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

In comparing the incidence of virally induced type 1 diabetes in F(1) crosses of RIP-LCMV mice to three different mouse strains identical at the major histocompatibility complex H-2D(b) locus, we surprisingly found that disease development was reduced by 80% in F(1) crosses to the SV129 genetic background and by 60% after eight backcrosses to the original C57BL/6 RIP-LCMV mice. In this model, diabetes is strongly dependent on a virally induced H-2D(b)-restricted cytotoxic T-cell (CTL) response. Importantly, numbers and effector functions of autoaggressive CD4 and CD8 lymphocytes were not decreased in the protected mice, and CTLs were still able to kill syngeneic islet cells in vitro with equal efficacy compared with CTLs from the original RIP-LCMV strain. Furthermore, CTLs were able to extravasate into islets in vivo, and no evidence for induction of regulatory cells was observed. However, regeneration of beta-cells in islets under "attack" occurred only in the protected SV129-crossed animals, whereas it was not evident at any time in any mice that developed diabetes. Thus, genetic factors can "override" the diabetogenic potential of high numbers of autoaggressive lymphocytes through, for example, increased islet regeneration. This finding has important implications for interpreting numbers and pathogenicity of autoreactive lymphocytes in prediabetic patients of genetically diverse backgrounds.
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PMID:Protection from type 1 diabetes in the face of high levels of activated autoaggressive lymphocytes in a viral transgenic mouse model crossed to the SV129 strain. 1172 52

Administration of autoantigens through DNA immunizations or via the oral route can prevent progression of islet destruction and lower the incidence of type 1 diabetes in animal models. This beneficial effect is mediated by autoreactive regulatory CD4 lymphocytes, and it is known that their induction depends on the precise dose and route of antigen administration. However, it is not clear which endogenous factors determine when such immunizations lead to activation of regulatory versus aggressive autoreactive lymphocytes and how a deleterious outcome can be avoided. Here we describe novel observations made in an animal model for virally induced type 1 diabetes, showing that the endogenous expression levels of the islet antigens and glutamic acid decarboxylase determine whether immunization with these antigens is beneficial or detrimental. Lower expression levels in beta-cells support immune regulation resulting in induction of autoreactive, regulatory cells characterized by increased IL-4 production (Th2-like), whereas higher levels favor Th1-like autoaggressive responses characterized by augmented IFN-gamma generation. Co-immunization with an IL-4-expressing plasmid reduces the risk of augmenting autoaggression and in this way increases the safety margin of this immune-based therapy. Our findings will be of importance for designing safe antigen-specific interventions for human type 1 diabetes.
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PMID:Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL-4 increases safety. 1175 51

Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the pancreatic lymph nodes and islets but not other lymph nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.
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PMID:Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. 1186 80

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a multiple sclerosis (MS) model, is a central nervous system (CNS) demyelinating disease characterized by early peripheral T cell responses to virus epitopes which spreads to myelin epitopes during chronic disease. We show that CD4(+) T cells isolated from the spinal cords of chronically infected SJL mice proliferate and secrete pro-inflammatory cytokines upon in vitro challenge with both TMEV epitopes and proteolipid protein (PLP(139-151)). Importantly, myelin-specific tolerance induced by intravenous administration of MP4, a fusion of the myelin proteins myelin basic protein (MBP) and PLP, to SJL mice with ongoing TMEV-IDD attenuated disease progression and resulted in significantly less demyelination and decreased inflammatory cell infiltration in the CNS. Paradoxically, peptide-specific splenic T cell proliferative and IFN-gamma responses were enhanced in the tolerized mice. Collectively, these results indicate that myelin-specific T cell responses contribute to chronic disease progression in this virus-induced model of MS, and suggest caution in the use of antigen-specific tolerance for treatment of ongoing autoimmune disease.
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PMID:Myelin-specific tolerance attenuates the progression of a virus-induced demyelinating disease: implications for the treatment of MS. 1188 Jan 45

Administration of anti-L-selectin (CD62L) mAb to neonatal nonobese diabetic (NOD) mice mediates long term protection against the development of insulitis and overt diabetes. These results suggested that CD62L has a key role in the general function of beta cell-specific T cells. To further examine the role of CD62L in the development of type 1 diabetes, NOD mice lacking CD62L were established. The onset and frequency of overt diabetes were equivalent among CD62L(+/+), CD62L(+/-), and CD62L(-/-) NOD littermates. Furthermore, patterns of T cell activation, migration, and beta cell-specific reactivity were similar in NOD mice of all three genotypes. Adoptive transfer experiments with CD62L(-/-) CD4(+) T cells prepared from BDC2.5 TCR transgenic mice revealed no apparent defects in migration to pancreatic lymph nodes, proliferation in response to beta cell Ag, or induction of diabetes in NOD.scid recipients. In conclusion, CD62L expression is not essential for the development of type 1 diabetes in NOD mice.
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PMID:L-selectin is not required for T cell-mediated autoimmune diabetes. 1188 30

Juvenile diabetes (type 1) is an autoimmune disease in which CD4(+) T cells play a major role in pathogenesis characterized by insulitis and beta cell destruction leading to clinical hyperglycemia. To date, no marker for autoimmune T cells has been described, although it was previously demonstrated that autoimmune mice have a large population of CD4(+) cells that express CD40. We show here that established, diabetogenic T cell clones of either the Th1 or Th2 phenotype are CD40-positive, whereas nondiabetogenic clones are CD40-negative. CD40 functionally signals T cell clones, inducing rapid activation of the transcription factor NFkappaB. We show that autoimmune diabetes-prone nonobese diabetic mice have high levels of CD40(+)CD4(+) T cells in the thymus, spleen, and importantly, in the pancreas. Finally, as demonstrated by adoptive transfers, CD4(+)CD40(+) cells infiltrate the pancreatic islets causing beta-cell degranulation and ultimately diabetes.
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PMID:Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes. 1189 Dec 96

Polyinosinic-polycytidylic acid (PolyIC), a "mimic" of double-stranded viral RNA, can induce diabetes when administered to rats with RT1(u), and immunization of normal H-2(d) mice (e.g., BALB/c) with insulin B:9-23 peptide (but not H-2(b)) results in the rapid induction of insulin autoantibodies. Because a mouse model of PolyIC/antigen-induced diabetes is lacking, we sought to produce insulitis and diabetes with either PolyIC and/or B:9-23 peptide immunization. Simultaneous administration of PolyIC and B:9-23 peptide to BALB/c mice (but with neither alone) induced insulitis. CD4 T lymphocytes predominated within islets, and the mice did not progress to hyperglycemia. Islets with transgene-induced expression of the costimulatory B7-1 molecule have enhanced diabetes susceptibility. Diabetes was frequently induced in B7-1 transgenic mice with H-2(d) in contrast to H-2(b) mice after PolyIC administration. Disease induction was accelerated by adding B:9-23 immunization to PolyIC. These studies demonstrate that "normal" mice have autoreactive T lymphocytes able to rapidly target islets and insulin given appropriate MHC alleles and that a peripherally administered insulin peptide (an altered peptide ligand of which is in clinical trials) can enhance specific anti-islet autoimmunity. These first PolyIC/insulin-induced murine models should provide an important tool to study the pathogenesis of type 1 diabetes with experimental autoimmune diabetes.
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PMID:Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. 1194 68

Type 1 diabetes is a chronic progressive autoimmune disease characterized by mononuclear cell infiltration, dominated by interleukin-12 (IL-12)-dependent Th1 cells, of the pancreatic islets, with subsequent destruction of insulin-producing beta-cells. Here, we demonstrate that treatment of adult nonobese diabetic (NOD) mice with an analog of 1alpha,25-dihydroxyvitamin D(3), an immunomodulatory agent preventing dendritic cell maturation, decreases lipopolysaccharide-induced IL-12 and gamma-interferon production, arrests Th1 cell infiltration and progression of insulitis, and inhibits diabetes development at nonhypercalcemic doses. Arrest of disease progression is accompanied by an enhanced frequency in the pancreatic lymph nodes of CD4(+)CD25(+) regulatory T-cells that are able to inhibit the T-cell response to the pancreatic autoantigen insulinoma-associated protein 2 and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells. Thus, a short treatment of adult NOD mice with an analog of 1,25-dihydroxyvitamin D(3) inhibits IL-12 production, blocks pancreatic infiltration of Th1 cells, enhances CD4(+)CD25(+) regulatory cells, and arrests the progression of type 1 diabetes, suggesting its possible application in the treatment of human autoimmune diabetes.
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PMID:A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. 1197 32

Soluble HLA-DR401 or -DR404 tetramers containing a peptide corresponding to an immunodominant epitope from human GAD65 were used to analyze peripheral blood T-cells of newly diagnosed type 1 diabetic patients and at-risk subjects. Peripheral blood mononuclear cells were expanded on antigen-presenting cells presenting GAD65 peptide and subsequently activated with specific plate-bound class II-peptide monomers. T-cell activation defined in flow cytometry by CD4(high) and/or CD25 markers were observed in all type 1 diabetic patients and some at-risk subjects, but not in normal control subjects. The activated T-cells stained positive with tetramers containing the GAD65 epitope 555-567. Tetramer-positive cells were CD4(high) T-cells with high avidity for an immunodominant GAD65 T-cell epitope. Phenotyping of T-cells utilizing HLA class II tetramers provides a new tool to characterize the autoimmune response in type 1 diabetes.
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PMID:Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. 1197 33

Studies of type 1 diabetes indicate that autoaggressive T cells specific to beta-cell antigens, reaching certain threshold levels, may play critical roles in the development of the disease. Flow cytometric analyses found that autoreactive T-cell lines from patients induced by beta-cell antigens consisted of four major subsets (CD4(+)CD56(-), CD4(+)CD56(+), CD8(+)CD56(-), and CD8(+)CD56(+)) and that CD56(+) NKT cells might be derived from CD56(-) T cells. Moreover, the proportion of CD56(+) NKT cells in the T-cell lines was influenced by time course of repeated antigen stimulation. beta-cell antigen-specific CD56(+) NKT (CD4(+) or CD8(+)) cells were more aggressive (HLA-restricted and -unrestricted) effector cells lysing target cells such as K562, Jurkat, P815 plus anti-CD3 antibody, and autologous B cells sensitized by beta-cell peptides, when compared with their CD56(-) counterparts. beta-cell antigen- specific CD4(+)CD56(+) NKT cells showed non-HLA-restricted cytotoxicity to human beta cells, insulinoma cell line CM, and to islet cell lines TRM-6 and HP62 expressing CD56 but not to four CD56(-) pancreatic cell lines of non- islet origin. The CD4(+)CD56(+) NKT cells showed stronger cytotoxicity to CM, TRM-6 and HP62 cells than did CD4(+)CD56(-) T cells. Moreover, isotope-unlabelled CD56(+) cells and anti-CD56 antibodies were able to inhibit cytotoxicity of CD4(+)CD56(+) NKT to CD56(+) target cells. These results suggest that CD56(+) NKT cells are aggressive cytotoxic cells to beta cells and that CD56 expression might be associated with the aggressiveness of effector T cells and the susceptibility of target cells.
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PMID:beta-cell antigen-specific CD56(+) NKT cells from type 1 diabetic patients: autoaggressive effector T cells damage human CD56(+) beta cells by HLA-restricted and non-HLA-restricted pathways. 1203 7


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