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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and experimental data support the concept that type I diabetes mellitus results from autoimmune destruction of pancreatic beta cells. Although both proteins and glycolipids are targets of anti-islet cell antibodies, the Ag have not been purified or characterized. Previously, we observed that rat insulinoma (RIN) cell lines varied in their reactivity with both human antibodies and murine mAb A2B5, which binds to polysialo gangliosides. To determine the chemical basis of the varied immunoreactivity, we analyzed the glycosphingolipids of 5 RIN lines. Glycolipids bound by two mAb and by antibodies in the sera of type I diabetics were identified. The more immunoreactive RIN lines contained a much higher content of gangliosides and a higher proportion of complex gangliosides. The major gangliosides were GM3, GD3, and GT3. By high performance TLC immunostaining, we demonstrated that A2B5 and R2D6, an anti-beta cell murine mAb, bound most strongly to ganglioside GT3. The binding of human sera to gangliosides was analyzed by an ELISA assay. Although both normal and diabetic sera contained antibodies to various glycolipids, binding to GT3 was significantly elevated in 31 new-onset type I diabetics (p less than 0.001). The presence of the GT3 trisialosyl epitope on human islet cells was shown by immunofluorescent staining by both R2D6 and A2B5. These findings support previous suggestions that gangliosides play an important role in the immunopathology of type I diabetes, and identify for the first time a specific ganglioside Ag that is the target for autoantibodies in a subset of diabetic patients.
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PMID:Antibodies against ganglioside GT3 in the sera of patients with type I diabetes mellitus. 265 94

Aberrant expression of major histocompatibility (MHC) antigens has been implicated as a factor contributing to organ-specific autoimmunity, such as progressive loss of pancreatic beta cells in type 1 diabetes. We investigated the potential of a rat beta cell tumour, RINM5F, to express enhanced levels of MHC antigens in vitro. To this purpose we treated RINM5F cells in vitro with recombinant rat gamma interferon (rIF gamma). We used monoclonal antibodies to RT1.A (class I) and RT1.B (class II) antigens of the rat MHC in conjunction with flowcytometry and immunoperoxidase techniques to analyse the expression of MHC antigens. Untreated RINM5F cells express low levels of RT1.A, whereas they are negative for RT1.B. Treatment with rIF gamma appeared to increase the expression of RT1.A antigens substantially. Most importantly, RT1.B antigens were newly expressed by rat insulinoma cells in vitro after treatment with rIF gamma. To our knowledge this is the first documentation of the potential of beta cells or their derivatives to express class II MHC antigens following IF gamma-treatment. This mechanism may play an important role in the augmentation and perpetuation of insulitis leading to type 1 diabetes mellitus.
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PMID:Recombinant gamma interferon induces class II major histocompatibility complex antigens on insulinoma cells. 303 89

Autoantibodies to adrenal medulla that gave a diffuse immunofluorescent staining pattern were detected in 17 out of 107 (16%) patients with newly diagnosed Type I diabetes mellitus, in 13 out of 178 (7%) patients with long lasting disease but in none of 80 mixed control sera tested. The antibodies were of IgG class and 31 of the 33 positive sera also fixed complement. In 32 out of 34 cases, detection of the antibodies was correlated with the presence in the serum of pancreatic islet cell antibodies (ICA). The specificity of adrenal medullary antibodies is distinct from ICA and from C-cell antibodies since their reactivity was not abolished by preabsorption with extracts from human insulinoma or thyroid C-cell carcinoma. The presence in the serum of antibodies to adrenal medulla is not related to a functional defect of the adrenal medulla, but this new specificity indicates a further autoimmune reaction related to the natural history of Type I diabetes.
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PMID:Autoantibodies to adrenal medullary and thyroid calcitonin cells in type I diabetes mellitus--a prospective study. 325 90

We have produced a monoclonal antibody 3A4 to the surface of islet cells by fusing spleen lymphocytes from nonobese diabetic (NOD) mice. To identify the molecular weight of specific target antigens reacting with 3A4, 125I-surface-labeled In-111 insulinoma cells were solubilized and extracts were absorbed with 3A4, and immunoprecipitates were followed by polyacrylamide gel electrophoresis and autoradiography. 3A4 recognized two major polypeptides with apparent molecular weights of radioactive 64K and inactive 28K. In order to evaluate the antibody-mediated cytotoxic mechanisms of 3A4, complement-dependent antibody-mediated cytotoxicity (C'-AMC) and antibody-dependent cellular cytotoxicity (ADCC) were tested using a method of specific 51Cr release. In the study for C'-AMC, even over wide ranges of concentration of antibody and rabbit complement, purified 3A4 had no apparent cytotoxic effects on In-111 cells. On the other hand, significant ADCC was observed at an antibody concentration of 10 micrograms/ml and a target:effector cell ratio of 1:40 (P less than 0.01). Finally, the effects of 3A4 on glucose-stimulated insulin release were examined in isolated rat islets. At a glucose concentration of 16.7 mM, 3A4 significantly inhibited the insulin release either in the presence or absence of complement (P less than 0.01). In conclusion, 3A4 could not only bind but also be active to the target cells. Therefore, this monoclonal antibody should be a useful tool to permit a detailed analysis of the pathogenesis of type I diabetes mellitus.
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PMID:Immunochemical characterization of anti-islet cell surface monoclonal antibody from nonobese diabetic mice. 351 30

Monoclonal antibody 3A4 to islet cell surface antigen has been previously established in our laboratory, using hybridization of spleen lymphocytes from non-obese diabetic (NOD) mice transferred into immunologically incompetent recipient mice. In the present study, monoclonal islet cell surface antibody 5C12 could be newly obtained in the 10:1 ratio of NOD mice spleen cells and mouse myeloma cells (SP2/0) without any modifications. Protein A radioligand assay and indirect immunofluorescence on living cells showed that 5C12 antibody reacted to normal rat islet cells and cultured rat insulinoma cells (RIN-r), but not to cultured lymphocytes (Bri-7, IM-9) and Chang-liver cells. Analysis of 125I-labeled antibody binding revealed that unlabeled 5C12 effectively inhibited subsequent 125I-5C12 binding to RIN-r cells, whereas unlabeled 3A4 did not. The scatchard plot from these data showed the curvilinearity, and about 150,000 binding sites to antibody per RIN-r cell were counted. The treatment of RIN-r cells with papain and neuraminidase reduced the binding of 5C12 to RIN-r cells, whereas the effect of trypsin was not observed. Immunoprecipitation of 125I-labeled insulinoma cell lysates followed by SDS-PAGE and autoradiography indicated that 5C12 recognized 105K dalton cell surface protein in RIN-r cells. Immunoblotting also showed that 5C12 antibody recognized 105K dalton cell surface protein in RIN-r cells. These results demonstrated that 5C12 was an important tool for clarifying the immunoresponse against certain antigenic determinants on pancreatic B cells. Furthermore, 5C12 has not only qualitatively and quantitatively improved diagnostic methodology, but it may also provide new reagents useful to the treatment and prevention of type 1 diabetes.
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PMID:[An analysis of islet cell surface antigen defined by monoclonal islet cell surface antibody 5C12]. 354 94

A micro enzyme-linked-immunosorbent-assay (ELISA) for monitoring circulating human proinsulin (hPI) was developed. A micro test plate was coated with guinea pig anti-insulin antibody. As labelling system peroxidase-labelled F(ab1)2-fragments of a guinea pig anti-human-C-peptide was used. The detection limit in buffer (95% level) was 0.6 pmol/l corresponding to 0.06 fmol/incubation well and to 1.2 pmol/l in serum, since samples were diluted 50%. Standard operating range was from 0-160 pmol/l. Interassay variation was 9% estimated from two human control materials (assayed within the range 6-9 pmol/l and 9-14 pmol/l, respectively). Insulin in samples did not interfere in concentrations below 400 pmol/l. Human C-peptide, porcine, and bovine proinsulins did not cross-react even at 10 000 pmol/l. In 38 healthy fasting subjects a reference range less than 1.2-13 pmol/l with a median of 4.1 pmol/l was found. Serum from total pancreatectomised patients showed values below the detection limit. The value from a patient with an insulinoma was 263 pmol/l. When stored at -20 degrees C human proinsulin appeared stable in serum or plasma for at least 9 mth. This ELISA, although among the most sensitive immunoassays for human proinsulin, is still not sensitive enough to measure the concentrations expected in samples from IDDM patients in the fasting state. In spite of this the method is useful in characterising beta-cell function in stimulated situations, as well as in the diagnosis of insulinoma.
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PMID:ELISA for human proinsulin. 371 86

The production of monoclonal antibodies to islet cell surface antigens, using hybridization of spleen lymphocytes from non-obese diabetic (NOD) mice has been reported previously from our laboratory. In the present study, the immunochemical characteristics of the monoclonal antibody (3A4) have been investigated using In-111 cells, a virus-induced insulinoma cell line derived from the Syrian golden hamster as target cells. The antibody 3A4 could be visually detected in the immunoenzymatic labelling of the surface of In-111 cells. To identify the molecular weight of target specific antigens reacting with 3A4, 125I-surface labelled In-111 cells were solubilized and extracts were absorbed with 3A4. The immunoprecipitates were subjected to polyacrylamide gel electrophoresis and autoradiography. 3A4 recognized two major polypeptides with apparent molecular weights of radioactive 64K and inactive 28K daltons. In order to evaluate antibody-mediated cytotoxic mechanisms of 3A4, complement-dependent antibody-mediated cytotoxicity (C'AMC) and antibody-dependent cellular cytotoxicity (ADCC) were tested, using a method of specific chromium release. In the study for C'AMC, even though over wide ranges of antibody concentration and rabbit complement, purified 3A4 had no apparent cytotoxic effects on In-111 cells. On the other hand, significant ADCC was observed at 10 micrograms/ml antibody concentration and 1:40 target: effector cell ratio. Finally, the effect of 3A4 on glucose-stimulated insulin release in isolated rat islets was examined. At 16.7 mM glucose concentration, 3A4 significantly inhibited the insulin release in the absence or presence of complement. Therefore, 3A4 can not only bind but also be active to the target cells in the cytotoxicity and suppression of insulin release, and it can be a useful tool to clarify the pathogenesis of type 1 diabetes mellitus. Furthermore, these results suggest that the relationship between islet cell surface antibody and cell-mediated immunity, especially immunoresponse against certain antigenic determinants on pancreatic B cells, seems to be important in the pathogenesis of type 1 diabetes mellitus.
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PMID:[Studies on the pathogenesis of type 1 diabetes mellitus--immunochemical studies with monoclonal islet cell surface antibody using hybridization of spleen lymphocytes from non-obese diabetic mice]. 388 86

We describe a nonradioactive microcytotoxicity assay for ICSA using a cloned rat insulinoma cell line. This assay system had good reproducibility (r = 0.93) and was suitable for the study of large numbers of samples. The following results were obtained by testing the sera of 111 patients with IDDM (type I diabetes) and all of their first-degree relatives. (1) Thirty-five percent of IDDM patients had ICSA, as compared with only 2% of healthy controls. (2) ICSA was found more frequently in patients within 2 yr of onset (45%) than in those with disease for longer than 2 yr (27%) (P less than 0.05). (3) The prevalence of ICSA was associated with the presence of cytoplasmic islet cell antibodies (ICA) (P less than 0.05). (4) No association was found between the prevalence of ICSA and specific HLA-DR alleles. Association with the HLA haplotypes in families with ICSA-positive probands, on the other hand, is suggested although not proven by these data. (5) Among the nondiabetic relatives of IDDM patients, 5% of the parents and 14% of the sibs had ICSA. Increased prevalence of ICSA occurred in the unaffected sibs of ICSA-positive probands (31%) but not in those of ICSA-negative probands (4%) (P less than 0.001); in fact, the relatives of ICSA-negative probands had ICSA with a frequency not higher than in unrelated controls. (6) Female relatives of ICSA-positive probands were more often ICSA-positive than males, but no such difference was found among probands. (7) In multiplex sibships, ICSA were not associated with disease in the sibs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytotoxic islet cell surface antibodies (ICSA) in patients with type I diabetes and their first-degree relatives. 389 95

Immunotherapeutic intervention has been studied in non-obese diabetic (NOD) mice. Twenty-five male NOD mice aged 6 weeks were treated with anti-mouse T lymphocyte serum (ATS), N-(2-carboxyphenyl)-4-chloroanthranilic acid disodium salt (CCA); a non-specific immunostimulant which seems to potentiate the suppressor T cell activity, and antiserum raised against previously reported monoclonal antibody 3A4 to the surface of islet cells. Pancreatic islets from NOD mice sacrificed at 12 weeks of age were scored morphologically for the severity and the frequency of insulitis. Both the severity of insulitis in each islet and the frequency of insulitis-positive islets in each pancreas were reduced in the groups treated with ATS (group B), antiserum to 3A4 (group D) and a combination of antiserum plus CCA (group E) in comparison with other groups (control: group A and CCA: group C). At 8 weeks of age, the binding capacities of sera to insulinoma cells measured by protein A radioligand assay were significantly decreased in the groups treated with antiserum to 3A4 (groups D and E) as compared with those in the other groups. These results suggest that both ATS and antiserum to 3A4 prevent the occurrence and the progress of insulitis in NOD mice, but the immunosuppressive mechanisms differ from each other; therefore, combination therapy with these suppressants may be more effective in the prevention of Type 1 diabetes mellitus.
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PMID:Effect of antiserum to monoclonal anti-islet cell surface antibody on pancreatic insulitis in non-obese diabetic mice. 391 69

This study compares the utility of nonenzymatically glycosylated serum proteins (lys-GSP) to glycosylated hemoglobins (HbA1a-c) as control indices of glucose homeostasis in patients with IDDM. The diagnostic value of lys-GSP was also examined in patients with non-insulin-dependent diabetes mellitus, in subjects with impaired glucose tolerance, and in two patients with insulinoma. The intraindividual fluctuation of lys-GSP in normoglycemic subjects is very small, resulting in an interindividual range of 3.0 +/- 0.3 lysine-bound glucose/mg protein (means +/- SD, N = 52). HbA1a-c with a normal range of 6.4 +/- 0.9% (N = 52) shows greater variability. In IDDM there is no overlap of lys-GSP levels between the normal and the diabetic range at the 95% confidence level. In patients treated with an open-loop insulin delivery system failure of normalization of the glucose balance was clearly discernible by an elevation of GSP. In contrast, in about 40% of the patients with incomplete glycemic control the HbA1a-c levels fell within the normal range. The utility of lys-GSP for diagnosis of diabetes is compared with the results of 60 oral glucose tolerance tests. Two patients suffering from insulinoma displayed decreased lys-GSP values. From these results it appears that determination of lys-GSP represents a more sensitive parameter for long-term control than HbA1a-c and is suitable for monitoring even small fluctuations of blood glucose.
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PMID:Clinical utility of nonenzymatically glycosylated blood proteins as an index of glucose control. 651 Jan 80


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