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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic beta-cell antiviral defense plays a critical role in protection from coxsackievirus B4 (CVB4)-induced diabetes. In the present study, we tested the hypothesis that interferon (IFN)-induced antiviral defense determines beta-cell survival after infection by the human pathogen CVB3, cytomegalovirus (CMV), and lymphocytic choriomeningitis virus (LCMV). We demonstrated that mice harboring beta-cells that do not respond to IFN because of the expression of the suppressor of cytokine signaling-1 (SOCS-1) succumb to an acute form of type 1 diabetes after infection with CVB3. Interestingly, the tropism of the virus was altered in SOCS-1 transgenic (Tg) mice, and CVB3 was detected in islet cells of SOCS-1-Tg mice before beta-cell loss and the onset of diabetes. Furthermore, insulitis was increased in SOCS-1-Tg mice after infection with murine CMV, and a minority of the mice developed overt diabetes. However, infection with LCMV failed to cause beta-cell destruction in SOCS-1 Tg mice. These findings suggest that CVB3 can cause diabetes in a host lacking adequate beta-cell antiviral defense, and that incomplete target cell antiviral defense may enhance susceptibility to diabetes triggered by CMV. In conclusion, suppressed beta-cell antiviral defense reveals the diabetogenic potential of two pathogens previously linked to the onset of type 1 diabetes in humans.
Diabetes 2003 Aug
PMID:Diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells. 1288 19

Infection of the pancreas with lymphocytic choriomeningitis virus results in rapid and differential expression among CXCR3 chemokines. IFN-gamma-inducible protein of 10 kDa (IP-10), in contrast with monokine induced by IFN-gamma and IFN-inducible T cell-alpha chemoattractant, is strongly expressed within 24 h postinfection. Blocking of IP-10, but not monokine induced by IFN-gamma, aborts severity of Ag-specific injury of pancreatic beta cells and abrogates type 1 diabetes. Mechanistically, IP-10 blockade impedes the expansion of peripheral Ag-specific T cells and hinders their migration into the pancreas. IP-10 expression was restricted to viruses infecting the pancreas and that are capable of causing diabetes. Hence, virus-induced organ-specific autoimmune diseases may be dependent on virus tropism and its ability to alter the local milieu by selectively inducing chemokines that prepare the infected tissue for the subsequent destruction by the adaptive immune response.
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PMID:Among CXCR3 chemokines, IFN-gamma-inducible protein of 10 kDa (CXC chemokine ligand (CXCL) 10) but not monokine induced by IFN-gamma (CXCL9) imprints a pattern for the subsequent development of autoimmune disease. 1466 90

Viruses can cause but can also prevent autoimmune disease. This dualism has certainly hampered attempts to establish a causal relationship between viral infections and type 1 diabetes (T1D). To develop a better mechanistic understanding of how viruses can influence the development of autoimmune disease, we exposed prediabetic mice to various viral infections. We used the well-established NOD and transgenic RIP-LCMV models of autoimmune diabetes. In both cases, infection with the lymphocytic choriomeningitis virus (LCMV) completely abrogated the diabetic process. Interestingly, such therapeutic viral infections resulted in a rapid recruitment of T lymphocytes from the islet infiltrate to the pancreatic draining lymph node, where increased apoptosis was occurring. In both models this was associated with a selective and extensive expression of the chemokine IP-10 (CXCL10), which predominantly attracts activated T lymphocytes, in the pancreatic draining lymph node, and in RIP-LCMV mice it depended on the viral antigenic load. In RIP-LCMV mice, blockade of TNF-alpha or IFN-gamma in vivo abolished the prevention of T1D. Thus, virally induced proinflammatory cytokines and chemokines can influence the ongoing autoaggressive process beneficially at the preclinical stage, if produced at the correct location, time, and levels.
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PMID:Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient. 1470 11

Type I diabetes is caused by an autoimmune-mediated elimination of insulin-secreting pancreatic islets. Genetic modification of islets offers a powerful molecular tool for improving our understanding of islet biology. Moreover, efficient genetic engineering of islets could allow for evaluation of new strategies aimed at preventing islet destruction. The present study evaluated the ability of a human immunodeficiency virus (HIV)-based lentiviral vector pseudotyped with various viral envelopes to target human islets ex vivo, with the goal of improving efficiency while minimizing toxicity. Transfer of the enhanced green fluorescent protein reporter gene in human islets was first evaluated with an HIV-based vector pseudotyped with the vesicular stomatitis virus (VSV), murine leukemia virus, Ebola, rabies, Mokola, or lymphocytic choriomeningitis virus (LCMV) envelope glycoprotein to optimize transduction efficiency. Results indicated that LCMV-pseudotyped vector transduced insulin-secreting beta cells with the highest efficiency. Moreover, toxicity associated with transduction of islets was found to be lower with LCMV-pseudotyped vector than with VSV-G-pseudotyped vector, the second most efficient vector for islet transduction. Overall, our study describes an improved methodology for achieving safe and efficient gene transfer into cells of human islets.
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PMID:Transduction of human islets with pseudotyped lentiviral vectors. 1497 93

Tissue-specific expression of Fas-ligand (Fas-L) can provide immune privilege by inducing apoptosis of "invading" lymphocytes expressing Fas. However, accelerated diabetes has been reported in transgenic mice expressing Fas-L in islets (RIP-Fas-L) as a result of Fas-dependent fratricide of beta-cells after transfer of diabetogenic clones. Here we studied whether Fas-L could protect islets from autoaggressive CD8 lymphocytes in a transgenic model of virally induced diabetes (RIP-LCMV-NP transgenic mice), in which the autoaggressive response is directed to a viral nucleoprotein (NP) expressed as a transgene in beta-cells. Indeed, disease incidence after viral (lymphocytic choriomeningitis virus [LCMV]) infection was reduced by approximately 30%, which was associated with a decrease of autoaggressive CD8 NP-specific lymphocytes in islets and pancreatic draining lymph nodes. However, surprisingly, a high degree (50%) of diabetes was seen in mice that expressed only Fas-L but not the viral transgene (NP) in beta-cells after infection with LCMV. This was due to induction of Fas on beta-cells after LCMV infection of the pancreas, resulting in Fas/Fas-L-mediated fratricide. Thus, although Fas-L can lend some immune privilege to islet cells, local virus-induced inflammation will induce Fas on beta-cells, leading to their mutual destruction if Fas-L is present. Expression of Fas-L therefore might not be protective in situations in which viral inflammation can be expected, resulting in Fas induction on the targeted cell itself.
Diabetes 2004 Mar
PMID:Virally induced inflammation triggers fratricide of Fas-ligand-expressing beta-cells. 1498 42

The T-box transcription factor T-bet is known to control lineage commitment and interferon-gamma production by T helper 1 (Th1) CD4 lymphocytes. We report here that T-bet is essential for development of CD8 lymphocyte-dependent autoimmune diabetes (type 1 diabetes [T1D]) in the rat insulin promoter-lymphocytic choriomeningitis virus (LCMV) transgenic model for virally induced T1D. In the absence of T-bet, autoaggressive (anti-LCMV) CD8 lymphocytes were reduced in number and produced less IFN-gamma, but increased IL-2 compared with controls. Further analysis showed that T-bet intrinsically controls the generation, but not apoptosis, maintenance, or secondary expansion of antiviral effector/memory CD8 lymphocytes. This observation points toward a therapeutic opportunity for the treatment of T1D and other autoimmune disorders.
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PMID:T-bet controls autoaggressive CD8 lymphocyte responses in type 1 diabetes. 1509 40

Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8(+) T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.
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PMID:Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. 1569 91

T cell responses are regulated by the affinity/avidity of the T cell receptor for the MHC/peptide complex, available costimulation and duration of antigenic stimulation. Altered peptide ligands (APLs) are usually recognized with a reduced affinity/avidity by the T cell receptor and are often able to only partially activate T cells in vitro or may even function as antagonists. Here we assessed the ability of APLs derived from peptide p33 of lymphocytic choriomeningitis virus (LCMV) to mediate lysis of target cells in vivo, confer anti-viral protection and cause auto-immune disease. In general, in vitro cross-reactivity between APLs was rather limited, and even strongly cross-reactive cytotoxic T lymphocytes were only able to mediate moderate anti-viral protection. Partial protection was observed for infection with LCMV or low doses of recombinant vaccinia virus, while no reduced viral titers could be seen upon infection with high dose of vaccinia virus. In a transgenic mouse model expressing LCMV glycoprotein in the islets of the pancreas, APLs induced a transient insulitis but failed to induce autoimmune diabetes. Thus, effector functions induced by even highly homologous APLs are rather limited in vivo.
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PMID:Limited in vivo reactivity of polyclonal effector cytotoxic T cells towards altered peptide ligands. 1585 5

During inflammation, chemokines are conductors of lymphocyte trafficking. The chemokine CXCL10 is expressed early after virus infection. In a virus-induced mouse model for type 1 diabetes, CXCL10 blockade abrogated disease by interfering with trafficking of autoaggressive lymphocytes to the pancreas. We have generated transgenic rat insulin promotor (RIP)-CXCL10 mice expressing CXCL10 in the beta cells of the islets of Langerhans to evaluate how bystander inflammation influences autoimmunity. RIP-CXCL10 mice have islet infiltrations by mononuclear cells and limited impairment of beta cell function, but not spontaneous diabetes. RIP-CXCL10 mice crossed to RIP-nucleoprotein (NP) mice expressing the NP of the lymphocytic choriomeningitis virus in the beta cells had massively accelerated type 1 diabetes after lymphocytic choriomeningitis virus infection. Mechanistically, we found a drastic increase in NP-specific, autoaggressive CD8 T cells in the pancreas after infection. In situ staining with H-2D(b)(NP(396)) tetramers revealed islet infiltration by NP-specific CD8 T cells in RIP-NP-CXCL10 mice early after infection. Our results indicate that CXCL10 expression accelerates the autoimmune process by enhancing the migration of Ag-specific lymphocytes to their target site.
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PMID:Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development. 1614 94

The portrait of autoimmune diabetes mellitus or type I diabetes can be copied by a transgenic model in which either the nucleoprotein (NP) or glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) is expressed in beta cells of the islets of Langerhans. In the absence of further environmental insult, diabetes does not occur. However, when LCMV or a dissimilar virus that shares cross-reactive T cell epitopes with LCMV initiates infection, diabetes ensues. If the self "viral" transgene is expressed only in the beta cells, then diabetes occurs acutely within 8 to 12 days. Specific antiviral (self) CD8 T cells are mandatory for disease, but CD4 T cells are not. In this instance, diabetes can occur in the absence of infection if interferon gamma or B7.1 molecules are also expressed in the islets but not when IL-2, IL-4, IL-10, or IL-12 is similarly expressed. In contrast, both CD8 and CD4 antiviral (self) specific T cells are required when the self "viral" transgene is expressed concomitantly in beta cells and in the thymus. In this instance, infection by LCMV or cross-reacting virus is essential to cause diabetes. Further, the time from onset of infection until disease depends, in part, on the host's MHC background and its quantitative influence on negative selection of high-avidity antiviral (self) T cells. Knowledge of the cells, their numbers, and the molecules required to cause diabetes allows the design of successful strategies to treat and prevent the autoimmune disease.
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PMID:Molecular and cellular mechanisms, pathogenesis, and treatment of insulin-dependent diabetes obtained through study of a transgenic model of molecular mimicry. 1632 91


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