UMLS:C0011854 - FACTA Search

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

The polyglandular autoimmune syndromes (PGA) are well known and are distinguished into type I, type II and type III. PGAI, also called APECED (autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy), is an autosomal recessive disorder, appearing in childhood and typically characterized by hypoparathyroidism (unusual in PGAII and PGAIII) and adrenal insufficiency. In APECED, autoimmune destruction of the pancreatic beta cells with development of insulin-dependent type 1 diabetes is possible, but less frequent than in the other PGAs, especially PGAII. The pathogenesis of this unique autoimmune disease is unknown. No HLA association seems to exist and genetic studies have assigned the autosomal APECED locus to chromosome 21. The case of a 28-years-old female suggesting the diagnosis of APECED, is presented, characterized by psycho-somatic abnormal development, teeth alterations, post-puberal gonadal failure with dystrophic hypoplasia of external genitalia, previous vaginal candidiasis, a slowly developing juvenile brittle diabetes. Intestinal malabsorption induced by Giardia lamblia occurred (probably resulting, like candidiasis, from immunological anergy). A strong familiarity linked to female sex was noticed (the mother, a sister, the little nice and some maternal female cousins being affected) while the father and a brother were healthy. Diabetes seems to be characterized by early onset and severe complications. In this patient no organo-specific antibodies were detected and the only immunologic disorder was a small decrease of CD3 and CD4/CD8 ratio, both CD4 and CD8 being at the lower normal range. This patient (and her female maternal relatives) needs a long-term follow-up in order to evaluate the function of endocrine glands and to initiate early treatment for hormonal deficits, as well as to detect the non-endocrine components of disease.
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PMID:[A rare case of juvenile diabetes mellitus associated with APECED (autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy) with strong X-linked familial inheritance]. 930 48

Insulin-dependent diabetes mellitus (IDDM) results from the destruction of pancreatic insulin-secreting cells by a T-cell-mediated autoimmune reaction. Distinct types of T helper cells (TH1 and TH2) have been characterised based on their cytokine secretion profiles following activation. Evidence from animal models favours the hypothesis that autoimmune diabetes is a TH1 response. However, there is no clear indication that a primary imbalance between protective TH2 and deleterious TH1 cells at early stages can trigger the autoimmune process. Protective CD4 + cells detected in nondiabetic young non-obese diabetic mice have not been shown to work through TH2 cytokines. In humans, there is little evidence that IDDM results from a TH1 response. Indeed, efficient experimental systems are lacking in humans to study the regulation of the autoimmune response in vitro. Interestingly, several immunotherapy strategies have aimed at inducing a TH2 response, even though TH2 cells have not been implicated in spontaneous disease development. However, recent ongoing trials in humans using oral administration of insulin to prevent diabetes are based on a protective mechanism which seems to depend essentially on transforming growth factor-beta. This cytokine is not dependent on TH1/TH2 dichotomy. Thus, although several attempts have been made to induce a TH1/TH2 switch to obtain a protective effect, a different and more complex mechanism probably (and paradoxically) accounts for the oral protection actually tested in animal models and humans.
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PMID:T-cell regulation in murine and human autoimmune diabetes: the role of TH1 and TH2 cells. 941 29

Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) is a disease controlled by the major histocompatibility complex (MHC) which results from T-cell-mediated destruction of pancreatic beta-cells. The incomplete concordance in identical twins and the presence of autoreactive T cells and autoantibodies in individuals who do not develop diabetes suggest that other abnormalities must occur in the immune system for disease to result. We therefore investigated a series of at-risk non-progressors and type 1 diabetic patients (including five identical twin/triplet sets discordant for disease). The diabetic siblings had lower frequencies of CD4-CD8- Valpha24JalphaQ+ T cells compared with their non-diabetic sibling. All 56 Valpha24JalphaQ+ clones isolated from the diabetic twins/triplets secreted only interferon (IFN)-gamma upon stimulation; in contrast, 76 of 79 clones from the at-risk non-progressors and normals secreted both interleukin (IL)-4 and IFN-gamma. Half of the at-risk non-progressors had high serum levels of IL-4 and IFN-gamma. These results support a model for IDDM in which Thl-cell-mediated tissue damage is initially regulated by Valpha24JalphaQ+ T cells producing both cytokines; the loss of their capacity to secrete IL-4 is correlated with IDDM.
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PMID:Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes. 942 63

HLA DQ8 (DQ A1*0301/DQB1*0302) molecule is implicated in the susceptibility to insulin dependent diabetes mellitus whereas, HLA DQ6 (DQ A1*0103/DQB1*0601) molecule may have a protective effect. In this study we used mice transgenic to HLA DQ8 and HLA-DQ6 to elucidate the T cell determinants on a putative islet cell target antigen, insulin. These mice do not express endogenous mouse class II heterodimers on cell surface. Using overlapping synthetic peptides spanning the complete sequence of huma pre-proinsulin, we identified the sequences recognized by T cells in DQ8 transgenic mice and compared these to those in DQ6 transgenic mice. We observed a differential pattern of recognition of epitopes on human pre-proinsulin (HPI) polypeptide presented by the HLA DQ8 allele as compared to HLA DQ6. The sequences 1-24 and 44-63 were immunodominant in DQ8 transgenic mice while DQ6 transgenic mice primarily recognized sequences 14-33 and 74-93 of HPI. We found that the immune response generated in HLA DQ8 transgenic mice against HPI 1-24 cross-reacted to the mouse pre-proinsulin sequence 1-24. The T cell response were specifically inhibited using anti-CD4 and anti-DQ8 monoclonal antibodies. This cross-recognition of self sequences raises the possibility of modulation of experimental diabetes using this peptide.
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PMID:T cell recognition of human pre-proinsulin peptides depends on the polymorphism at HLA DQ locus: a study using HLA DQ8 and DQ6 transgenic mice. 943 6

Approximately one-half of Caucasians with newly diagnosed insulin-dependent diabetes mellitus (IDDM) have autoantibodies to insulin, and the majority of those express the HLA-DR4 genotype [Ziegler, R., Alper, C. A., Awdeh, Z. L., Castano, L., Brink, S. J., Soeldner, J. S., Jackson, R. A. & Eisenbarth, G. S. (1991) Diabetes 40, 709-714]. However, it has been difficult to demonstrate T cell proliferative responses to human insulin in IDDM patients [Durinovic-Bello, I., Hummel, M. & Ziegler, A. G. (1996) Diabetes 45, 795-800]. We have immunized transgenic mice expressing the susceptible HLA-DR (alpha1*0101,beta1*0401) (hereafter called DRB1*0401) and human CD4 molecules on a murine major histocompatibility complex class II null background, with human preproinsulin (PPI), proinsulin (PI), and insulin and derived large panels of T cell hybridomas to determine the immunogenic epitopes of these proteins. These results show that the prohormones PI or PPI carry the major immunogenic T cell epitope in the DRB1*0401 transgenic mice. The PPI/PI immunodominant epitope LALEGSLQK was localized at the C-peptide/A-chain junction. This T cell epitope PPI/PI LALEGSLQK is unusual because, normally, it is proteolytically destroyed during the maturation of the insulin molecule. Additionally, this T cell epitope is both processed and presented by human DRB1*0401-positive Epstein-Barr virus transformed B cells, and it can also stimulate T cells from the peripheral blood of HLA-DR4-positive patients with type 1 diabetes. These findings may partly explain why susceptibility to type 1 diabetes is associated with HLA-DR4-positive individuals and why T cell responses to the mature insulin protein are rarely detected in IDDM patients.
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PMID:T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin. 952 Apr 53

T lymphocytes recognise peptide antigens through the T cell antigen receptor, which is composed of variable alpha and beta chains. There are forty-six functional variable regions on the beta chain. In this study the expression of the T cell receptor beta-chain variable regions 2S1 and 3S1, in a large cohort of multiplex insulin-dependent diabetes mellitus families, have been determined by use of monoclonal antibodies and flow cytometry. Peripheral blood was collected from these multiplex families and three control groups, healthy individuals, sporadic insulin-dependent diabetes mellitus patients and non-insulin-dependent diabetes mellitus patients. The level of TCRBV2S1 expression in the multiplex families was significantly higher than all the control groups for both the CD4+ and CD8+ T lymphocyte subsets. Detailed analysis of the family data showed that this increased expression was not associated with age, sex, HLA type or the diabetic phenotype. The TCRBV3S1 expression in all the diabetic cohorts was significantly lower than the healthy controls, in the CD4 subset only. Detailed analysis of the family data showed only the fathers TCRBV3S1 expression was lower than the healthy controls. This study gives further insight into TCRBV usage which could reflect the mechanism of the autoimmune response in IDDM multiplex families.
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PMID:Individuals from multiplex insulin-dependent diabetes mellitus (IDDM) families express higher levels of TCRBV2S1 than controls. 954 38

Spontaneously diabetic nonobese diabetic (NOD/Lt) mice were treated with anti-T-cell monoclonal antibodies (mAbs) at the time of grafting with vascularized segmental pancreas isografts. Recipients were either untreated or given anti-CD4 and/or anti-CD8 mAbs (0.5 mg/20-g mouse on each of 4 consecutive days), which reduced target cell levels to <5% of normal. Graft function was monitored by measuring blood glucose (BG) levels. Transplants were removed for histological examination when BG returned to >20 mmol/l for two consecutive readings. Isografts from 3- to 4-week-old prediabetic mice placed in untreated diabetic NOD mice ceased functioning in 9-13 days with a mean survival time (MST) +/- SD of 10 +/- 2. Treatment with anti-CD4 prolonged survival significantly (MST = 61 +/- 35 days, P < 0.05 compared with untreated control mice). Anti-CD8 treatment was less effective, but it still significantly improved graft survival (MST = 24 +/- 9 days, P < 0.05 compared with untreated control mice). Anti-CD8 plus anti-CD4 treatment was highly effective in inhibiting autoimmune destruction of the grafts (MST = 97 +/- 8 days). This clearly demonstrates that transient inactivation of most T-cells with anti-CD4 plus anti-CD8 mAbs effectively controls autoimmune disease in the isograft, despite recovery of CD4 and CD8 T-cells to normal levels. Although insulitis developed in the long-term grafts, insulitis scores did not increase between 33 and 100 days, and none of the mice progressed to IDDM in 100 days. Histology showed a predominantly peri-islet T-cell and macrophage infiltrate with ductal expression of the cytokines interleukin (IL)-4, IL-2, and interferon-gamma. There was little infiltrate or expression of cytokines within the islets. Thus, mAb treatment at the time of grafting allowed isograft survival and prevented progression from insulitis to beta-cell destruction.
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PMID:Long-term survival of segmental pancreas isografts in NOD/Lt mice treated with anti-CD4 and anti-CD8 monoclonal antibodies. 972 27

Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA1*0301/ DQB1*0302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8(+)/I-Abo transgenic mice expressing functional HLA-DQ8 molecules and devoid of endogenous mouse class II. DQ8(+)/I-Abo mice produced antigen-specific antibodies and formed germinal centers after immunization with GAD65 peptides. Two GAD peptide-specific (247-266 and 509-528), DQ8 restricted Th1 CD4(+) T cell lines, were generated from immunized DQ8(+)/I-Abo mice. They induced severe insulitis after adoptive transfer into transgene positive (but not negative) mice who were treated with a very low dose of streptozotocin that alone caused no apparent islet pathology. In addition to CD4, islet mRNA from these mice also showed expression of CD8, IFNgamma, TNFalpha, Fas, and Fas ligand. Our data suggest that a mild islet insult in the presence of HLA-DQ8 bearing antigen-presenting cells promotes infiltration of GAD peptide reactive T cells into the islet.
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PMID:Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice. 972 63

Fetal pig islets, xenografted after organ culture into non-immunosuppressed prediabetic NOD mice, are rejected within 10 days. Immunosuppression with anti-T cell (anti-CD4 and anti-CD3) monoclonal antibodies alone is highly effective in delaying graft rejection in this discordant model, but rejection eventually occurs, usually within 80 days, despite marked depletion of T cells. In an attempt to prevent rejection, we used cyclophosphamide (CP), a powerful anti-B cell agent, or CTLA4Ig, an inhibitor of T-cell co-stimulation [via B7-1 (CD80) and B7-2 (CD86)], either given in combination with anti-CD4 (GK1.5) or anti-CD3 (KT3) MAb to the recipient mice. The addition of cyclophosphamide in a dose that significantly depleted B cells in peripheral blood was highly effective in preventing rejection, with xenografts surviving for at least 112 days, when the experiment was terminated. CTLA4Ig, administered alone, did not prevent delayed rejection (rejection occurred in <60 days) and, in contrast to CP, did not prevent delayed rejection when used in combination with GK1.5 and KT3 treatment. Thus, immunosuppressive agents found to be highly effective in other strains, e.g., CTLA4Ig and anti-T cell MAbs, had a lesser effect in NOD mice but the addition of an anti-B cell drug, CP, was useful. This finding may be applicable to patients with IDDM.
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PMID:Cyclophosphamide, but not CTLA4Ig, prolongs survival of fetal pig islet grafts in anti-T cell monoclonal antibody-treated NOD mice. 974 60

During development of IDDM mononuclear cell infiltration is seen in the islets of Langerhans in both man and rodent models. This process is not synchronized in time and space. To create a synchronized model for investigation of the cellular and molecular events during IDDM development, we isolated and transplanted 200 neonatal BB-DP rat islets under the kidney capsule of 30 day old BB-DP rats. Islet transplantations were also carried out from Wistar Furth (WF) to WF rats, from WF to Wistar Kyoto (WK) rats and from WK to BB-DP rats to compare disease occurrence in an islet syngraft with changes in islet syngrafts or allografts in non-diabetes prone recipients and with changes in islet allografts in diabetes prone recipients, respectively. Pancreata and grafts were harvested at pre-scheduled time points before onset of diabetes and at onset of diabetes, and stained for insulin, MHC class I, MHC class II, alphabeta-TCR, CD4, CD8 or ED1. Diabetes incidence in the syngrafted BB-DP rats was 75% at 78 +/- 5 days of age. The incidence and time of onset of IDDM was unaffected by islet syngrafting. Positive correlations were found between the percentage of infiltrated islets in situ and the number of infiltrating cells in the islet syngraft from the same BB-DP rats (p = 0.003-p < 0.0001, r = 0.5-0.7). The number of infiltrating cells regardless of cell type in the graft was inversely correlated to the graft insulin content (p = 0.0003-p < 0.0000, r = -0.6 to -0.8). The graft insulin content was 70% and 90% in BB-DP rats before onset of diabetes and BB-DP rats not developing diabetes respectively, and 30% in the diabetic rats (p < 0.01). Interestingly only 5% of the allografted BB-DP rats developed diabetes. No correlation was found between the number of infiltrating cells in the graft and islets in situ in the BB-DP rats not developing diabetes. Only baseline infiltration was seen in grafts from syngrafted WF rats. In allografted WF islet to WK rats graft rejection was seen 12 days after transplantation. No correlation was found between the number of infiltrating cells in the graft and islets in situ. In conclusion the cellular infiltration in syngeneic but not allogeneic islets grafted to 30 day old BB-rats mirrors that seen in islets in situ. Syngeneic islet grafting in BB-DP rats may be useful for studying the cellular and molecular events during the development of IDDM.
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PMID:Syngeneic islet transplantation in prediabetic BB-DP rats--a synchronized model for studying beta-cell destruction during the development of IDDM. 977 79

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