both compounds. The strongest effects were found at the concentrations of 10 micrograms/ml thymosin and 10 ng/ml insulin. Thymosin was more effective than insulin. This experiment also suggested that the activated lymphocytes stimulated by mitogens (PHA or ConA) were required when insulin exerted a significant effect on suppressor T cells. We conclude that thymosin and insulin in vitro can exert immuno-regulatory or immunostimulating effects on suppressor T cells.

Topics: Adult; Cells, Cultured; Concanavalin A; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Lymphocyte Activation; Male; Reference Values; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Thymosin; Time Factors

The biological basis for autoimmunity and immunoincompetence in the BB rat has yet to be localized. In spite of normal thymic histology, thymocyte subsets and blastogenesis, thymus gland products (thymosins) have yet to be studied. In the present report, thymus gland function was studied by measuring thymosin alpha 1 levels at one time point in the BB rat compared with control rates, and BB rat responses to exogenous thymosin (Thymosin fraction 5) were observed. At five months of age, BB rats had thymosin alpha 1 levels comparable to Lewis and Wistar furth rats. Thymosin fraction 5 increased the ratio of peripheral blood W3/25 positive to OX8 positive cells, but otherwise had no effect on the BB rats' T-cell immunodeficiency, or frequencies of tissue autoantibodies or insulin-dependent diabetes. Although B-lymphocyte counts were normal in BB rats, splenocyte responses to B-lymphocyte mitogens were depressed. However, thymosin fraction 5 improved the BB rat B-lymphocyte blastogenesis to near normal for Mycoplasma neurolyticum. Coupled with our previous work, our results suggest that the immune derangement in the BB rat resides outside the thymus.

Topics: Animals; Autoantibodies; Bacterial Toxins; Concanavalin A; Diabetes Mellitus, Type 1; Disease Models, Animal; Leukocytes; Lymphocyte Activation; Mycoplasma; Rats; Rats, Inbred BB; Rats, Inbred Lew; Rats, Inbred WF; Thymalfasin; Thymosin; Thymus Gland