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)

The role of resveratrol and curcumin is well documented in cancer, inflammation, diabetes and various other diseases. However, their immunosuppressive action on T cells, B cells and macrophages is not well documented. In the present study, we have ascertained the effect of resveratrol and curcumin on T and B cells and macrophages. The most striking findings were that both resveratrol and curcumin suppressed the activity of T and B cells and macrophages, as evidenced by significant inhibition in proliferation, antibody production and lymphokine secretion. Interestingly, curcumin imparted immunosuppression by mainly down-regulating the expression of CD28 and CD80 and up-regulating CTLA-4. Resveratrol also functioned by decreasing the expression of CD28 and CD80, as well as by augmenting the production of interleukin (IL)-10.
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PMID:Resveratrol and curcumin suppress immune response through CD28/CTLA-4 and CD80 co-stimulatory pathway. 1717 75

Successful Ag activation of naive T helper cells requires at least two signals consisting of TCR and CD28 on the T cell interacting with MHC II and CD80/CD86, respectively, on APCs. Recent evidence demonstrates that a third signal consisting of proinflammatory cytokines and reactive oxygen species (ROS) produced by the innate immune response is important in arming the adaptive immune response. In an effort to curtail the generation of an Ag-specific T cell response, we targeted the synthesis of innate immune response signals to generate Ag-specific hyporesponsiveness. We have reported that modulation of redox balance with a catalytic antioxidant effectively inhibited the generation of third signal components from the innate immune response (TNF-alpha, IL-1beta, ROS). In this study, we demonstrate that innate immune-derived signals are necessary for adaptive immune effector function and disruption of these signals with in vivo CA treatment conferred Ag-specific hyporesponsiveness in BALB/c, NOD, DO11.10, and BDC-2.5 mice after immunization. Modulating redox balance led to decreased Ag-specific T cell proliferation and IFN-gamma synthesis by diminishing ROS production in the APC, which affected TNF-alpha levels produced by CD4(+) T cells and impairing effector function. These results demonstrate that altering redox status can be effective in T cell-mediated diseases such as autoimmune diabetes to generate Ag-specific immunosuppression because it inhibits the third signal necessary for CD4(+) T cells to transition from expansion to effector function.
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PMID:Disruption of innate-mediated proinflammatory cytokine and reactive oxygen species third signal leads to antigen-specific hyporesponsiveness. 1720 52

Chemokines and their receptors are part of polarized T helper 1 (Th1)- and Th2-mediated immune responses which control trafficking of immunogenic cells to sites of inflammation. The chemokine stromal cell-derived factor-1 CXCL-12 (SDF-1) and its ligand the CXCR4 chemokine receptor are important regulatory elements. CXCR4 is expressed on the surface of CD4(+) T cells, dendritic cells and B lymphocytes. Levels of CXCR4 mRNA were increased in pancreatic lymph nodes (PLNs) of 4-week-old non-obese diabetic (NOD) mice in comparison to Balb/C mice. However, a significant reduction of CXCR4 was noticed at 12 weeks both at the mRNA and protein levels while expression increased in the inflamed islets. The percentage of SDF-1 attracted splenocytes in a transwell chemotaxis assay was significantly increased in NOD versus Balb/c mice. SDF-1 attracted T cells completely abolished the capacity of diabetogenic T cells to transfer diabetes in the recipients of an adoptive cell co-transfer. When T splenocytes from NOD females treated with AMD3100, a specific CXCR4 antagonist, were mixed with diabetogenic T cells during adoptive cell co-transfer experiments, prevalence of diabetes in the recipients rose from 33% to 75% (P < 0.001). This effect was associated with an increase of interferon (IFN)-gamma mRNA and a reduction of interleukin (IL)-4 mRNA levels both in PLNs and isolated islets. AMD3100 also reduced IL-4 and IL-10 production of plate-bound anti-CD3 and anti-CD28-stimulated splenocytes. Immunofluorescence studies indicated that AMD3100 reduced the number of CXCR4(+) and SDF-1 positive cells in the inflamed islets. We can conclude that the CXCL-12/CXCR4 pathway has protective effects against autoimmune diabetes.
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PMID:The CXCR4/CXCL12 (SDF-1) signalling pathway protects non-obese diabetic mouse from autoimmune diabetes. 1737 36

The absence of B7-2-mediated costimulation protects NOD mice from the development of diabetes. Although the effects of B7-2 on T cell priming are well known, its impact on the function of APCs is not fully elucidated. We tested APC function and survival in mice lacking B7-2. A significant reduction in the phagocytic ability was observed in both splenic and pancreatic lymph node-associated dendritic cells (DCs) in B7-2 knockout (KO) mice. DCs from B7-2KO mice exhibited enhanced susceptibility to death, which was reflected by their reduced total cell numbers. Phenotypic analysis of APCs in B7-2KO mice revealed a significantly decreased proportion of CD8alpha+CD205+ DCs. Interestingly, an enhanced proportion of B7-H1+ and B7-DC+ DCs were observed in B7-2KO mice. Lastly, we found that B7-2 deficiency significantly diminished the PKC-epsilon response in APCs upon CD28-Ig stimulation. In conclusion our data suggests that B7-2 promotes the generation of a mature APC repertoire and promotes APC function and survival.
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PMID:B7-2 regulates survival, phenotype, and function of APCs. 1747 51

T cell activation is a complex process that requires a multitude of interactions between antigen-presenting cells (APC) and T cells. The primary signal is provided via the binding of the antigen (Ag) presented by the major histocompatibility complex (MHC) on an APC and the T cell receptor (TCR). This signal determines the specificity of the immune response but it is not sufficient to mount an effective antigen-specific immune response; co-signals are additionally required for that purpose. These co-signals are costimulatory pathways that can be either positive or negative and consequently determine the nature of the immune response. The B7-1/2/CD28 costimulatory axis is one of the most extensively studied positive signaling pathways, and it has been shown that this signal leads to a robust T cell activation, proliferation and survival. In this article we discuss the recently described PD-1/PD-L1/PD-L2 costimulatory axis, whose role in pancreatic autoimmunity is only just becoming more deeply understood. The blockade or deficiency of PD-1 leads to an exacerbation of diabetes, signifying that the role of PD-1 is to provide negative signals to T cells. On the other hand, the PD-1 ligand, PD-L1, has been shown to provide both positive and negative signals. The prediction of the existence of a non-PD-1 receptor on T cells capable of transmitting positive signals further adds to the complex nature of this costimulatory pathway.
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PMID:Costimulation and pancreatic autoimmunity: the PD-1/PD-L conundrum. 1749 6

Recent advances in human allogeneic islet transplantation have established beta-cell replacement therapy as a potentially viable treatment option for individuals afflicted with Type 1 diabetes. Two recent successes, one involving neonatal porcine islet xenografts transplanted into diabetic rhesus macaques treated with a costimulation blockade-based regimen and the other involving diabetic cynomolgus monkeys transplanted with adult porcine islet xenografts treated with an alternative multidrug immunosuppressive regimen have demonstrated the feasibility of porcine islet xenotransplantation in nonhuman primate models. In the current study, we assessed whether transplantation of adult porcine islet xenografts into pancreatectomized macaques, under the cover of a costimulation blockade-based immunosuppressive regimen (CD28 and CD154 blockade), could correct hyperglycemia. Our findings suggest that the adult porcine islets transplanted into rhesus macaques receiving a costimulation blockade-based regimen are not uniformly subject to hyperacute rejection, can engraft (2/5 recipients), and have the potential to provide sustained normoglycemia. These results provide further evidence to suggest that porcine islet xenotransplantation may be an attainable strategy to alleviate the islet supply crisis that is one of the principal obstacles to large-scale application of islet replacement therapy in the treatment of Type 1 diabetes.
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PMID:Engraftment of adult porcine islet xenografts in diabetic nonhuman primates through targeting of costimulation pathways. 1784 61

The induction of transplantation tolerance and the improvement of immune reconstitution after allogeneic bone marrow transplantation are the main research fields in the clinic organ transplantation and transplantation immunology. Over the past 5 years serial studies have been performed in our lab to induce robust transplantation tolerance by using combined strategies and improve the immune reconstitution of mice following allogeneic bone marrow transplantation by using gene-engineered bone marrow stromal cells. The results are encouraging. (1) The long-term survival of allografts was received by blockade of both CD28/B7 and CD40/CD40L or CD28/B7 and OX40/OX40L costimulation signals. In the case of blockade of both CD28/B7 and OX40/OX40L, the islet allograft survival was over 150 days compared to the control 14 days. (2) The CTLA4Ig-FasL fusion molecule expressed by adenoviral vector containing CTLA4Ig-FasL gene can prevent the autoimmune diabetes of mice and significantly prolong the survival time of cardiac allografts in rats, indicating that Fas-FasL-mediated apoptosis is able to enhance CTLA4Ig-induced transplantation tolerance. (3) In the time-window of peripheral tolerance induced by various methods, the systemic infusion of donor bone marrow cells and spleen cells obtained stable allogeneic mixed chimerism and robust transplantation tolerance. In the case of CTLA4Ig-FasL treatment combined with donor bone marrow cells more than 20% donor-origin blood cells chimerism, and more than 200 days prolonged skin allograft survival were obtained or received. (4) The murine bone marrow stromal cell line QXMSC1 transfected with IL-6 gene or IL-2+IL-3 genes significantly improved the immune reconstitution of mice following allogeneic bone marrow transplantation. Furthermore, It was observed that the mesenchymal stem cells transfected with IL-7 gene suppressed 90% of GVHD and expressed antileukemic effect, while accelerating immune reconstitution in mice following allogeneic bone marrow transplantation, which might be valuable in the clinic setting.
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PMID:[Studies on the induction of transplantation tolerance and immune reconstitution through combined strategies]. 1794 May 78

NOD.Idd3/5 congenic mice have insulin-dependent diabetes (Idd) regions on chromosomes 1 (Idd5) and 3 (Idd3) derived from the nondiabetic strains B10 and B6, respectively. NOD.Idd3/5 mice are almost completely protected from type 1 diabetes (T1D) but the genes within Idd3 and Idd5 responsible for the disease-altering phenotype have been only partially characterized. To test the hypothesis that candidate Idd genes can be identified by differential gene expression between activated CD4+ T cells from the diabetes-susceptible NOD strain and the diabetes-resistant NOD.Idd3/5 congenic strain, genome-wide microarray expression analysis was performed using an empirical Bayes method. Remarkably, 16 of the 20 most differentially expressed genes were located in the introgressed regions on chromosomes 1 and 3, validating our initial hypothesis. The two genes with the greatest differential RNA expression on chromosome 1 were those encoding decay-accelerating factor (DAF, also known as CD55) and acyl-coenzyme A dehydrogenase, long chain, which are located in the Idd5.4 and Idd5.3 regions, respectively. Neither gene has been implicated previously in the pathogenesis of T1D. In the case of DAF, differential expression of mRNA was extended to the protein level; NOD CD4+ T cells expressed higher levels of cell surface DAF compared with NOD.Idd3/5 CD4+ T cells following activation with anti-CD3 and -CD28. DAF up-regulation was IL-4 dependent and blocked under Th1 conditions. These results validate the approach of using congenic mice together with genome-wide analysis of tissue-specific gene expression to identify novel candidate genes in T1D.
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PMID:Genome-wide microarray expression analysis of CD4+ T Cells from nonobese diabetic congenic mice identifies Cd55 (Daf1) and Acadl as candidate genes for type 1 diabetes. 1817 47

There are many inhibitory mechanisms that function at the cellular and molecular levels to maintain tolerance. Despite this, self-reactive clones escape regulatory mechanisms and cause autoimmunity in certain circumstances. We hypothesized that the same mechanisms that permit T cells to expand during homeostatic proliferation may inadvertently promote autoimmunity under certain conditions. One major homeostatic cytokine is IL-7, and studies have linked it or its receptor to the development of multiple sclerosis and other autoimmune diseases. We show in a model of beta-islet cell self-reactivity that the transfer of activated autoreactive CD4 T cells can prime and expand endogenous autoreactive CD8 T cells in a CD28- and CD40-dependent manner through the licensing of dendritic cells. Despite this, mice do not develop diabetes. However, the provision of exogenous IL-7 or the physiological production of IL-7 associated with lymphopenia was able to profoundly promote the expansion of self-reactive clones even in the presence of regulatory T cells. Autoimmune diabetes rapidly ensued with CD4 help and the subsequent activation of CD8 T cells, which contributed to disease progression. With the advent of many biologicals targeting TNFalpha, IL-6, and IL-1 and their effective use in the treatment of autoimmune diseases, we propose that IL-7 and its receptor may be promising targets for biological agents in the treatment of autoimmunity.
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PMID:CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. 1828 17

Role of OX40 blockade was investigated in islet xenograft model in chemically diabetic C57B1/6 and spontaneously diabetic NOD mice. The effect of OX40/OX40L blockade on effector function of diabetogenic T cells was studied in an adoptive transfer model. 2000 IEQ of porcine islets were transplanted under the kidney capsule of diabetic C57B1/6 or NOD mice and were treated i.p. with control Ig, anti-OX40L, or CTLA4Ig. Graft survival was assessed using blood glucose (BG) measurement. Cells from diabetic NOD spleens and pancreatic lymphnodes were injected i.v. into NOD.scid mice. Recipients were treated i.p. with anti-OX40L, CTLA4Ig alone, or in combination; control mice received Ig. Diabetes incidence was assessed using BG measurement. Anti-OX40L treatment delayed xenoislet rejection significantly in chemically diabetic animals, although CTLA4Ig delayed rejection even further. Neither treatment completely prevented rejection. In spontaneously diabetic NOD mice, rejection of xenoislet graft was delayed by anti-OX40L treatment but not by CTLA4Ig. Anti-OX40L alone and in combination with CTLA4Ig significantly delayed diabetes transfer by activated diabetogenic T cells, compared with control and CTLA4Ig treatment. Preliminary mechanistic studies suggest that anti-OX40L treatment preserves Treg numbers, unlike CTLA4Ig that diminishes Tregs. Our studies show that OX40 blockade offers better xenoislet graft survival than CTLA4Ig in spontaneous autoimmune NOD model, suggesting that preactivated T cells use alternate costimulatory pathways, independent of CD28. Results from adoptive transfer studies further support the role of OX40 signaling in effector function of diabetogenic T cells. These data suggest that OX40/OX40L may offer novel therapeutic target for xenoislet graft protection in type 1 diabetic patients.
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PMID:Blockade of OX40 signals enhance survival of xenoislet grafts in spontaneously diabetic NOD mice. 1837 9


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