L C Harrison

..The 'accelerator hypothesis' proposes 'three processes in type 1 diabetes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity'...

..We define for the first time a novel posttranslational modification that is required for T cell recognition of the insulin A-chain in T1D...

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..The mucosa is a major immunoregulatory barrier, and cow's milk happens to be the first dietary protein it encounters. The basic question is whether impaired mucosal immune function predisposes to type 1 diabetes...

..Recent trials of a nasal insulin vaccine in humans at risk of type 1 diabetes provide evidence of tolerance induction as a basis for clinical efficacy...

..Mucosa-mediated tolerance remains the predominant mode of antigen-specific therapy but awaits demonstration of clinical efficacy in human autoimmune disease...

..Although effective in rodent models of autoimmune disease, these strategies have so far been disappointing in humans. This review discusses the prospects of vaccination to prevent T1D, focusing on autoantigen-specific mucosal tolerance...

..Initial trials of insulin-specific immunotherapy in humans show promise and reveal ways of optimising this approach that are also applicable to other autoimmune diseases...

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..To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first-degree relatives of patients with type 1 diabetes mellitus...

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..These results indicate the existence of a gene that acts at an early stage in IDDM development, screening for which may identify a specific subset of at-risk individuals...

..RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children...

..The finding of a further CD4(+) T cell epitope in the N-terminal A-chain region of human insulin underscores the importance of this region as a target of CD4(+) T cell responses in human T1D...

..We conclude that modulation of inflammation against xenografts by anti-CD45RB antibody is due to effects on both T cell priming and trafficking...

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..The mechanisms by which grafts elicit innate immunity are a fertile subject for further investigation and an important target for therapeutic intervention...

..Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP...

..The requirement for Mphi reflects their ability to mount a rapid, local innate response that stimulates T cell recruitment and, having received T cell help, to act as direct effectors of rejection...

..The present format of the database allows text string matching searches but can easily be converted for use in conjunction with sequence analysis packages. The database can be accessed via Internet using WWW, FTP or Gopher...

..We propose that an imbalance favoring development of DC from myeloid-committed progenitors predisposes to autoimmune disease in NOD mice...

..We conclude that TCRgammadelta IEL at the mucosal interface between self and nonself play a key role in maintaining peripheral tolerance both physiologically and during oral tolerance induction...

..This antigen-specific immunotherapeutic strategy could be applied to prevent T1D and other autoimmune diseases in humans...

..Our findings are consistent with the hypothesis that molecular mimicry with RV could promote autoimmunity to islet Ags...

..In this perspective, we review the nomenclature, diagnostic criteria, genetics, pathology and therapy of LADA, to arrive at recommendations that might advance knowledge and management of this form of diabetes...

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..Laminin-I had a dominant effect via alpha-DG to promote cell survival and beta-cell differentiation, which was modestly inhibited by alpha6 signaling...

..These findings infer an immunoregulatory role for extrathymic-derived IEL, developing under the influence of the thymus and conditioned by early exposure to the exogenous environment...

..These findings indicate that members of the TGF-beta superfamily regulate pancreas epithelial cell development and can promote the formation of islet-like structures in vitro...

..05). It is concluded that hyperglycemia in experimental type 1 diabetes can be effectively treated by islets seeded into a vascularized chamber functioning as a "pancreatic organoid."..

..These findings suggest that CTL immunity is likely to be a consequence of mucosal antigen delivery, regardless of the regimen, and should be considered in the clinical application of mucosal tolerance to autoimmune disease prevention...

..88. The results of this study are expected to be of practical interest to immunologists for efficient identification of peptides as candidates for immunotherapy...

..These findings suggest that T-cell hyperactivity in type 1 diabetes is an acquired trait and could reflect persisting virus expression...

..Transient CD40L blockade therefore dissociates pathogenic from protective immunity and should enhance the efficacy and safety of oral tolerance for preventing autoimmune disease...

..The transfer of DC progenitors encoding a disease-specific autoantigen is, therefore, an effective immunotherapeutic strategy that could be applied to humans...

..Our findings also have implications for GC treatment in that it would be more difficult to abrogate an ongoing T-cell mediated inflammatory response than to prevent its induction...

..NaB-treated RIN cells may serve as a model to study the role of gangliosides in the function and lineage relationships of islet cells...

..We created a model of accelerated beta-cell destruction mediated by T cells from spontaneously diabetic NOD mice to facilitate the direct detection of apoptosis in beta cells...

..We compared genetic, immunologic, and clinical features in relatives of people with T1D, who developed early- versus late-onset diabetes...

..Using the CFSE assay we were able to measure directly the proliferation of human CD4(+) T cells from healthy donors in response to the type 1 diabetes autoantigens glutamic acid decarboxylase (GAD) and proinsulin (PI)...

..This indicates that radiation resistance in the NOD hematopoietic compartment is a property primarily of mature T lymphocytes...

..This finding has important implications for the use of synthetic peptides in screening and epitope mapping studies and their use as vaccines in humans...

..Drawing on the expanding knowledge of pancreas development, beta-cell regeneration and stem cell research, this review focuses on progenitor cells in the adult pancreas as a potential source of beta-cells...

..In addition, the ability of the CFSE assay to allow analysis of the phenotype and function of autoantigen-responsive T cells may improve discrimination...

..This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a "tolerogenic" autoantigen peptide can be compromised by the presence of an integral CTL epitope...

..5 pancreatic cells to proliferate and form cystoid and solid colonies. These results demonstrate that laminin-1 and EGF signaling pathways interact to promote pancreas development...

..Sixty proinsulin- and 47 glutamic acid decarboxylase-specific clones were obtained from six and two donors, respectively. In conclusion, the CFSE-based method is ideal for cloning rare, autoantigen-specific, human CD4+ T cells...

..These results demonstrate a convergence of BMP and Ln-1 signaling through P13K and MAP kinase pathways to induce proliferation and colony formation in E15.5 fetal mouse pancreatic cells...

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..Therefore, we found that the co-stimulation requirements for the thymic development of TR cells differed from those for peripheral homeostasis...

..To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades...

..These results indicate that the cogeneration of Foxp3(hi) Tregs in response to allergen may be a mechanism for controlling allergic reactions in healthy individuals, which is impaired in those with allergies...

..Fulminant diabetes occurs primarily in Asia, particularly in Japan, but with widespread population migration clinicians need to be aware of this form of diabetes...

..This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit...

..Taking steps to reduce this insulin resistance could therefore delay the development of type 1 diabetes...

..The IL12B 3' UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases...

..CTL to the IA-2 self-peptide were therefore not disease-specific, consistent with other evidence that autoreactive T cells are present in healthy individuals...

..IEL proliferation and emigration under lymphopenic conditions suggests similar IEL turnover, albeit at a lower level, under physiological conditions...

..This points to a possible clinical use of FL to prevent autoimmune disease...

..We conclude that proinsulin satisfies these criteria. As a corollary, proinsulin is a potential immunotherapeutic tool for the prevention of T1D...

..Thus, effective peripheral tolerance can be induced by resting DC in the presence of CD4(+) and CD8(+) T cells with specificity for the same Ag...

..The readily detectable co-expression of GFP and RFP in grafts derived from transplanted EBs demonstrated the utility of Pdx1(GFP/w)Ins1(RFP/w) ESCs for investigating pancreatic differentiation in vitro and in vivo...

..Self-antigen expression by peripheral myeloid cells extends the umbrella of "immunological self" and, by analogy with the thymus, may be implicated in peripheral immune tolerance...

..The lower frequency of GAD antibodies in recent-onset IDDM subjects indicates either that immunoreactivity is lost with near-total beta-cell destruction or that GAD antibodies denote a low risk of progression to clinical disease...

..Oncogene (2000) 19, 4290 - 4297..

..Laminin-1 was shown to be expressed in the epithelial basement membrane of the 13.5- to 17.5-day fetal pancreas. These findings provide the first evidence of a role for laminin-1 to promote differentiation of pancreatic beta-cells...

..IAR Ab may play an important role in the prediction of IDDM...

..Such Abs are not elicited by transplanting FPP into immunocompetent mice. Nevertheless, a contribution of Ab to rejection in immunocompetent mice cannot be excluded...

..They provide an explanation for the unusual IGF-II binding properties of human placental membranes and may have a specific role in placental growth and/or function...

..Peptides from the library were used to initiate assembly of recombinant HLA-B8, HLA-B15 and HLA-A2, facilitating the identification of candidate T-cell epitopes from preproinsulin...

..The present format of the database allows text string matching searches but can easily be converted for use in conjunction with sequence analysis packages. The database can be accessed via Internet using WWW or FTP...

..The ELISA should facilitate screening to evaluate the role of autoimmunity to GAD in the development of IDDM...

..The expression of both GAD 67 and GAD 65 genes specifically in islet beta-cells indicates that both GAD forms are candidate autoantigens in rodent models of insulin-dependent diabetes mellitus...

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..Embracing a holistic view of the diabetes syndrome will help us to understand the environmental basis for the epidemic of diabetes and improve preventative strategies...

..These findings are a basis for further investigation of the role of extracellular matrix molecules and their receptors in pancreas function...

..We aimed to characterize macrophage phenotype and function in human subcutaneous and omental adipose tissue in relation to insulin resistance in obesity...

..CONCLUSIONS: At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA...

..We suggest, therefore, that signal transduction by TSH in the thyroid involves direct linkage of the TSH receptor to actin microfilaments by ABP and that TABP may interact with ABP to mediate TSH-induced actin microfilament disruption...

..Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment...

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..We propose that PAQR10 may act at the level of the mitochondrion to regulate pancreatic endocrine cell development/survival...

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..This suggests that islet inflammation can substitute for proinsulin-specific CD4(+) T cell help to activate IGRP(206-214)-specific T cells...

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..The diabetes is mild enough so that most diabetic mice can be maintained to 40 weeks of age without parenteral insulin. This consistency of diabetes avails that outcomes of intervention can be interpreted with confidence...

..Compared to thymocytes, insulinoma cells and islets from NOD mice were characterised by low basal and cytokine-induced caspase-3 activity...

..In this review, we consider the nature and function of such antigen-specific T(Reg) cells, and strategies for their therapeutic induction are discussed...

..In this review, we will focus on these areas to highlight recent advances in understanding the pathogenesis of autoimmune diabetes, drawing extensively on insights gained by studying the non-obese diabetic (NOD) mouse...

..Human rotaviruses replicated in monkey islets only. This islet susceptibility shows that rotavirus infection of the pancreas in vivo might be possible...

..The CD4+ cytokine response in the lungs may be a useful measure of immunogenicity to determine the most effective influenza reassortant for inclusion in vaccines...

..Furthermore, at least in NIT-1 cells, the extrinsic FasL/Fas pathway has only a minor additive effect on cytokine-induced Deltapsim impairment...