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)

Transgenic mice whose pancreata express transforming growth factor-beta (TGF-beta) directed by an insulin promoter (Ins-TGF-beta mice) were used to assess the effect of local TGF-beta1 on allograft rejection and on autoimmune diabetes occurring as a cross-reaction to viral antigens. Pancreatic TGF-beta1 did not delay allograft rejection, nor did it inhibit autoimmune diabetes after lymphocytic choriomeningitis infection of double transgenic mice (LCMV/TGF-beta1 mice). These results suggest that local TGF-beta1 does not serve as an immunosuppressive agent for allograft rejection or virus-mediated autoimmune diabetes.
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PMID:Transforming growth factor-beta fails to inhibit allograft rejection or virus-induced autoimmune diabetes in transgenic mice. 862 95

It is widely accepted that T cells play an important role in the destruction of beta cells leading to autoimmune type I diabetes, but the involved effector mechanisms have remained unclear. We addressed this issue by testing the role of perforin-dependent cytotoxicity in a disease model involving transgenic mice expressing glycoprotein of lymphocytic choriomeningitis virus (LCMV-GP) in the beta cells of the endocrine pancreas. In such mice, LCMV infection leads to a potent LCMV-GP-specific T cell response resulting in rapid development of diabetes. We report here that in perforin-deficient LCMV-GP transgenic mice, LCMV infection failed to induce diabetes despite the activation of LCMV-GP-specific T cells. Deletion of nu beta 6+ T cells in Mls-1a perforin-deficient mice and the activation of LCMV-GP-specific T cells in perforin-deficient LCMV-GP transgenic mice, however, indicated that thymic tolerance induction by negative selection was not affected by the disruption of the perforin gene and that there is no fundamental difference between the T cell repertoires of normal control and perforin-deficient mice. In addition, adoptive transfer of LCMV-GP-specific TCR transgenic perforin-deficient T cells activated by LCMV-GP recombinant vaccinia virus led to marked insulitis with infiltration of CD4+ and CD8+ T cells without the development of diabetes. These findings indicate that perforin-dependent cytotoxicity is not required for the initiation of insulitis but is crucial for the destruction of beta cells in the later phase of the disease process. Other mechanisms or soluble factors present in the inflammatory islet infiltrate apparently lack the ability to efficiently induce diabetogenic beta cell damage.
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PMID:Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity. 864 24

Studies with perforin-deficient mice have demonstrated that two independent mechanisms account for T cell-mediated cytotoxicity: A main pathway is mediated by the secretion of the pore-forming protein perforin by the cytotoxic T cell, whereas an alternative nonsecretory pathway relies on the interaction of the Fas ligand that is upregulated during T cell activation with the apoptosis-inducing Fas molecule on the target cell. NK cells use the former pathway exclusively. The protective role of the perforin-dependent pathway has been shown for infection with the noncytopathic lymphocytic choriomeningitis virus, for infection with Listeria monocytogenes, and for the elimination of tumor cells by T cells and NK cells. In contrast, perforin-dependent cytotoxicity is not involved in protection against the cytopathic vaccinia virus and vesicular stomatitis virus. LCMV-induced immunopathology and autoimmune diabetes have been found to require perforin-expression. A contribution of perforin-dependent cytotoxicity to the rejection of MHC class I-disparate heart grafts has also been observed. Its absence is efficiently compensated in rejection of fully allogeneic organ or skin grafts. So far, evidence for a role of Fas-dependent cytotoxicity as a T cell effector mechanism in vivo is lacking. Current data suggest that the main function of Fas may be in regulation of the immune response and apparently less at the level of an effector mechanism in host defense. Further analysis is necessary, however, to settle this point finally.
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PMID:Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. 871 13

We evaluated the role of the costimulatory molecule B7-1 in overcoming peripheral ignorance in transgenic mice, which expressed the glycoprotein (GP) or nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) as the self-antigen in pancreatic beta cells. The viral transgenes or B7-1 alone did not induce autoimmune diabetes (IDDM). However, in bigenic mice expressing B7-1 and LCMV-GP, anti-self (viral) cytotoxic T lymphocytes (CTL) were activated without viral infection and spontaneous IDDM occurred. In contrast, bigenic RIP-B7-1 x RIP-NP mice with thymic expression of the self (viral-NP) antigen deleted the majority of their autoreactive CTL and did not develop spontaneous IDDM. However, these mice developed fast-onset IDDM 14 days after LCMV infection, whereas single-transgenic RIP-NP littermates developed IDDM only within 4-5 months. Rapid IDDM was associated with increased numbers of anti-self CTL and a predominance of IFN gamma produced by islet-infiltrating lymphocytes, whereas single transgenic RIP-NP littermates with slow-onset IDDM displayed less anti-self CTL and more IL-4- and IL-10-producing T lymphocytes in pancreatic infiltrates.
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PMID:Coexpression of B7-1 and viral ("self") transgenes in pancreatic beta cells can break peripheral ignorance and lead to spontaneous autoimmune diabetes. 877 18

Oral administration of self-antigens has been proposed as a therapy to prevent and treat autoimmune diseases. Here we report that oral treatment with insulin prevents virus-induced insulin-dependent diabetes mellitus (IDDM) in a transgenic (tg) mouse model. Such mice express the viral nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter in their pancreatic beta cells and < 2% spontaneously develop diabetes. However, 2 mo after challenge with LCMV, IDDM occurs in > 95% of tg mice but not in controls. Oral treatment with 1 mg of insulin twice per week for 2 mo starting either 1 wk before or 10 d after initiating LCMV infection prevents IDDM in > 50% of the tg mice (observation time 8 mo). Thus, insulin therapy is effective in preventing progression to overt IDDM in prediabetic tg mice with ongoing islet infiltration. Oral administration of insulin does not affect the generation of LCMV-NP-specific anti-self cytotoxic T lymphocytes nor the infiltration of lymphocytes into the pancreas. However, less beta cells are destroyed in insulin-treated mice, upregulation of MHC class I and II molecules does not occur, and antiviral (self) cytotoxic T lymphocytes are not found in the islets, events present in tg mice developing IDDM. The majority of lymphocytes in the islets of insulin-treated tg mice without IDDM produces IL-4, IL-10, and TGF-beta. In contrast, lymphocytes from islets of tg mice developing IDDM mainly make gamma-IFN.
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PMID:Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice. 882 97

Autoimmune mediated destruction of beta cells of the islets of Langerhans leads to insulin-dependent diabetes mellitus (IDDM). Rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) transgenic mice that express the nucleoprotein (NP) or glycoprotein (GP) of LCMV under control of the RIP in their beta cells develop IDDM after infection with LCMV and serve as a model for virus-induced IDDM. Recently, Kagi et al. (Kagi, D., B. Odermatt, P. Ohashi, R.M. Zinkernagel, and H. Hengartner, 1996, J. Exp. Med. 183:2143-2149) showed, using RIP LCMV perforin-deficient mice, that IDDM does not occur in the absence of perforin. They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for beta cell injury and destruction. Here we provide evidence that killing of beta cells is more complex and multifactorial. By the use of our RIP LCMV model, we show that in perforin competent but interferon-gamma (IFN-gamma)-deficient mice, beta cell injury is limited and IDDM does not occur. For these studies, double transgenic mice were generated that were genetically deficient in the production of IFN-gamma and express LCMV NP or GP in their beta cells. In such mice, IDDM was aborted despite the generation of LCMV-specific antiself CTLs that displayed normal cytolytic activity in vitro and in vivo and entered the pancreas. However, mononuclear infiltration into the islets did not occur, and upregulation of class I and II molecules usually found in islets of RIP LCMV single transgenic mice after LCMV infection preceding the onset of clinical IDDM was not present in these bigenic mice. Our findings indicate that in addition to perforin, beta cell destruction, development of insulitis, and IDDM also depend on the cytokine INF-gamma, presumably through enhancement of major histocompatibility complex expression and antigen presentation.
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PMID:Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus. 905 53

Bystander activation, i.e., activation of T cells specific for an antigen X during an immune response against antigen Y may occur during viral infections. However, the low frequency of bystander-activated T cells has rendered it difficult to define the mechanisms and possible in vivo relevance of this nonspecific activation. This study uses transgenic mice expressing a major histocompatibility complex class I-restricted TCR specific for glycoprotein peptide 33-41 of lymphocytic choriomeningitis virus (LCMV) to overcome this limitation. CD8+ T cells from specific pathogen-free maintained, unimmunized "naive" TCR transgenic mice can differentiate into LCMV-specific cytolytic effector CTL during infections with vaccinia virus or Listeria monocytogenes in vivo or mixed lymphocyte culture in vitro. We show that in these model situations (a) nonspecifically activated CTL are able to confer antiviral protection in vivo, (b) bystander activation is largely independent of the expression of a second T cell receptor of different specificity, (c) bystander activation is not mediated by a broadly cross-reactive TCR, but rather by cytokines, (d) bystander activation can be mediated by cytokines such as IL-2, but not alpha/beta-IFN in vitro; (e) bystander activation is, overall, a rare event, occuring in vivo in roughly 1 in 200 of the LCMV-specific CTL during infection of TCR transgenic mice with vaccinia virus; (f) bystander activation does not have a significant functional impact on nontransgenic CTL memory under the conditions tested; and (g) even in the TCR transgenic situation, where unphysiologically high numbers of T cells of a single specificity are present, bystander activation is not sufficient to cause clinically manifest autoimmune disease in a transgenic mouse model of diabetes. We conclude that although bystander activation via cytokines may generate cytolytically active CTL from naive precursors, quantitative considerations suggest that this is usually not of major biological consequence.
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PMID:Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model. 910 11

RIP-LCMV transgenic mice that express the viral glycoprotein (GP) or nucleoprotein (NP) from lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter (RIP) in pancreatic beta-cells develop autoimmune diabetes (IDDM) after infection with LCMV. Previous reports have described that the viral infection activates naive, potentially autoreactive CD8+ cytotoxic T-lymphocytes (CTL) that are present in the periphery of these mice, thus leading to the breaking of immunological unresponsiveness to the viral self-antigen expressed on beta-cells. However, we find that adoptive transfer of such CTL that were active in vitro and in vivo into uninfected RIP-LCMV recipients rarely resulted in hyperglycemia nor in insulitis, despite their ability to home to the islets and induce peri-insulitis. These observations indicated that, in addition to activated autoreactive lymphocytes, other factor(s) were required for beta-cell destruction. The present study shows that upregulation of MHC class II molecules associated with the attraction/activation of antigen presenting cells (APCs) to the islets occurs as soon as 2 days after LCMV inoculation of transgenic mice, clearly before CD4+ and CD8+ lymphocytes are found entering the islets (days 6 and 7 after LCMV inoculation). In contrast, although some MHC class II upregulation is also found in islets of non-transgenic mice 2-4 days after LCMV infection, no insulitis or IDDM develops and MHC is downregulated to normal (pre-infection) levels by day 7-10 in these mice. Associated with the activation of APCs and MHC upregulation observed in transgenic mice, viral (LCMV) infection of islets was detectable 2 days post-viral inoculation in some mice. Thus, beta-cell destruction by activated autoreactive lymphocytes is a multifactorial process that is likely to require changes within the islet milieu or dysfunction of islets.
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PMID:Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM. 921 48

The adenovirus (Ad) genome contains immunoregulatory and cytokine inhibitory genes that are presumed to function in facilitating acute infection or in establishing persistence in vivo. Some of these genes are clustered in early region 3 (E3), which contains a 19-kDa glycoprotein (gp19) that inhibits the transport of selected class I major histocompatibility complex (MHC) molecules out of the endoplasmic reticulum. In addition, the E3 region contains three protein inhibitors of the cytolytic function of tumor necrosis factor alpha (TNF-alpha). Because type I autoimmune diabetes destroys islets by mechanisms that involve class I MHC and TNF-alpha, we investigated whether the entire cassette of Ad E3 genes might prevent the onset of diabetes in a well studied lymphocytic choriomeningitis viral (LCMV) murine model of virus-induced autoimmune diabetes. In this model, a LCMV polypeptide (either glycoprotein or nucleoprotein) expressed as a transgene in the islets is a target for autoimmune destruction of beta cells after LCMV infection. In this scenario the LCMV-induced immune response is directed not only against the virus but also against the LCMV transgenes expressed in the beta cells. Our experiments demonstrated a very efficient prevention of this LCMV-triggered diabetes by the Ad E3 genes. This resulted from the inhibition of target cell recognition by a fully competent and LCMV-primed immune system. Unlike the results from the beta-2 microglobulin gene deletion experiments, our approach shows that selective regulation at the level of the target cell is sufficient to prevent autoimmune diabetes without disrupting the function of the systemic immune response. Although the Ad genes in these experiments were provided as transgenes, recent experiments may permit the introduction of such genes through the use of viral vectors. Although the decrease in class I MHC in islets by Ad genes was demonstrated in these in vivo studies, the relative importance of this process and the control of TNF-alpha cytolysis must await further genetic dissection of the introduced Ad genes.
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PMID:Expression of adenoviral E3 transgenes in beta cells prevents autoimmune diabetes. 927 7

Tumor necrosis factor (TNF)-alpha is a multipotent cytokine associated with many cellular functions, including inflammation and anti-viral defense. Many studies have implicated TNF-alpha in the pathogenesis of autoimmune diseases. TNF-alpha responses are mediated through binding to specific cell surface receptors, TNFRp55 and TNFRp75. The objective of the present study was to investigate the contribution of the TNFRp55 in the inflammatory response associated with autoimmune diabetes development in a viral transgenic model. In this model, the animals express lymphocytic choriomeningitis virus (LCMV)-glycoprotein (gp) in the beta cells of the pancreas under the control of the rat insulin promoter (RIP-gp). Diabetes is induced following LCMV infection due to beta cell destruction by LCMV-specific CD8+ cytotoxic T lymphocytes. TNFRp55-deficient RIP-gp animals were examined to assess the importance of the TNFRp55. The kinetics and onset of lymphocytic infiltration into the pancreatic islets and hyperglycemia was not altered in the absence of TNFRp55 after LCMV infection. Animals were evaluated following recombinant LCMV-gp vaccinia virus infection to test whether properties of the infectious agent influence autoimmunity. Interestingly, the kinetics were accelerated and the frequency of diabetes was increased in TNFRp55-deficient mice compared with control animals. This accelerated onset of diabetes is likely a result of increased viral replication in the TNFRp55-deficient host. Thus, these data demonstrate that TNFRp55 is not essential for producing the local inflammatory effects which contribute to organ-specific autoimmunity in this transgenic model. However, the absence of TNFRp55 altered the kinetics and incidence of the disease in a pathogen-dependent fashion.
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PMID:Absence of TNFRp55 influences virus-induced autoimmunity despite efficient lymphocytic infiltration. 962 May 96


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