Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prior to the development of type 1 diabetes, T cells are primed in the pancreatic lymph nodes (PLN) where they interact with APC displaying beta cell-derived peptides. The details concerning the regulation of autoreactive T cell responses in the PLN are unclear. BDC2.5/B6g7 TCR transgenic mice represent a simplified model of type 1 diabetes, in which beta cell-specific CD4+ T cells expressing a diabetogenic transgenic TCR are first activated in the PLN and subsequently home to the pancreas where they mediate killing of beta cells. DNAX-activating protein of 12 kDa (DAP12) is an adaptor molecule carrying an ITAM motif. It associates with receptors on lymphoid and myeloid cells, including APC. We here show that introduction of a DAP12 null mutation in BDC2.5/B6g7 mice accelerated diabetes development and promoted an augmented activation state of PLN T cells expressing the transgenic TCR. Transferred BDC2.5 T cells proliferated more efficiently in the PLN of DAP12-deficient B6g7 recipients, which correlated with a decreased impact of co-transferred BDC2.5+CD4+CD25+ T cells. We propose that signaling through a DAP12-associated receptor on APC facilitates activation of Treg in the PLN and by this contributes to the maintenance of peripheral tolerance to beta cell-derived antigens.
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PMID:Increased diabetes development and decreased function of CD4+CD25+ Treg in the absence of a functional DAP12 adaptor protein. 1892 76

Drak2 is a serine/threonine kinase expressed in T and B cells. The absence of Drak2 renders T cells hypersensitive to suboptimal stimulation, yet Drak2(-/-) mice are enigmatically resistant to experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. We show in this study that Drak2(-/-) mice were also completely resistant to type 1 diabetes when bred to the NOD strain of mice that spontaneously develop autoimmune diabetes. However, there was not a generalized suppression of the immune system, because Drak2(-/-) mice remained susceptible to other models of autoimmunity. Adoptive transfer experiments revealed that resistance to disease was intrinsic to the T cells and was due to a loss of T cell survival under conditions of chronic autoimmune stimulation. Importantly, the absence of Drak2 did not alter the survival of naive T cells, memory T cells, or T cells responding to an acute viral infection. These experiments reveal a distinction between the immune response to persistent self-encoded molecules and transiently present infectious agents. We present a model whereby T cell survival depends on a balance of TCR and costimulatory signals to explain how the absence of Drak2 affects autoimmune disease without generalized suppression of the immune system.
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PMID:Drak2 regulates the survival of activated T cells and is required for organ-specific autoimmune disease. 1901 48

Steady-state cell apoptosis plays an important role in maintenance of self-tolerance. Based on this notion, the use of apoptotic cells to restore self-tolerance to beta cell antigens is a rational approach to type 1 diabetes (T1D) prevention. Our previous study demonstrated that transfusion of apoptotic beta cells induced immune tolerance to beta cell antigens in NOD mice. However, concerned about the limited beta cell source for future clinical applications, we attempted in the present study to develop a more practical approach for T1D prevention using apoptotic non-beta cells. We found that UVB-irradiation-induced apoptotic NOD splenic stromal cells significantly suppressed beta cell antigen-specific T cell proliferation in vitro and in vivo. Furthermore, TCR-transgenic CD4(+) T cells primed by the antigens to which they were specific in the presence of UVB-irradiated stromal cells were rendered unresponsive to the antigen restimulation, a result that was partially attributed to the induced IL-10-producing regulatory T cells. Of more interest, transfusion of UVB-irradiated stromal cells appeared to induce beta cell antigen-responding IL-10-producing regulatory T cells in vivo. Most importantly, transfusion of UVB-irradiated stromal cells effectively prevented T1D in NOD mice, which is consistent with these findings. This study suggests that it is possible to use apoptotic non-beta cells such as peripheral blood mononuclear cells to induce beta cell antigen-specific tolerance, thereby preventing T1D in humans.
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PMID:Apoptotic non-beta cells suppress beta cell antigen-reactive T cells and induce beta cell antigen-specific regulatory T cells. 1912 Feb 88

CD4(+)CD25(+)FOXP3(+) Treg cells require TCR engagement for suppressive function, thus ensuring that suppression occurs only in the presence of specific antigens; however, to date no studies have addressed the function of self-antigen-specific Treg in humans. These studies were designed to determine whether peripheral generation and function of islet antigen-specific adaptive Treg are defective in human subjects with type 1 diabetes (T1D). Islet antigen-specific adaptive Treg were induced in vitro by activation of CD4(+)FOXP3(-) T cells with glutamic acid decarboxylase and islet-specific glucose-6-phosphate catalytic subunit-related protein peptides in the context of T1D-associated HLA-DRbeta alleles. Antigen-specific Treg were characterized using flow cytometry for FOXP3 and class II tetramer and assessed for the ability to inhibit proliferation. These adaptive Treg were then compared with influenza-specific Treg from the same study population. The function of tetramer(+) cells that expressed FOXP3 was similar for both influenza and islet antigens generated from control and T1D subjects. In fact, the potency of suppression correlated with FOXP3 expression, not antigen specificity. Thus, these data suggest that development of functional adaptive Treg can occur in response to islet antigens and activation of islet-specific Treg may potentially be used as a targeted immunotherapy in T1D.
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PMID:Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects. 1918 Apr 73

Mouse antithymocyte globulin (mATG) prevents, as well as reverses, type 1 diabetes in NOD mice, through mechanisms involving modulation of the immunoregulatory activities of T lymphocytes. Dendritic cells (DC) play a pivotal role in the generation of T cell responses, including those relevant to the autoreactive T cells enabling type 1 diabetes. As Abs against DC are likely generated during production of mATG, we examined the impact of this preparation on the phenotype and function of DC to elucidate novel mechanisms underlying its beneficial activities. In vivo, mATG treatment transiently induced the trafficking of mature CD8(-) predominant DC into the pancreatic lymph node of NOD mice. Splenic DC from mATG-treated mice also exhibited a more mature phenotype characterized by reduced CD8 expression and increased IL-10 production. The resultant DC possessed a potent capacity to induce Th2 responses when cultured ex vivo with diabetogenic CD4(+) T cells obtained from BDC2.5 TCR transgenic mice. Cotransfer of these Th2-deviated CD4(+) T cells with splenic cells from newly diabetic NOD mice into NOD.RAG(-/-) mice significantly delayed the onset of diabetes. These studies suggest the alteration of DC profile and function by mATG may skew the Th1/Th2 balance in vivo and through such actions, represent an additional novel mechanism by which this agent provides its beneficial activities.
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PMID:Rabbit polyclonal mouse antithymocyte globulin administration alters dendritic cell profile and function in NOD mice to suppress diabetogenic responses. 1934 35

Congenic DRF.(f/f) rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF.(f/f) rat line, DRF.(f/f) rats were crossed to inbred BBDR or DR.(lyp/lyp) rats to generate congenic sublines that were genotyped and monitored for T1D, and positional candidate genes were sequenced. All (100%) DR.(lyp/lyp) rats developed T1D by 83 days of age. Reduction of the DRF.(f/f) F344 DNA fragment by 26 Mb (42.52-68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41-70.17 Mb) (region 1) resulted in 47% protection and significantly delayed onset (P < 0.001 compared with DR.(lyp/lyp)). Retaining <1 Mb of F344 DNA at the distal end (76.49-76.83 Mb) (region 2) resulted in 28% protection and also delayed onset (P < 0.001 compared with DR.(lyp/lyp)). Comparative analysis of diabetes frequency in the DRF.(f/f) congenic sublines further refined the RNO4 region 1 interval to approximately 670 kb and region 2 to the 340 kb proximal to gimap5. All congenic DRF.(f/f) sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels, but <20% of islets in nondiabetic rats showed islet infiltration. Coding sequence analysis revealed TCR Vbeta 8E, 12, and 13 as candidate genes in region 1 and znf467 and atp6v0e2 as candidate genes in region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4.
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PMID:Genetic dissection reveals diabetes loci proximal to the gimap5 lymphopenia gene. 1935 9

Islet specific CD4 cells expressing inhibitory receptors may be a useful therapeutic tool for treating type 1 diabetes (T1D). Engagement of transgenic Ly49A inhibits CD4 cell activation and delays onset of T1D in mice. However, in vitro studies suggest the inhibitory effect of Ly49A is incomplete. Here we report that following simultaneous TCR and Ly49A engagement, phosphorylation of Zap70, Erk1/2 and c-Jun were significantly diminished. Kinetic studies indicated that Ly49A did not simply delay activation but had a long-lasting effect. In contrast, when only costimulatory signals were provided through CD28, Ly49A engagement did not block p38 MapK or Akt phosphorylation. Likewise, expression of the downstream targets Bcl-xl and Baff were unaffected. Together these data suggest that engagement of Ly49A selectively inhibits signals downstream of the TCR but spares those unique to CD28. These results suggest that when considering its use as an immunotherapy, the potency of inhibitory receptors such as Ly49A may be further improved by pairing them with costimulatory blockade.
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PMID:Engagement of transgenic Ly49A inhibits mouse CD4 cell activation by disrupting T cell receptor, but not CD28, signaling. 1936 13

Treg can suppress autoimmune diseases such as type 1 diabetes, but their in vivo activity during suppression remains poorly characterized. In type 1 diabetes, Treg activity has been demonstrated in the pancreatic lymph node, but little has been studied in the pancreas, the site of autoimmune islet destruction. In this study we induced islet-specific Treg from the BDC-6.9 TCR transgenic mouse by activation of T cells in the presence of TGF-beta. These Treg can suppress spontaneous diabetes as well as transfer of diabetes into NOD.scid mice by diabetic NOD spleen cells or activated BDC-2.5 TCR transgenic Th1 effector T cells. In the latter transfer model, we observed infiltration of the pancreas by both effector T cells and Treg, suggesting that Treg are active in the inflammatory site and are not just restricted to the draining lymph node. Within the pancreas, we demonstrate that Treg transfer causes a reduction in the number of effector Th1 T cells and macrophages, and also inhibits effector T-cell cytokine and chemokine production. Although we found no role for TGF-beta in vitro, transfection of effector T cells with a dominant-negative TGF-beta receptor demonstrated that in vivo suppression of diabetes by TGF-beta-induced Treg is TGF-beta-dependent.
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PMID:Regulatory T cells enter the pancreas during suppression of type 1 diabetes and inhibit effector T cells and macrophages in a TGF-beta-dependent manner. 1940 82

The activation threshold for antigen-specific T cell responses is dependent on the avidity of the trimolecular interaction between TCR, antigen, and MHC. We compared CD4+ T cell avidities for the diabetes-associated autoantigen glutamic acid decarboxylase 555-567 (GAD 555) among serial samples from autoantibody-positive subjects at high risk of progression to type 1 diabetes (T1D). T cells from three at-risk subjects demonstrated significant avidity increases (p<0.05 by F test) over time. This avidity shift correlated with the outgrowth of T cells expressing TCR BV 9, 15, 17 or 20 that demonstrated higher GAD 555 tetramer-binding levels compared to cells expressing other TCR BV genes. Similar analysis of autoantibody-negative, first-degree relatives and T1D patients did not demonstrate similar changes in avidity. These data implicate the outgrowth of T cells expressing higher affinity TCR in a process of antigen-specific T cell avidity maturation during the pre-clinical stage of T1D.
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PMID:Changes in autoreactive T cell avidity during type 1 diabetes development. 1948 55

The NOD mouse is a well characterized model of type 1 diabetes that shares several of the characteristics of Ets1-deficient targeted mutant mice, viz: defects in TCR allelic exclusion, susceptibility to a lupus like disease characterized by IgM and IgG autoantibodies and immune complex-mediated glomerulonephritis, and deficiencies of NK and NKT cells. Here, we sought evidence for allelic variation of Ets1 in mice contributing to the NK and NKT cell phenotypes of the NOD strain. ETS1 expression in NK and NKT cells was reduced in NOD mice, compared to C57BL/6 mice. Although NKT cells numbers were significantly correlated with ETS1 expression in both strains, NKT cell numbers were not linked to the Ets1 gene in a first backcross from NOD to C57BL/6 mice. These results indicate that allelic variation of Ets1 did not contribute to variation in NKT cell numbers in these mice. It remains possible that a third factor not linked to the Ets1 locus controls both ETS1 expression and subsequently NK and NKT cell phenotypes.
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PMID:Allelic variation of Ets1 does not contribute to NK and NKT cell deficiencies in type 1 diabetes susceptible NOD mice. 1980 40


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