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

The active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is a potent immunomodulator known to affect T-cells through targeting antigen-presenting cells such as dendritic cells (DCs). We studied the effects of a novel nonhypercalcemic 1,25(OH)(2)D(3) analog, TX527, on DC differentiation, maturation, and function with respect to stimulation of a committed human GAD65-specific autoreactive T-cell clone. Continuous addition of TX527 impaired interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF)-driven DC differentiation as well as lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-induced maturation into Th1-promoting DC (DC1), as characterized by marked changes in DC morphology and abrogation of IL-12p70 release upon CD40 ligation. Addition of TX527 during maturation did not affect DC morphology but significantly changed DC cytokine profiles. The potential of treated DCs to alter the response pattern of committed autoreactive T-cells was found to depend on the timing of TX527 exposure. Continuously TX527-treated DCs significantly inhibited T-cell proliferation and blocked IFN-gamma, IL-10, but not IL-13 production, whereas DCs treated during maturation failed to inhibit T-cell proliferation but affected IL-10 and IFN-gamma production. Collectively, we provide evidence that nonhypercalcemic TX527 is a potent in vitro DC modulator, yielding DCs with the potential to change cytokine responses of committed autoreactive T-cells.
Diabetes 2002 Jul
PMID:Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). 1208 41

The autoimmune diabetes of the DRBB rat shares important similarities with autoimmune diabetes in humans. We have tested the ability of CD40/154 blockade using an anti-CD154 antibody (AH.F5) to prevent autoimmune diabetes in DRBB rats. The rats were treated with two intravenous doses/wk of AH.F5 (15mg/kg/dose) starting at 2-6wks of age. RT6.1 T-cell depletion and poly I/C was started at 4wks of age. Control rats developed diabetes within 25 days after start of depletion therapy. Six of 7, 11 of 13, 7 of 12, and 4 of 11 rats treated with AH.F5 did not develop diabetes when treatment was started at 2-3, 4, 5, and 6wks of age, respectively. The rats that did not develop diabetes were maintained for a minimum of 72 days to >150 days following the last dose of AH.F5. Eleven rats maintained for >150 days underwent an additional depletion and 5/11 developed diabetes within 8-19 days following start of depletion.Histological examination indicated that AH.F5 prevented and possibly reversed insulitis. Islets in about 50% of the treated rats remained free of inflammation following a second course of RT 6.1 T-cell depletion after the serum concentration of AH.F5 was negligible. In summary, CD40/154 blockade with AH.F5 prevents development of autoimmune diabetes if treatment is started prior to overt signs of beta cell destruction. The results indicate that the CD40/154 blockade can prevent diabetes by modifying the expansion or effector phase of the autoimmune diabetes.
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PMID:Prevention of autoimmune diabetes in the DRBB rat by CD40/154 blockade. 1241 84

Dendritic cells (DCs) not only induce but also modulate T cell activation. 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] induces DCs with a tolerogenic phenotype, characterized by decreased expression of CD40, CD80, and CD86 costimulatory molecules, low IL-12 and enhanced IL-10 secretion. We have found that a short treatment with 1,25(OH)(2)D(3) induces tolerance to fully mismatched mouse islet allografts that is stable to challenge with donor-type spleen cells and allows acceptance of donor-type vascularized heart grafts. This effect is enhanced by co-administration of mycophenolate mofetil (MMF), a selective inhibitor of T and B cell proliferation that has also effects similar to 1,25(OH)(2)D(3) on DCs. Graft acceptance is associated with an increased percentage of CD4(+)CD25(+) regulatory cells in the spleen and in the draining lymph node that can protect 100% of syngeneic recipients from islet allograft rejection. CD4(+)CD25(+) cells, able to inhibit the T cell response to a pancreatic autoantigen and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells, are also induced by treatment of adult nonobese diabetic (NOD) mice with 1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor vitamin D(3) (BXL-698). This treatment arrests progression of insulitis and Th1 cell infiltration, and inhibits diabetes development at non-hypercalcemic doses. The enhancement of CD4(+)CD25(+) regulatory T cells, able to mediate transplantation tolerance and to arrest type 1 diabetes development by a short oral treatment with VDR ligands, suggests possible clinical applications of this approach.
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PMID:Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. 1252 May 19

Our previous studies demonstrated that adoptive transfer of dendritic cells (DC) prevents diabetes in young nonobese diabetic (NOD) mice by inducing regulatory T(H)2 cells. In this report, as a means of treating NOD mice with more advanced insulitis, we infected DC with adenoviral vectors expressing interleukin (IL)-4 (Ad.IL-4), eGFP (Ad.eGFP), or empty vector (Ad psi 5). DC infected with any of the Ad vectors expressed higher levels of CD40, CD80, and CD86 molecules than uninfected DC and Ad.IL-4 DC produced IL-4 after lipopolysaccharide (LPS) and interferon (IFN)-gamma stimulation. Ad-infected DC efficiently stimulated allogeneic T cells, and cultures of T cells with Ad.IL-4 DC produced lower levels of IFN-gamma and marginally higher levels of IL-4. In vivo studies demonstrated that the Ad.eGFP DC trafficked to the pancreatic lymph nodes within 24 hr of intravenous administration, and could be visualized in the T cell areas of the spleen. The intrapancreatic IFN-gamma:IL-4 or IFN-gamma:IL-10 cytokine ratios were lower in 10-week-old mice treated with Ad.IL-4 DC, and these mice were significantly protected from disease. These results demonstrate, for the first time, that genetically modified DC can prevent diabetes in the context of advanced insulitis.
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PMID:Dendritic cells transduced to express interleukin-4 prevent diabetes in nonobese diabetic mice with advanced insulitis. 1257 55

Dendritic cells (DCs) not only induce but also modulate T cell activation. 1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] induces DCs with a tolerogenic phenotype, characterized by decreased expression of CD40, CD80, and CD86 co-stimulatory molecules, low IL-12, and enhanced IL-10 secretion. We have found that a short treatment with 1,25-(OH)(2)D(3) induces tolerance to fully mismatched mouse islet allografts, and that this tolerance is stable to challenge with donor-type spleen cells and allows acceptance of donor-type vascularized heart grafts. This effect is enhanced by co-administration of mycophenolate mofetil (MMF), a selective inhibitor of T and B cell proliferation, that also has effects similar to 1,25-(OH)(2)D(3) on DCs. Graft acceptance is associated with impaired development of type 1 CD4(+) and CD8(+) cells and an increased percentage of CD4(+)CD25(+) regulatory cells expressing CD152 in the spleen and in the draining lymph node. Transfer of CD4(+)CD25(+) cells from tolerant mice protects 100% of the syngeneic recipients from islet allograft rejection. CD4(+)CD25(+) cells that are able to inhibit the T cell response to a pancreatic autoantigen and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells are also induced by treatment of adult nonobese diabetic (NOD) mice with a selected vitamin D receptor (VDR) ligand. This treatment arrests progression of insulitis and Th1 cell infiltration, and inhibits diabetes development at non-hypercalcemic doses. The enhancement of CD4(+)CD25(+) regulatory T cells able to mediate transplantation tolerance and to arrest type 1 diabetes development by a short oral treatment with small organic compounds that induce tolerogenic DCs, like VDR ligands, suggests possible clinical applications of this approach.
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PMID:Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes. 1272 48

CD11c+/CD11b+dendritic cells (DC) with high levels of major histocompatibility complex (MHC) class II and co-stimulatory molecules have been derived from spleen cells cultured with granulocyte-macrophage colony stimulating factor (GM-CSF) + flt-3L + interleukin (IL)-6 (flt-3L-DC). Investigating in vivo the function of DC in non-obese diabetic mice (NOD), we showed that a single injection of this in vitro-derived subset of DC prevents the development of diabetes into prediabetic female mice. In contrast, DC derived from bone marrow cells cultured with GM-CSF + IL-4 [bone marrow (BM)-DC] induced no protection. Moreover, protection against diabetes following injection of flt-3L-DC was associated with IL-4 and IL-10 production in the spleen and the pancreatic lymph nodes of recipient mice, indicating that this DC population is able to polarize the immune response towards a Th2 pathway. As we shown previously, NOD BM-DC exhibit an enhanced capacity to produce IL-12p70 in response to lipopolysaccharide (LPS) and anti-CD40 stimulation compared to BM-DC from control mice. In contrast, NOD flt-3L-DC, as their control mouse counterpart, produced no IL-12p70 to these stimuli. Our findings show that a subset of DC, characterized by a mature phenotype and the absence of IL-12p70 production can be derived from NOD mouse spleen favouring IL-4 and IL-10 regulatory responses and protection from diabetes development.
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PMID:Passive transfer of flt-3L-derived dendritic cells delays diabetes development in NOD mice and associates with early production of interleukin (IL)-4 and IL-10 in the spleen of recipient mice. 1463 42

To investigate the regulatory effects of decoy receptor 3 (DcR3) on the differentiation and function of dendritic cells (DCs), bone marrow-derived DCs (BM-DCs) from nonobese diabetic (NOD) mice were cultured with recombinant DcR3.Fc protein. Their differentiating phenotypes and T cell-stimulating functions were then evaluated. Expression of CD11c, CD40, CD54, and major histocompatibility complex I-A(g7) was reduced in cells cultured with additional DcR3.Fc, compared with DCs incubated with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4, indicating that DcR3 interferes with the differentiation and maturation of BM-DCs. One of the most striking effects of DcR3.Fc on the differentiation of DCs was the up-regulation of CD86 and down-regulation of CD80, suggesting a modulatory potential to skew the T cell response toward the T helper cell type 2 (Th2) phenotype. Consistent with this, the proliferation of CD4(+) T cells cocultured with DcR3.Fc-treated DCs was significantly reduced compared with that of T cells stimulated by normal DCs. Moreover, the secretion of interferon-gamma from T cells cocultured with DcR3.Fc-treated DCs was profoundly suppressed, indicating that DcR3 exerts a Th1-suppressing effect on differentiating DCs. Furthermore, adoptive transfer experiments revealed that NOD/severe combined immunodeficiency mice received DcR3.Fc-treated DCs, and subsequently, autoreactive T cells showed delayed onset of diabetes and a decrease in diabetic severity compared with mice that received normal DCs and T cells, suggesting a future therapeutic potential in autoimmune diabetes. Data from two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight analysis show an up-regulation of some proteins-such as mitogen-activated protein kinase p38 beta, cyclin-dependent kinase 6, and signal-induced proliferation-associated gene 1-and a down-regulation of the IL-17 precursor; tumor necrosis factor-related apoptosis-inducing ligand family member-associated nuclear factor-kappaB activator-binding kinase 1; and Golgi S-nitroso-N-acetylpenicillamine in cells treated with DcR3, further demonstrating its effect on DC differentiation and function.
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PMID:Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication. 1463 66

Islet transplantation in children with autoimmune diabetes will require immunosuppression that has minimal toxicity and side-effects, and overcomes the barrier of autoimmunity. Since antibodies directed against the CD40/154 co-stimulatory pathway may meet these criteria, we have tested the ability of hamster antirat CD154 (AH.F5, Biogen) to prevent rejection of renal subcapsular islet allografts in streptozotocin (STZ) or autoimmune (AUTO) diabetic diabetes-resistant biobreeding (DRBB) rats. STZ diabetic rats that received anti-CD154 at 15 mg/kg per dose but not 10 mg/kg per dose did not have evidence of rejection until about 80-120 d post-transplantation, by which time antibody concentrations had returned to undetectable levels. Rats retreated with anti-CD154 before recurrence of diabetes had a prolonged period of disease-free survival. Most of these rats had recurrence following a spleen cell challenge. In contrast, AUTO diabetic DRBB rats treated with anti-CD154 had recurrence of diabetes between 7 and 12 d following transplantation of the Dark Agouti (DA) islets. In a separate set, AUTO diabetic rats that received a simultaneous islet isograft, islet allograft and thyroid allograft had focal accumulation of lymphocytes at the periphery of the isograft, while the islet and thyroid allografts had diffuse infiltration with lymphocytes and destruction of tissue with no residual staining for glucagon. Therefore, autoimmunity adds an additional barrier to islet allotransplantation that is not overcome with CD40/154 blockade in an animal model that closely parallels autoimmune diabetes in humans. The results indicate the importance of testing regimen of islet transplantation in animal models of autoimmune diabetes.
Pediatr Diabetes 2001 Dec
PMID:CD40/154 blockade and rejection of islet allografts in the streptozotocin and autoimmune diabetic rat. 1501 84

We have dissected the helper requirements for converting a tolerogenic CD8 T cell response into one capable of causing destruction of the pancreatic islets. Injection of naive OVA-specific CD8 T cells into transgenic mice expressing OVA in the pancreas only resulted in islet destruction when activated CD4 Th cells were coinjected. This requirement for activated CD4 T cell help for induction of primary CD8 T cell-mediated immunity to tissue Ags contrasts recent reports suggesting that help is only important for CTL memory. Our findings show that signaling of CD40 on the dendritic cell presenting to CD8 T cells is important, but not sufficient, for induction of diabetes. Furthermore, once helpers are activated, they need not recognize Ag on the dendritic cells they license. This provides insight into the helper requirements for adoptive transfer immunotherapy of tumors and suggests key points for inhibition of CTL-mediated autoimmunity.
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PMID:Helper requirements for generation of effector CTL to islet beta cell antigens. 1510 Feb 83

Type 1 diabetes results from the breakdown of peripheral tolerance. As regulators of T cell activation, antigen-presenting cells (APC) modulate peripheral tolerance and hence contribute to the immune dysregulation characteristic of insulin-dependent diabetes mellitus (IDDM). We initially observed an increased importance of NOD B cell APC function in a T cell priming assay as compared to non-autoimmune strains. Consistent with this increased APC function, we found that NF-kappa B nuclear translocation is increased in unmanipulated NOD and NOD.B10Sn-H2(b) B cells and that, in addition, NOD B cells are more sensitive to NF-kappa B-activating stimuli. We obtained similar results using NOD bone marrow-derived dendritic cell (BMDC) cultures. As costimulatory molecules have been shown to be NF-kappa B responsive, we examined the expression of these markers on NOD APC. Both B cells and BMDC expressed elevated levels of CD80 and CD40. Finally, NOD B cells provided better allostimulation than B cells from non-autoimmune strains. Therefore, hyperactivation of NF-kappa B and increased expression of CD80 and CD40 by NOD B cells and BMDC may be a contributing factor in the selection of effector T cells observed in IDDM.
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PMID:Increased NF-kappa B activity in B cells and bone marrow-derived dendritic cells from NOD mice. 1511 73


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