Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tolerance induction of autoreactive T cells against pancreatic beta cell-specific autoantigens such as glutamic acid decarboxylase 65 (GAD65) and insulin has been attempted as a method to prevent autoimmune diabetes. In this study, we investigate whether adenoassociated virus (AAV) gene delivery of multiple immunodominant epitopes expressing GAD(500-585) could induce potent immune tolerance and persistently suppress autoimmune diabetes in NOD mice. A single muscle injection of 7-wk-old female NOD mice with rAAV/GAD(500-585) (3 x 10(11) IU/mouse) quantitatively reduced pancreatic insulitis and efficiently prevented the development of overt type I diabetes. This prevention was marked by the inactivation of GAD(500-585)-responsive T lymphocytes, the enhanced GAD(500-585)-specific Th2 response (characterized by increased IL-4, IL-10 production, and decreased IFN-gamma production; especially elevated anti-GAD(500-585) IgG1 titer; and relatively unchanged anti-GAD(500-585) IgG2b titer), the increased secretion of TGF-beta, and the production of protective regulatory cells. Our studies also revealed that peptides 509-528, 570-585, and 554-546 in the region of GAD(500-585) played important roles in rAAV/GAD(500-585) immunization-induced immune tolerance. These data indicate that using AAV, a vector with advantage for therapeutic gene delivery, to transfer autoantigen peptide GAD(500-585), can induce immunological tolerance through active suppression of effector T cells and prevent type I diabetes in NOD mice.
 ...
PMID:Active tolerance induction and prevention of autoimmune diabetes by immunogene therapy using recombinant adenoassociated virus expressing glutamic acid decarboxylase 65 peptide GAD(500-585). 1581 72

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) has been identified as a novel CD8(+) T cell-specific autoantigen in NOD mice. This study was undertaken to identify MHC class II-specific CD4(+) T cell epitopes of IGRP. Peptides named P1, P2, P3, P4, P5, P6, and P7 were synthesized by aligning the IGRP protein amino acid sequence with peptide-binding motifs of the NOD MHC class II (I-A(g7)) molecule. Peptides P1, P2, P3, and P7 were immunogenic and induced both spontaneous and primed responses. IGRP peptides P1-, P2-, P3-, and P7-induced responses were inhibited by the addition of anti-MHC class II (I-A(g7)) Ab, confirming that the response is indeed I-A(g7) restricted. Experiments using purified CD4(+) and CD8(+) T cells from IGRP peptide-primed mice also showed a predominant CD4(+) T cell response with no significant activation of CD8(+) T cells. T cells from P1-, P3-, and P7-primed mice secreted both IFN-gamma and IL-10 cytokines, whereas P2-primed cells secreted only IFN-gamma. Peptides P3 and P7 prevented the development of spontaneous diabetes and delayed adoptive transfer of diabetes. Peptides P1 and P2 delayed the onset of diabetes in both these models. In summary, we have identified two I-A(g7)-restricted CD4(+) T cell epitopes of IGRP that can modulate and prevent the development of diabetes in NOD mice. These results provide the first evidence on the role of IGRP-specific, MHC class II-restricted CD4(+) T cells in disease protection and may help in the development of novel therapies for type 1 diabetes.
 ...
PMID:Identification of CD4+ T cell-specific epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein: a novel beta cell autoantigen in type 1 diabetes. 1584 27

A HLA-DR1 transgenic mouse (NOD/scid-DR1) was derived by breeding the existing B10.M/J-[Tg]DR1 mouse with the NOD/scid mouse. The intention was to enhance engraftment of human T cells by providing human class II elements in the tissues. Thymus and spleen fragments from adult NOD/scid-DR1 mice were transplanted under the syngeneic kidney capsules, followed by injection of human cord blood mononuclear cells (CBMNC) into transplanted tissues. FACS analyses showed that human T and B cells were consistently detected in the peripheral blood and spleen, of the chimeric mice. An average of 20% of human cells was found in the spleen and the engrafted thymus/spleen tissues. Furthermore, human cells from these tissues could proliferate with anti-human CD3 antibody and these mice could generate humoral and cellular responses to allogeneic human cells. Cytokines, such as IL-10, GMCSF, IFN-gamma, and TNF-alpha were also detected in the supernatants of the cultured human cells from the chimeric mice, when they were stimulated with allogeneic cells. Therefore, a novel mouse model with functional circulating human T and B cells was established that would facilitate the exploration of vaccine, the disease processes of autoimmunity, HIV infection, and human cancer.
 ...
PMID:Intra-thymic/splenic engraftment of human T cells in HLA-DR1 transgenic NOD/scid mice. 1592 19

Interleukin (IL)-10 has proven effective in various allogeneic transplantation models and for preventing recurrent autoimmune rejection of syngeneic islets in NOD mice. Therefore, we evaluated systemic IL-10 overexpression on allogeneic islet graft survival. Diabetic NOD mice received a single injection of recombinant adeno-associated virus (rAAV) serotype 2 encoding murine IL-10 (rAAV-IL-10) four weeks prior to renal subcasular islet transplantation. In a model having both autoimmune and allogeneic responses, IL-10 failed to protect C57BL/6 islets in spontaneously diabetic NOD mice. In an allograft model (C57BL/6 islets into young male streptozotocin-induced diabetic NOD mice), long-term (i.e., >169 days) islet survival was only seen in 2 of 14 rAAV-IL-10 treated mice. These failures occurred despite in vivo IL-10 production at transplant previously associated with protection of syngeneic islet grafts in NOD mice. Thus, IL-10 appears insufficient in protecting transplanted islet cells from allogeneic rejection and suggests important mechanistic variances between alloreactivity and autoimmunity in terms islet graft loss.
 ...
PMID:Systemic overexpression of interleukin-10 fails to protect allogeneic islet transplants in nonobese diabetic mice. 1612 29

NOD mice can be protected from transferred diabetes for long periods by short-term treatment with CD8 mabs. This protection has previously been shown to be thymus-dependent as thymectomised mice do not show the long-term protection observed in intact mice. In this study we show that the thymus is required only during antibody treatment as its removal thereafter does not affect protection. Recent thymic emigrants (RTEs) are not necessary for long-term tolerance induction and irradiation plays no part as anti-CD8 treatment cannot protect NOD.scid recipients from diabetes development. IL-10 is also shown to play an important role in the anti-CD8 induced protection in intact mice as it is reversed by IL-10R blockade.
 ...
PMID:Characterisation of CD8 monoclonal antibody-induced protection from diabetes in NOD mice. 1639 Aug 12

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is recognized as a major autoantigen for autoimmune type 1 diabetes (T1D) in the NOD mouse model. This study was undertaken to examine CD4+ T cell responses toward IGRP in human subjects. The tetramer-guided epitope mapping approach was used to identify IGRP-specific CD4+ T cell epitopes. IGRP(23-35) and IGRP(247-259) were identified as DRA1*0101/DRB1*0401-restricted epitopes. IGRP(13-25) and IGRP(226-238) were identified as DRA1*0101/DRB1*0301-restricted epitopes. IGRP-specific tetramers were used to evaluate the prevalence of IGRP-reactive T cells in healthy and T1D subjects. More than 80% of subjects with either DRB1*0401 or DRB1*0301 haplotype have IGRP-specific CD4+ T cell responses for at least one IGRP epitope. IGRP-specific T cells from both healthy and T1D groups produce both gamma-IFN and IL-10. DRA1*0101/DRB1*0401 IGRP(247-259)-restricted T cells also show cross-reactivity to an epitope derived from liver/kidney glucose-6-phosphatase. The detection of IGRP-reactive T cells in both type 1 diabetic subjects and healthy subjects and recent reports of other autoreactive T cells detected in healthy subjects underscore the prevalence of potentially autoreactive T cells in the peripheral immune system of the general population.
 ...
PMID:Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. 1649 34

This study aims to extend understanding of the relationship between TLR3-involved cell signaling and dsRNA-induced embryo resorption. Upon stimulation of dsRNA, the resorption rate of embryos was boosted dramatically in syngeneic mating BALB/c mice, but not significantly influenced in syngeneic mating NOD/SCID mice. Accordingly, there was an enhanced cell surface expression of TLR3 on placental CD45(+) cells derived from BALB/c mice, concomitant with both increased percentages of CD45(+)CD80(+) cells and CD8alpha(+)CD80(+) cells in flow cytometric analysis. In addition, both increased IL-2 and decreased IL-10 expression could be observed in CD45(+) cell group in the intracellular detection by flow cytometry. In contrast, no such trends were observed in NOD/SCID model, and its resorption rate of embryos was kept at a low level throughout pregnancy. Neutralizing Abs against TLR3 could abrogate the embryo rejection induced by dsRNA in BALB/c mice, and simultaneously could reduce the CD80(+) percentage in the CD45(+) cell group. These results indicate that the interaction between dsRNA and TLR3 may be involved in the mobilization of CD45(+)CD80(+) and CD8alpha(+)CD80(+) cells, followed by the up-regulation of IL-2 and down-regulation of IL-10 expression at the feto-maternal interface, and finally resulting in embryo rejection. The relatively low responsiveness of NOD/SCID mice may be one of the reasons why these mice appeared to be resistant to dsRNA-induced embryo resorption.
 ...
PMID:TLR3-involved modulation of pregnancy tolerance in double-stranded RNA-stimulated NOD/SCID mice. 1654 51

Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.
 ...
PMID:Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. 1669 71

Interleukin (IL)-10 is a potent anti-inflammatory cytokine and ablation of IL-10 exacerbates Th1-type autoimmune diseases. Even though type 1 diabetes (T1D) in NOD mice is believed to be Th1-mediated, the incidence and severity of T1D is unaltered in IL-10-deficient NOD mice raised under pathogen-free conditions. We describe for the first time, the outcome of IL-10 deficiency on islet and other organ-specific autoimmunity in NOD mice raised in a conventional facility. IL-10-deficient NOD mice under such conditions were protected from spontaneous as well as cyclophosphamide-induced diabetes, but were susceptible to diabetes induced by adoptive transfer of splenocytes from spontaneously diabetic NOD mice. Whereas the incidence of rectal prolapse was very high in this NOD.IL-10(-/-) mouse colony, IL-10-deficient C57Bl/6 mice raised under similar conditions seldom developed rectal prolapse. While injection of complete Freund's adjuvant (CFA) significantly reduced insulitis, it did not ameliorate colitis in IL-10-deficient NOD mice indicating differential regulation of organ-specific autoimmunity by CFA. Phenotypic characterization of IL-10(-/-) mice revealed a significant increase in splenic macrophage numbers in NOD but not on the B6 background. This was accompanied by a heightened systemic inflammatory cytokine response and mortality following in vivo challenge with a toll-like receptor 9 agonist, CpG-containing DNA.
 ...
PMID:IL-10-deficiency unmasks unique immune system defects and reveals differential regulation of organ-specific autoimmunity in non-obese diabetic mice. 1674 Mar 91

Functional polarization of T helper (Th) subsets of lymphocytes has been implicated in promoting or conferring risk to Type 1 diabetes mellitus (T1DM) development in human and diabetic animal models. It is assumed that an immoderate preponderance of type 1 immunity establishes the prerequisite for this development. Over the past years, various immune-intervention strategies have been tested to protect diabetic animals from developing overt diabetes. These protocols implicate a protective mechanism that is attributed to a change in the set of autoreactive Th cells from their Th1 to the Th2 phenotype. The studies were aimed at improving the effectiveness of Th2 cells to secrete the principal cytokines, IL-4 and IL-10, in order to mediate protection from diabetes in NOD mice. In contrast, some immune-modulation protocols utilizing non-specific reagents report that diabetes protection is apparently attributed to preferential survival of both Th1 and Th2 cells, rather than via a shift from their Th1 to Th2 phenotypes. Even though we know that excessive immune responses against self antigens are also controlled and terminated by regulatory T cells, this article focuses on the polarization of Th effector cells and discusses the controversial findings regarding the Th1/Th2 hypothesis to draw a conclusion on its relevance in T1DM from the existing knowledge.
 ...
PMID:Imbalance in Th cell polarization and its relevance in type 1 diabetes mellitus. 1749 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>