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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied 18 newly diagnosed diabetic patients (8 males and 10 females, aged 18-26 years, within 10-120 days from the onset of symptoms) who were submitted for 15 days to intensive insulin therapy performed via subcutaneous insulin infusion (CSII). We investigated some metabolic and immunological parameters in order to identify a possible marker to predict the selection of patients potentially more responsive to CSII treatment for the remission of type 1 diabetes. In accordance with the International Diabetes Immunology Group we considered clinical remission as being the withdrawal of insulin therapy for at least 3 months. In order to assess beta-cell function a fasting and post-prandial serum C-peptide, blood glucose and HbA1c were performed on all patients before, and 3 days after, the discontinuation of CSII. Islet cell antibodies were determined in all sera by indirect immunofluorescence. Analysis of T-lymphocyte subpopulations was carried out before starting the therapy. The following monoclonal antibodies were used: CD4, CD8, CD57, CD25, HLA-DR. The levels of C3 and C4 and serum IgG, IgA and IgM were also evaluated. After CSII, 11 of 18 patients showed remission. At the beginning of the study we observed no major difference in metabolic parameters between the two groups. Interestingly, the patients who exhibited remission presented a statistically higher percentage of positive cells for CD57, HLA-DR and CD25 surface antigens, significantly lower C4 levels and CD4/CD8 ratio and significantly higher IgG levels compared with patients who did not show any remission.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res Clin Pract 1992 May
PMID:In search of predictive markers of remission from insulin dependence in type 1 diabetes: a preliminary report. 160 Aug 53

BB/Wor rats develop spontaneous autoimmune diabetes similar to human insulin-dependent diabetes mellitus. A T-cell-mediated pathogenesis for BB/Wor diabetes is indicated because disease is prevented by neonatal or adult thymectomy and treatment of diabetes-prone rats with monoclonal antibodies directed against CD5 or CD8 T-cell surface markers. Disease can be adoptively transferred with injections of concanavalin A-activated spleen cells from either acutely diabetic or RT6.1 T-cell-depleted diabetes-resistant BB/Wor rats. We used microbial superantigens to stimulate spleen cells from RT6.1 T-cell-depleted diabetes-resistant rats and demonstrated that such cells activated with staphylococcal enterotoxins (SEs) can also transfer diabetes. The diabetogenic effector T cells are readily activated by SEA, SEC3, and SEE, whereas SEB- and SEC2-activated cells are far less effective in the adoptive transfer of diabetes. These results demonstrate that microbial superantigens are capable of activating self-reactive and diabetes-inducing T cells in vitro in the BB/Wor rat. Ubiquitous microorganisms may be the environmental trigger for autoimmunity in susceptible individuals.
Diabetes 1992 Apr
PMID:Staphylococcal enterotoxin-activated spleen cells passively transfer diabetes in BB/Wor rat. 160 77

To develop somatic gene therapy for diabetes, we studied an animal model with proinsulin-producing fibroblasts with an immunological safety system. Cultured mouse fibroblasts of the Ltk- cell line were transfected first with the efficient human proinsulin expression vector pBMG-Neo-Ins. Initially, 2 x 10(6) cells with a proinsulin-production rate of 91 ng.24 h-1.10(6) cells-1 were transplanted i.p. into streptozocin-induced diabetic C3H mice. The blood glucose concentrations improved between the first and the 28th day, but the animals died of hypoglycemia between the 29th and 46th days. The proinsulin-producing Ltk- cells were further transfected with a second plasmid, pHEBo-CD8.2, encoding BALB/c mouse T-cell differentiation antigen. The CD8.2 allotype is different from CD8.1 allotype by only one amino acid substitution and should be only slightly antigenic to the recipient C3H mice. Somatic gene therapy with these doubly transfected cells followed by the consecutive administration of a monoclonal antibody to CD8.2 resulted in an initial decrease of blood glucose concentrations followed by the permanent recurrence of hyperglycemia, thus proving the complete removal of the transplanted cells. Cultured fibroblasts were thus proven capable of supplying sufficient proinsulin to lower the blood glucose concentrations in diabetic animals. The immunological safety system with a combination of artificial expression of cell surface antigen and the administration of the specific monoclonal antibody was an effective safety system for somatic gene therapy.
Diabetes 1992 Aug
PMID:Somatic gene therapy for diabetes with an immunological safety system for complete removal of transplanted cells. 162 70

Pancreatic beta cell destruction in the non-obese diabetic (NOD) mouse is mediated by T lymphocytes and macrophages and accelerated by cyclophosphamide. We purified pancreatic T lymphocytes from the NOD mouse for comparative phenotypic and functional analysis with T lymphocytes from spleen, peripheral blood and regional lymph nodes. Pancreatic T lymphocytes from NOD-Wehi mice, which have an incidence of spontaneous diabetes of less than 5%, had a CD4:CD8 ratio of 1.25 +/- 0.23 compared with 2.44 +/- 0.31 for peripheral blood lymphocytes. After cyclophosphamide, the CD4:CD8 ratio of pancreatic lymphocytes increased to 2.30 +/- 0.24 at day 7. T lymphocytes bearing IL-2 receptors increased two- to three-fold in number and their secretion of GM-CSF/IL-3 and IFN-gamma increased to a maximum on day 7. Pancreatic insulin content and mRNA levels declined sharply between days 10 and 12, at which time the majority of pancreatic T lymphocytes in hyperglycaemic mice were CD8+ (CD4:CD8 ratio 0.63 +/- 0.04 compared to 4.14 +/- 1.05 in peripheral blood). The pancreatic T lymphocyte CD4:CD8 ratio in prediabetic NOD-Lt mice, which have an incidence of spontaneous diabetes of about 60% at 150 days, was similar to that in untreated NOD-Wehi mice, but 25% of their pancreatic CD8 T lymphocytes were IL-2-receptor positive. Thus, significant changes in the phenotype of NOD pancreatic T lymphocytes following cyclophosphamide were not reflected in peripheral blood or spleen T lymphocytes. The earliest change after cyclophosphamide was an increase in activated, predominantly CD4+ T lymphocytes; with the development of beta cell destruction and hyperglycaemia, pancreatic T lymphocytes were, as in human IDDM, predominantly CD8+.
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PMID:Characterization of pancreatic T lymphocytes associated with beta cell destruction in the non-obese diabetic (NOD) mouse. 167 32

Interactions of pancreatic islets and islet-associated mononuclear cells (IAMCs) from the nonobese diabetic (NOD) mouse were morphologically investigated. To obtain IAMCs, pancreatic islets isolated from adult NOD mice were cultured for 7 days with interleukin 2. Noted by light microscopy, interactions between IAMCs and freshly isolated islets from young NOD mice began 30 min after the initiation of the coculture, and 6 h later, normal cellular array of the islets was lost. By electron microscopy, most IAMCs had low nucleus-cytoplasm ratio, the nucleus was notched and exhibited condensed chromatin along the nuclear membrane, and well-developed Golgi complexes and several mitochondria were distributed in the cytoplasm. These IAMCs adhered to beta-cells, but not to alpha- or delta-cells, with their pseudopods and caused cytolysis of beta-cells. Immunohistochemical study with antibodies specific for pancreatic hormones demonstrated that only cells reacting with anti-insulin antibody were selectively lost as the incubation time proceeded. Electron immunohistochemistry by immunogold technique showed that effector cells in IAMCs reacted with anti-CD8 (Lyt-2) antibody, but not anti-CD4 (L3T4) or anti-asialogangliosideM1 antibody. In addition, the concentration of pancreatic hormones in the culture medium, used as a marker of cytolysis, also demonstrated that insulin was significantly increased after 6 h of culture, whereas glucagon and somatostatin were not. These results suggest that CD8+ cytotoxic T lymphocytes are involved in the selective destruction of pancreatic beta-cells in the NOD mouse.
Diabetes 1991 Sep
PMID:Morphological analysis of selective destruction of pancreatic beta-cells by cytotoxic T lymphocytes in NOD mice. 168 98

IL-2 receptor positive T-cells from leukocyte-infiltrated pancreatic islets of diabetes prone or acutely diabetic NOD mice were propagated in vitro by culture in interleukin-2 containing medium. Of 13 lines obtained after limiting dilution all were positive for the T-cell marker Thy-1 and for CD8. Considerable heterogeneity in T-cell receptor usage was noted. Seven lines expressed T-cell receptors using V beta 8, one line was positive for V beta 5 and two lines expressed a non V beta 5, non V beta 8 receptor. Finally, two further lines lacked T-cell receptors. None of the cell lines were cytotoxic to islet cells although 10 lines showed non MHC restricted lysis of one or more tumour cells including rat insulinoma cells. We conclude that IL-2 receptor positive CD8+ T-lymphocytes from NOD islets are heterogenous with respect to V beta T-cell receptor usage. The majority of these cells are not cytotoxic to islet cells.
Diabetes Res 1991 Feb
PMID:Analysis of IL-2 receptor positive CD8(+)-T-lymphocytes grown from islets of NOD mice. 168 10

The object of this study was to further characterize the pathophysiology of the peripheral T lymphopenia in the BB rat. Towards this end, surface markers on unseparated thymocytes and purified thymocyte subsets from age- and sex-matched diabetes-resistant (BBn) and diabetes-prone (BBd) rats were analyzed by two-color flow cytometry. The proportions of thymocytes falling into each of the four main phenotypic subsets were comparable in BBn (n = 9) and BBd (n = 8) rats: respectively, 4.6 +/- 0.6% and 4.4 +/- 0.8%, CD4-8-; 68.1 +/- 1.9% and 71.1 +/- 3.2%, CD4+8+; 18.3 +/- 1.5% and 15.4 +/- 2.3%, CD4+8-; 9.1 +/- 0.9% and 9.1 +/- 1.0%, CD4-8+. In addition, absolute numbers of thymocytes were not significantly different. The levels of expression of CD4, TCR-alpha beta within each thymocyte subset were comparable in BBn and BBd animals as were the anti-TCR-induced proliferative responses of their CD4+8- and CD4-8+ thymocytes. However, phenotypic abnormalities within the CD4-8+ thymocyte subset of the BBd rat were found. A very significant (p less than 0.005) deletion of mature CD4-8+, TCR-alpha beta + thymocytes and a proportional increase (p less than 0.005) of immature CD4-8+, TCR-alpha beta low thymocytes. Moreover, a twofold decrease of CD8 expression by mature CD4-8+ thymocytes was observed in BBd animals. These results suggest that an impaired thymic maturation contributes to the peripheral T lymphopenia of the BBd rat.
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PMID:Abnormal thymocyte maturation in spontaneously diabetic BB rats involves the deletion of CD4-8+ cells. 168 92

Diabetes-prone (DP) BB rats develop spontaneous autoimmune insulin-dependent diabetes mellitus (IDDM). The cell populations involved in the expression of diabetes are not precisely known but probably include natural killer (NK) cells, macrophages, and T lymphocytes. Because the DP rat has few lymphocytes of the CD5+/CD+ phenotype, cytotoxic T lymphocytes (Tc) are not believed to be important in the process. Diabetes-resistant (DR) BB rats that are depleted of RT6+ T lymphocytes also become diabetic and provide an additional model of IDDM. We report that diabetes in DR rats depleted of RT6+ T lymphocytes is prevented by the concomitant depletion of either the CD5+ or the CD8+ population. In contrast, coadministration of anti-asialogangliosideM1 (alpha-ASGM1), an antiserum that principally recognizes NK cells, failed to prevent hyperglycemia in RT6-depleted rats. We propose that the initiation of diabetes in both DP and RT6-depleted DR rats is T-lymphocyte dependent. However, the final common pathway leading to autoimmune beta-cell destruction in IDDM may be different in these models. The RT6-depleted DR rat requires a cell that is sensitive to anti-CD8 (possibly a Tc), whereas the DP rat requires an anti-ASGM1-sensitive cell.
Diabetes 1991 Apr
PMID:T-lymphocyte requirement for diabetes in RT6-depleted diabetes-resistant BB rats. 170 18

Insulitis occurs by 5 wk of age in all NOD mice. However, diabetes is detectable only after 3-5 mo of age and only in approximately 50% of females and 10% of males in our colony. Therefore, it is predictable that changes in the T-lymphocyte repertoire of diabetes-prone mice occur and predispose them to disease. We demonstrate here that an altered (with respect to control BALB/cJ mice) thymic T-lymphocyte maturation reflected by a depletion (approximately 12%) of CD4+CD8+ T lymphocytes and a reciprocal increase in CD4-CD8- T lymphocytes precedes the onset of diabetes. This depletion was detected only approximately 3 mo after insulitis and is manifested by a specific loss (approximately 3%) of immature T lymphocytes bearing V beta 8lo (lo is a relative level of expression) T-lymphocyte receptor. By onset of diabetes, an even greater decrease (approximately 35%) of CD4+CD8+ and a reciprocal increase of CD4-CD8- T lymphocytes were apparent and accompanied by the same depletion (3%) of V beta 8 lo T lymphocytes. Administration of cyclophosphamide (CY), which accelerates the appearance of diabetes in NOD mice, caused similar depletions of CD4+CD8+ and V beta 8lo thymic T lymphocytes. The same alterations in the distribution of these thymic T-lymphocyte subsets were evident even earlier in insulitis- and diabetes-free NON mice, indicating that these changes in thymic T-lymphocyte development may be necessary but not sufficient to give rise to diabetes. Despite the common genetic origin of NOD and NON mice, differences at their MHC-linked and -unlinked loci may account for their differential susceptibility to diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Apr
PMID:Altered thymic and peripheral T-lymphocyte repertoire preceding onset of diabetes in NOD mice. 182 79

The onset of insulin-dependent (type I) diabetes is predictable before hyperglycemia by the presence of islet cell autoantibodies (ICAs) and competitive insulin autoantibodies (CIAAs). CIAA+ICA+ first-degree relatives of individuals with type I diabetes have increased numbers of CD4 cells bearing the CD45R antigen and reciprocal depressions of the CD4 cells bearing the CD29 determinant. In addition, depressed CD4/CD8 ratios are present. In this study, we investigated the correlation between autoantibody levels and T-lymphocyte changes in the prediabetic state. The data demonstrate a clear linear relationship between rising CIAA levels, a marker of disease rate, and rising elevations in the CD4+CD45R+/CD4+CD29+ ratio in 37 CIAA+ICA+ and CIAA+ICA- relatives (r = 0.93). In marked contrast, the degree of CD4/CD8 depression found in individuals with prediabetes or long-term diabetes failed to correlate with either CIAA (r = 0.32) or ICA (r = 0.29) levels. The investigation of T-lymphocyte changes in siblings of individuals with type I diabetes with different stable autoantibody patterns (CIAAs and/or ICAs), and thus varying risks for diabetes, revealed differences in the prediabetic groups. Fifteen CIAA+ICA- relatives with high CIAA levels (greater than 80 nU/ml) had high CD4+CD45R+/CD4+CD29+ ratios (P = 0.03) and depressed CD4/CD8 ratios (P = 0.008). In contrast, CIAA+ICA- relatives with low CIAA levels (39-80 nU/ml), and thus low risk of diabetes, had no alteration in their CD4/CD8 ratio (P = 0.75) or CD4+CD45R+/CD4+CD29+ ratio (P = 0.33). Nineteen CIAA-ICA+ siblings with a predicted intermediate risk for diabetes showed heterogeneity in the presence of T-lymphocyte abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 May
PMID:T-lymphocyte changes linked to autoantibodies. Association of insulin autoantibodies with CD4+CD45R+ lymphocyte subpopulation in prediabetic subjects. 182 80


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