Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several peripheral mechanisms appear to be operational in limiting autoimmune damage of the islets of Langerhans and organ-specific T cell-mediated autoimmunity in general. These include cyclophosphamide sensitive T regulatory cells (Treg cells) and Th2 derived cytokine downregulation. We used the model of multiple low doses of streptozotocin (MLD-STZ) induced diabetes in susceptible C57BL/6 mice and resistant BALB/c mice to study these regulatory mechanisms. We show that low dose cyclophosphamide (CY) sensitive CD4(+)CD25(+)FoxP3(+) Treg cell-dependent mechanisms can be demonstrated in C57Bl/6 mice susceptible to MLD-STZ diabetes induction. CY pretreatment decreased Foxp3(+) cell count, glycemia, glycosuria and insulitis. In contrast, CY did not overcome resistance to diabetes induction in BALB/c mice. However, in BALB/c mice, deletion of ST2, an orphan member of the IL-1R family responsible for Th2 cell signaling leads to enhanced susceptibility to diabetes induction as evaluated by level of glycemia and glycosuria, number of infiltrating cells and beta cell loss. RT-PCR analysis of mRNA transcripts of diabetogenic cytokines revealed that the expression of TNF-alpha, and IFN-gamma was significantly enhanced in pancreatic lymph nodes by day 10 after diabetes induction in ST2-deficient mice in comparison with wild type BALB/c mice while IL-17 was detected only in ST2(-/-) mice by day 21. Our results are compatible with the notion that Treg cells are involved in MLD-STZ diabetes in susceptible mice and demonstrate that ST2-mediated signaling may also be involved in limiting Th1/Th17-mediated autoimmune pathology in diabetes resistant strain.
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PMID:Regulatory T cells and ST2 signaling control diabetes induction with multiple low doses of streptozotocin. 1935 1

Dopamine receptors have five isoforms, termed D1-D5. The D1 and D5 receptors form the D1-like group that couples with the Galphas class of G proteins, while D2, D3 and D4 form the D2-like group that couples with the Galphai class of G proteins. In our previous studies, a D1-like-R antagonist, SCH23390, inhibited DC-mediated Th17 differentiation and exhibited preventive and therapeutic effects on experimental autoimmune encephalomyelitis (EAE) in mice. We herein demonstrate in the current study that in the pancreas obtained from NOD mice, islet infiltrates appear to be composed of mononuclear cells positive for IL-23R, one of the specific markers for Th17. Thereafter, NOD mice were orally administered SCH23390 from week 6 to week 26. At week 26, 67% and 25% of mice developed diabetes in the control and the SCH23390 groups, respectively (p<0.05). A histological examination of SCH23390-treated mice exhibited a typical normal islet structure with no signs of periductal and perivascular infiltrates, whereas the islets from vehicle controls showed insulitis. In week 26, spleen cells were re-stimulated with anti-CD3 and anti-CD28 antibodies in vitro and exhibited an augmentation of IFNgamma induction and the suppression of IL-17 induction in the SCH23390-treated mice. These findings indicate that antagonizing D1-like-R suppresses IL-17 expression, thereby leading to a decreased occurrence of NOD.
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PMID:Dopamine D1-like receptor antagonist, SCH23390, exhibits a preventive effect on diabetes mellitus that occurs naturally in NOD mice. 1937 25

IL-17-producing CD8(+) T cells (Tc17) appear to play a role in a range of conditions, such as autoimmunity and cancer. Thus far, Tc17 cells have been only marginally studied, resulting in a paucity of data on their biology and function. We demonstrate that Tc17 and Th17 cells share similar developmental characteristics, including the previously unknown promoting effect of IL-21 on Tc17 cell differentiation and IL-23-dependent expression of IL-22. Both STAT1 and STAT4 are required for optimal development of Tc17 cells and maximal secretion of cytokines. Tc17 cells are cytotoxic, and they can be either pathogenic or nonpathogenic upon adoptive transfer in the model of autoimmune diabetes. Tc17 cells treated with TGF-beta1 plus IL-6 are not diabetogenic, whereas IL-23-treated cells potently induce the disease. IL-17A and IL-17F are necessary but not sufficient for diabetes induction by Tc17 cells. Tc17 cells treated with TGF-beta1 plus IL-6 or IL-23 likely differ in pathogenicity due to their disparate capacity to attract other immune cells and initiate inflammation.
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PMID:IL-23 drives pathogenic IL-17-producing CD8+ T cells. 1938 Jul 76

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-gamma, TNF-alpha, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN-gamma and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.
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PMID:Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. 1949 26

Glutamic acid decarboxylase 65 (GAD) and proinsulin are major diabetes-associated autoantigens that drive autoreactive T cells. Altered peptide ligands (APL) have been proposed as reagents for the modification of autoimmune reactions. Here, we have prepared GAD-derived protease-resistant APL (prAPL) by cleavage site-directed modification. The resulting prAPL are resistant to lysosomal and serum proteases, bind with high-affinity to HLA-DRB1(*)0401 and have a prolonged half-life in the serum. GAD-derived prAPL significantly decreased the secretion of proinflammatory cytokines by a GAD-specific human T cell clone. Likewise, the production of IL-17, TNF-alpha, and secretion of IL-6 by peripheral blood lymphocytes from patients with type 1 diabetes mellitus (T1D) was reduced, when stimulated with both GAD and GAD-derived prAPL. Thus, prAPL with high affinity for HLA-DRB1(*)0401 mitigate the response of GAD-reactive human Th17 cells. The strategy of designing specific immunomodulatory protease-resistant altered peptide ligands provides the basis for novel avenues of therapeutic intervention.
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PMID:Protease-resistant human GAD-derived altered peptide ligands decrease TNF-alpha and IL-17 production in peripheral blood cells from patients with type 1 diabetes mellitus. 1950 24

Cordyceps sinensis (CS) is a parasitic fungus, and it has been used widely in traditional Chinese medicines (TCM) for centuries. Many studies have shown that CS has immunoregulatory activity in many disease models, but the underlying mechanism remains elusive. We studied whether CS could suppress the onset of diabetes by altering T lymphocyte subsets in non-obese diabetic (NOD) mice. We found that the onset of type 1 diabetes in NOD mice was associated with an imbalance of CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells and IL-17 producing Th17 cells. Oral administration of CS resulted in reduction in the overall incidence of diabetes, and this was due to an increase in the ratio of Treg cells to Th17 in the spleen and pancreatic lymph nodes (PLNs). Taken together, these data imply that CS is able to modulate Treg to Th17 cell ratio in vivo, thus contributing to the inhibition of diabetes.
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PMID:Immunoregulatory Cordyceps sinensis increases regulatory T cells to Th17 cell ratio and delays diabetes in NOD mice. 1955 79

Whether interleukin (IL)-17 promotes a diabetogenic response remains unclear. Here we examined the effects of neutralization of IL-17 on the progress of adoptively transferred diabetes. IL-17-producing cells in non-obese diabetic (NOD) mice were identified and their role in the pathogenesis of diabetes examined using transfer and co-transfer assays. Unexpectedly, we found that in vivo neutralization of IL-17 did not protect NOD-severe combined immunodeficiency (SCID) mice against diabetes transferred by diabetic splenocytes. In NOD mice, gammadelta(+) T cells were dominated by IL-17-producing cells and were found to be the major source of IL-17. Interestingly, these IL-17-producing gammadelta T cells did not exacerbate diabetes in an adoptive transfer model, but had a regulatory effect, protecting NOD mice from diabetes by up-regulating transforming growth factor (TGF)-beta production. Our data suggest that the presence of IL-17 did not increase the chance of the development of diabetes; gammadelta T cells protected NOD mice from diabetes in a TGF-beta-dependent manner, irrespective of their role as major IL-17 producers.
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PMID:Interleukin-17-producing gammadelta+ T cells protect NOD mice from type 1 diabetes through a mechanism involving transforming growth factor-beta. 1982 17

BACKGROUND.: Oleanolic acid (OA) is a ubiquitous triterpenoid, with potent antioxidant and anti-inflammatory properties. Here, we tested whether these combined properties of OA can prevent nonimmunologic primary nonfunctioning and immunologic phenomena ascribed to graft rejection hence prolong islet allograft survival. METHODS.: Islet transplants were performed under kidney capsule of streptozotocin-induced diabetic C57BL/6 mice with BALB/c islets. Recipients were treated with 0.5 mg/day of OA intraperitoneally, and serum samples were collected once in 2 days and used for luminex, ELISA, and donor-specific antibody screening. Transplanted mice were killed at different time intervals to obtain splenocytes and kidney samples for ELISPOT, mixed leukocyte reaction, and immunohistochemical studies. RESULTS.: After transplantation, the decrement of blood glucose was significantly faster in mice receiving OA less than 2+/-1 days compared with untreated (4+/-2 days). OA prolonged survival of transplanted islets up to 23+/-3 days and reversed diabetes even with 250 islets. Treatment group showed increased serum interleukin (IL)-10 (twofold) and decreased inducible protein-10 and IL-4 (threefold) in luminex. Significantly reduced frequency of interferon-gamma (4.5-fold), IL-4 (3.5-fold), IL-2 (2.3-fold), and IL-17 (fourfold) producing T-cell populations were found in ELISPOT. OA-treated grafts had significant reduced and delayed infiltration of CD4+ and CD8+ T cells. OA also delayed donor-specific antibody generation up to 19 days after transplantation. Combined treatment with cyclosporine A, OA further prolonged the islet allograft survival to 34+/-3 days. CONCLUSIONS.: In conclusion, OA is an attractive, dietary nontoxic plant triterpenoid, which suppresses the production of proinflammatory cytokines and delays graft-specific immune responses to prolong islet allograft survival.
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PMID:Oleanolic Acid, a plant triterpenoid, significantly improves survival and function of islet allograft. 1985 44

The impact of several environmental and genetic factors on diabetes and its complications is well documented. The present study was aimed to examine the serum levels of IL-17A and IFN-gamma as antagonistic cytokines in nephropathic and non-nephropathic type-2 diabetic patients. In this experimental study, serum samples were obtained from 180 type-2 diabetic patients, 100 nephropathic type-2 diabetic patients and 100 healthy controls. Serum levels of IL-17A and IFN-gamma was detected by ELISA. Results of this study showed that the serum level of IFN-gamma was higher in both diabetic patients (nephropathic and non-nephropathic) in comparison to the controls. In terms of IL-17A, while non-nephropathic type-2 diabetic patients showed an increased serum level of it, the other patients group had a lower serum level. Based on these findings, it can be concluded that the lower serum level of IL-17A is possibly associated with nephropathic complications of type-2 diabetes.
Diabetes Res Clin Pract 2010 Jan
PMID:Nephropathic complication of type-2 diabetes is following pattern of autoimmune diseases? 2053 45

The precise pathomechanisms of human autoimmune diseases are still poorly understood. However, a deepened understanding of these is urgently needed to improve disease prevention and early detection and guide more specific treatment approaches. In recent years, many new genes and signalling pathways involved in autoimmunity with often overlapping patterns between different disease entities have been detected. Major contributions were made by experiments using DNA microarray technology, which has been used for the analysis of gene expression patterns in chronic inflammatory and autoimmune diseases, among which were rheumatoid arthritis, systemic lupus erythematosus, psoriasis, systemic sclerosis, multiple sclerosis, and type-1 diabetes. In systemic lupus erythematosus, a so-called interferon signature has been identified. In psoriasis, researchers found a particular immune signalling cluster. Moreover the identification of a new subset of inflammatory T cells, so-called Th17 T cells, secreting interleukin (IL)-17 as one of their major cytokines and the identification of the IL-23/IL-17 axis of inflammation regulation, have significantly improved our understanding of autoimmune diseases. Since a plethora of new treatment approaches using antibodies or small molecule inhibitors specifically targeting cytokines, cellular receptors, or signalling mechanisms has emerged in recent years, more individualized treatment for affected patients may be within reach in the future.
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PMID:Cytokines and cytokine profiles in human autoimmune diseases and animal models of autoimmunity. 1988 85


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