UMLS:C0011849 - FACTA Search

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

To define more clearly the roles of CD80 (RIP-CD80) and CD86 (RIP-CD86) in the activation of autoreactive T cells in vivo, we generated transgenic mice expressing either or both costimulatory molecules on the beta cells of the pancreas. While RIP-CD80 mice do not show any sign of autoimmunity, at the age of 7 mo RIP-CD86 transgenic mice develop a lymphoid infiltrate with both IFN-gamma- and IL-4-positive cells in the vicinity of the islets; these mice, however, never progress to diabetes. This fundamental difference in the ability of CD80 and CD86 to activate self-reactive T cells in vivo is, however, obliterated when the level of TCR signaling is increased by either TNF-alpha or transgenic MHC class II expression. These results support the suggestion that CD80 and CD86 mainly differ at the level of the intensity of the signals they deliver.
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PMID:Autoimmunity without diabetes in transgenic mice expressing beta cell-specific CD86, but not CD80: parameters that trigger progression to diabetes. 972 4

Pathogenic autoreactive T lymphocytes are mediators of spontaneous insulin-dependent diabetes in nonobese diabetic (NOD) mice. This is demonstrated by their capacity to transfer diabetes into syngeneic immunoincompetent recipients. In addition, especially in prediabetic NOD mice, peripheral CD4+ T lymphocytes were identified that are highly effective, in conventional mixing cotransfer experiments, at preventing disease transfer. The present data demonstrate that mature heat-stable Ag-TCR alpha beta+CD8-thymocytes from prediabetic NOD mice also express this inhibitory capacity. Selection using an L-selectin (CD62L)-specific Ab showed that TCR alpha/beta+CD4+CD62L+ thymocytes, emerging from the mainstream differentiation pathway, concentrate this ability to regulate autoreactive effectors. Compared with mature TCR alpha beta+CD8- thymocytes, significantly lower numbers of TCR alpha beta+CD4+CD62L+ were sufficient to achieve an efficient inhibition of disease transfer into NOD-scid recipients. This protective ability was potentiated following in vitro culture in the presence of IL-7. In contrast, TCR alpha beta+CD62L- thymocytes, highly enriched in class I-restricted NK T cells, were unable to influence diabetes transfer. Identical results were obtained using thymocytes that have been cultured in vitro for 4 days in the presence of IL-7. These results support the active role in NOD mice of a thymus-derived CD4+ subset that controls peripheral pathogenic autoimmune effectors.
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PMID:Mature mainstream TCR alpha beta+CD4+ thymocytes expressing L-selectin mediate "active tolerance" in the nonobese diabetic mouse. 972 64

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

Type 1 diabetes, insulin-dependent diabetes mellitus (IDDM) results from autoimmune T cell-dependent destruction of insulin producing beta-cells in the pancreatic islets of Langerhans. T cells from recent-onset IDDM patients specifically proliferate to beta cell membrane Ag enriched fractions, containing the mitochondrial 38 kD islet antigen (Imogen). Recently, we identified a peptide epitope (Imogen p55-70) that is recognized by a 38 kD-specific, Th1 clone from an IDDM patient. In animal models of autoimmune diseases, altered self peptide ligands (APL) have been used effectively in peptide-based immune prevention or therapy. No such APL, however, have been reported so far that can modulate autoreactive T-cell responses in IDDM. Here, we have designed APL of p55-70. These APL efficiently downregulate in vitro activation of the 38 kD-specific Th1 clone induced by either p55-70 or by native beta cell autoantigens. Self peptide reactive T-cell proliferation could be inhibited only when APL and the self peptide were present on the same APC. Unrelated peptides with equal HLA-DR binding affinity were not effective, excluding simple MHC competition as the mechanism for T-cell modulation. APL triggered upregulation of CD69 and CD25 expression, but not T-cell proliferation, TCR down-modulation or T-cell anergy. Thus, the p55-70 APL inhibit beta cell autoantigen-induced activation of an Imogen-reactive T-cell clone derived from an IDDM patient, by acting as partial TCR agonists that inhibit TCR down-modulation.
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PMID:Altered peptide ligands of islet autoantigen Imogen 38 inhibit antigen specific T cell reactivity in human type-1 diabetes. 977 13

To investigate host leukocytes recruited to the pancreas by diabetogenic T cells, we administered islet-specific CD4(+) T cell clones to 2-week-old nonobese diabetic (NOD) mice and examined the resulting pancreatic infiltrate by flow cytometry. Two different Vbeta4(+)CD4(+) T cell clones, BDC 2.5 and BDC 6.9, were found to recruit a heterogeneous T cell population as determined by staining with a panel of anti-TCR Vbeta monoclonal antibodies. The majority of the diabetes-initiating, Vbeta4(+) T cell clones migrated to the spleen whereas only 5-8% of the T cell population infiltrating the pancreas was Vbeta4(+). Anti-IL-2 receptor staining indicated that fewer than 10% of the total population of infiltrating lymphocytes within the pancreas were in a highly activated state. We have further found that normal splenic T cells from the NOD mouse proliferate poorly to IL-2 in vitro, yet secrete IFN-gamma in response to IL-2 stimulation. These results suggest that the recruited host T cells in our disease transfer system are not directly pathogenic but, rather, are responding to the small numbers of inflammatory T cell clones by providing cytokines that facilitate the disease process.
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PMID:Analysis of leukocytes recruited to the pancreas by diabetogenic T cell clones. 979 Jul 22

The diabetes-susceptible class II MHC genes (in human and mouse) share unique nonaspartic acid residues at position 57 of the class II beta-chain. Transgenic expression of a mutant I-A(g7), substituting histidine and serine at position 56 and 57 of beta-chain with proline and aspartic acid (I-A(g7)PD), respectively, inhibits diabetes development in the nonobese diabetic mouse model. Here, we demonstrate that immature thymocytes expressing a diabetogenic islet Ag-specific transgenic TCR are positively selected by I-A(g7)PD class II MHC to give rise to mature CD4+ T cells. However, splenic APCs expressing the same I-A(g7)PD fail to present pancreatic islet Ag to mature T cells bearing this diabetogenic TCR. These results indicate that nonaspartic acid residues at position 57 of class II MHC beta-chain is important for diabetogenic CD4+ T cell activation in the periphery but is not essential for the formation of a diabetogenic T cell repertoire in the thymus.
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PMID:Thymic positive selection and peripheral activation of islet antigen-specific T cells: separation of two diabetogenic steps by an I-A(g7) class II MHC beta-chain mutant. 979 72

Heat shock protein 65 (hsp65) and a derived peptide, p277, are autoantigens reported in IDDM. I.p. injection of hsp65 reduced diabetes incidence in NOD mice and administration of p277 cured already diabetic mice. Also, intrathymic (i.t.) administration of whole islets or GAD65 prevented diabetes in NOD mice. The aim of this study was to evaluate whether i.t. injection of mycobacterial hsp65 or p277 can prevent diabetes in NOD mice. Three-week-old NOD female mice were injected intrathymically with 50 microg of hsp65 (n=30), 5 microg of p277 (n=30), and PBS (n=29). Diabetes incidence was observed for the following 300 days. Pancreas was then used for histological and immunohistological evaluation. No significant differences in diabetes incidence were observed among the three groups of mice. Interestingly, hsp65-treated mice developed diabetes slightly faster at 177+/-6 days compared to 202+/-8 days (p=0.015) for the p277-treated group and 197+/-7 days (p=0.033) for controls. The insulitis score and average islet size did not differ significantly among the three groups of diabetic mice. Scattered TCR-gamma/delta positive cells were found in the pancreas of all groups of mice. In contrast, a huge infiltrate of TCR-gamma/delta positive cells was detected in four out of eight (50%) p277-diabetic NOD mice. Thus, our data show an earlier onset of diabetes in hsp65-treated mice and no improvement in the incidence with either hsp65 or p277, suggesting that hsp65 acts in a different way from what was reported with GAD65. Caution is advised in future vaccination studies as hsp65 poses a potential danger.
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PMID:Effect of intrathymic administration of mycobacterial heat shock protein 65 and peptide p277 on the development of diabetes in NOD mice: caution required in vaccination studies. 983 5

Previous studies have shown that induction of autoimmune diabetes by adult thymectomy and split dose irradiation of PVG.RT1(u) rats can be prevented by their reconstitution with peripheral CD4(+)CD45RC-TCR-alpha/beta+RT6(+) cells and CD4(+)CD8(-) thymocytes from normal syngeneic donors. These data provide evidence for the role of regulatory T cells in the prevention of a tissue-specific autoimmune disease but the mode of action of these cells has not been reported previously. In this study, autoimmune thyroiditis was induced in PVG.RT1(c) rats using a similar protocol of thymectomy and irradiation. Although a cell-mediated mechanism has been implicated in the pathogenesis of diabetes in PVG.RT1(u) rats, development of thyroiditis is independent of CD8(+) T cells and is characterized by high titers of immunoglobulin (Ig)G1 antithyroglobulin antibodies, indicating a major humoral component in the pathogenesis of disease. As with autoimmune diabetes in PVG. RT1(u) rats, development of thyroiditis was prevented by the transfer of CD4(+)CD45RC- and CD4(+)CD8(-) thymocytes from normal donors but not by CD4(+)CD45RC+ peripheral T cells. We now show that transforming growth factor (TGF)-beta and interleukin (IL)-4 both play essential roles in the mechanism of this protection since administration of monoclonal antibodies that block the biological activity of either of these cytokines abrogates the protective effect of the donor cells in the recipient rats. The prevention of both diabetes and thyroiditis by CD4(+)CD45RC- peripheral cells and CD4(+)CD8(-) thymocytes therefore does not support the view that the mechanism of regulation involves a switch from a T helper cell type 1 (Th1) to a Th2-like response, but rather relies upon a specific suppression of the autoimmune responses involving TGF-beta and IL-4. The observation that the same two cytokines were implicated in the protective mechanism, whether thymocytes or peripheral cells were used to prevent autoimmunity, strongly suggests that the regulatory cells from both sources act in the same way and that the thymocytes are programmed in the periphery for their protective role. The implications of this result with respect to immunological homeostasis are discussed.
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PMID:Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes. 989 10

Insulin-dependent diabetes mellitus (IDDM) is not a disease of unbridled destruction. The autoimmune attack on pancreatic beta cells has two distinct stages - insulitis and diabetes - and progression of the former to the latter appears to be highly regulated. Identifying the factors controlling this transition has been difficult because it is a complex process that occurs non-universally and asynchronously. We have overcome these difficulties by coupling a simplified TCR transgenic (tg) model of IDDM and the immunosuppressive drug cyclophosphamide (CY). Young BDC2.5 TCR tg mice show insulitis but not diabetes; CY treatment provoked diabetes in 100% of animals with rapid, highly reproducible kinetics. This allowed a detailed temporal analysis of changes in cellular organization and cytokine gene expression within the lesion. The monokines IL-18, IL-12 and TNF-alpha were pivotal, their induction occurring almost immediately and their coordinate action being required for the onset of aggression. Other cytokines with direct toxicity for beta cells, including IL-1 -beta, IL-6 and IFN-gamma, were subsequently induced; in contrast, there was no cellular or molecular evidence of cell contact-mediated mechanisms of beta cell death.
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PMID:Cellular and molecular changes accompanying the progression from insulitis to diabetes. 993 6

Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cells are associated with pathogenesis leading to destruction of islet beta-cells and disease onset. Lymphocyte extravasation from blood into tissue is regulated by multiple adhesion receptor/counter-receptor pairs and chemokines. To identify events that regulate entry of CD4 cells into the pancreas, we transferred Th1 or Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells into immunodeficient (NOD.scid) recipients. Although both subsets infiltrated the pancreas and elicited multiple adhesion receptors (peripheral lymph node addressin, mucosal addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on vascular endothelium, entry/accumulation of Th1 cells was more rapid than that of Th2 cells, and only Th1 cells induced diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by the capacity to synthesize several chemokines that included lymphotactin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha, whereas both subsets produced macrophage inflammatory protein-1beta. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polarization of chemokine expression by Th1 vs Th2 cells, which, within the microenvironment of the pancreas, accounts for distinctive inflammatory infiltrates that determine whether insulin-producing beta-cells are protected or destroyed.
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PMID:Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. 1007 90

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