Matthias G Von Herrath

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..Here we analysed the effect of B:9-23/IFA immunisation at later stages of the disease and the underlying mechanisms...

..Here, we propose that the immunological process that is at the root of T1D is relapsing-remitting in nature and discuss the unresolved controversies and therapeutic implications of this hypothesis...

..Both will be discussed in this chapter and suitable combinatorial approaches will be suggested...

..g. autoimmunity). Conversely, regulatory cells and cytokines operative at low homeostatic levels should unfold therapeutic capacities by further embellishment but not additional reduction...

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..The recent development of novel technologies will allow more precise quantification of in vivo destruction and regeneration in order to test these hypotheses...

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..This finding has important implications for interpreting numbers and pathogenicity of autoreactive lymphocytes in prediabetic patients of genetically diverse backgrounds...

..The compound is currently undergoing phase II clinical trials...

..Thus, administration of nonmitogenic CD3 prevents diabetes by sufficient systemic reduction of (auto)aggressive lymphocytes, but without compromising antiviral immune competence...

..In combination, these two immune elements have the potential to permanently stop type 1 diabetes. It is my belief that only combination therapies will enable the permanent prevention and curing of type 1 diabetes...

..This commentary addresses the utility and limitations of these models for facilitating the 'translation' of immunology research into clinical applications...

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..This review addresses why in silico modeling is needed in immunology research, highlights some of the major areas of research and suggests what may be important for the future of immunoinformatics...

..Thus, SOCS expression renders beta-cells resistant to CTL attack in a mouse model of T1D...

..We investigated the differential effect of this cytokine on CD8(+) T-cells in autoimmunity and antiviral immunity...

..Sequential heterologous viral infections might therefore act in concert to precipitate clinical autoimmune disease, even if single exposure to a viral mimic does not always cause sufficient tissue destruction...

..Our results indicate that CXCL10 expression accelerates the autoimmune process by enhancing the migration of Ag-specific lymphocytes to their target site...

..Thus, autoreactivity toward de novo-expressed beta-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present...

..These results suggest that the TLR9 signaling pathway is involved in the efficacy of plasmid vaccination; therefore, it should remain a focus in the development or amelioration of vaccines to treat infections in humans...

..Thus, memory precursors can be identified among primary effector cells and are selected for survival and differentiation by CD8alphaalpha...

..We identify novel mechanisms by which TLR2 promotes immunoregulation and controls autoimmune diabetes in naïve or infected hosts. This work should help understand T1D etiology and develop novel immune-based therapeutic interventions...

..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...

..This observation points toward a therapeutic opportunity for the treatment of T1D and other autoimmune disorders...

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..Therefore, autoantigens such as insulin that are expressed at higher levels in beta cells might have a more profound impact on diabetes pathogenesis...

..Thus, DC-derived exosomes do not appear to contribute significantly to CTL priming during acute LCMV infection...

..We conclude that IL-21R controls both antigen transport by DCs and the crucial beacon function of CD4(+) cells for autoreactive CD8(+) cells to reach the islets...

..Therapeutic IL-10R blockade broke the cycle of IL-10-mediated immune suppression, preventing IL-10 priming by CD8alpha- DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology...

..Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition...

..In terms of safety it is encouraging that resolution of the infection, at least in the case of LCMV, is not inhibited...

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..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...

..We conclude that viral elimination and type 1 diabetes can occur in the absence of detectable IL-17A production, suggesting IL-17A is not essential in these settings...

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..Furthermore, protection of prediabetic recipients was autoantigen specific and did not result in generalized immunosuppression. The origin, function, and therapeutic potential of these bitypic NK/DC regulatory cells is discussed...

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..In this review we will focus on the pathogenesis of T1D in a virus-induced transgenic mouse model and discuss possibilities of how an aggressive type 1-dominated immune response can be restrained and autoimmunity be abrogated...

..In this review, we will take a closer look at mechanistic evidence for a potential role of viruses in T1D, with a special focus on molecular mimicry...

..Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen...

..First, we review recent findings that blockade of IL-10/IL-10R interaction can resolve chronic viral infection and second, we reflect on how neutralization of the chemokine CXCL10 can abrogate virus-induced type 1 diabetes...

..Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course...

..Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans...

..Thus, our results indicate that an intrinsic property of the epitope (MHC binding affinity) and an intrinsic property of the host (naive precursor frequency) jointly dictate the immunodominance hierarchy of CD8(+) T cell responses...

..Here we provide a model of how experienced autoaggressive CD8 lymphocytes are dying by apoptosis as a result of beta cell-specific TNF-alpha expression at a time when the autoimmune process is already ongoing...

..Thus, secretion of IFN-gamma-inducible protein-10 by autoaggressive CD8(+) lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion...

..Our findings will be of importance for designing safe antigen-specific interventions for human type 1 diabetes...

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..Altogether, these results chart the way for novel prevention and intervention strategies for viral myocarditis...

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..Already activated autoreactive cells might be easier re-activated and primed for effector functions by cross-reactive ligands than naive lymphocytes...

..First, we review recent findings that blockade of IL-10/IL-10R interaction can resolve chronic viral infection and second, we reflect on how neutralization of the chemokine CXCL10 can abrogate virus-induced type 1 diabetes...

..However, we have recent evidence that virus specific CD25+ cells can be generated and are able to affect antiviral responses in vivo...

..This review will concentrate on two different types of regulatory T-cells, the naturally occurring ('professional') CD4+CD25+ T-cells and antigen-induced ('adaptive') CD4+ Th2-like regulatory T-cells...

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..We discuss how future combination therapies can be used to inhibit viral synthesis as well as strengthen the antiviral response without increasing immunopathology or the development of autoimmune disease...

..2007) find that secondary necrosis of beta-cells can prime the autoimmune response via uptake by and activation of antigen-presenting cells through Toll-like receptor 2...

..Such ideal interventions will hopefully retain a diverse repertoire of pathogen-specific T cells, while maintenance of self-, foreign- and alloantigen-specific Tregs ensures life-long graft tolerance...

..Our findings hold important implications to understand and predict the success of antigen-based clinical trials, where responsiveness to immunotherapy might vary from patient to patient...

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..While in cases of rapid microbial (CD8)-driven T1D CD103 antibody blockade may not limit disease progression or severity, in mucosally-driven cases of T1D anti-CD103 antibody treatment may provide a new and safe therapeutic avenue...

..This clinical Phase I/II trial is relevant to fine-tuning interventive protocols and contributing to the further development of suitable combination therapies to prevent and treat Type 1 diabetes...

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..In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D...

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

..Knowledge of mechanisms that underlie either positive or negative effects of infections on autoimmunity will facilitate exploration of molecular details for prospective clinical studies in the future...

..In this review, we discuss the current knowledge on NKG2D and its ligands in the context of autoimmune diseases and immune-mediated diseases that inadvertently target endogenous cells and/or tissue...

..Understanding the cellular dynamics during T1D development is critical for the rational design of immunotherapies...

..Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects...

..There are, however, a number of concerns that should be addressed in order to improve future therapeutic strategies...

..It remains questionable, however, whether these surviving cells can physiologically sense and respond to glucose stimuli...

..Reemergence of autoreactivity is likely the main culprit underlying long-term islet graft failure, and new strategies will need to be tested to circumvent this homeostatic expansion and recurrent autoreactivity...

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..Accumulating evidence on the immunomodulatory roles of dsRNAs warrants a reconsideration of various models of immune homeostasis...

..Thus, a lack of CD103 expression does not affect functional impairment of effector T-cell responses during chronic viral infection...

..Finally, we outline implications on the earlier concept of T1/T2 dichotomy, supporting a model in which these two subsets, rather than being mutually antagonistic, together facilitate the recovery from infection...

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..By allowing the escape of subdominant T cells, this process still preserves a relatively broad peripheral TCR repertoire that can actively participate in antiviral and/or autoreactive immune responses...

..These mechanisms are discussed in the context of multiple sclerosis, myocarditis, and diabetes, three immune-medicated diseases often linked with virus infections...

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..Thus, diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions...

..These findings have implications for the physiologic, pathological, and therapeutic regulation of costimulation...

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..Additionally, we expect that this symposium will be of interest to junior faculty working in the areas of autoimmune disease research, as well as patient advocacy groups. ..

..These assays should provide strong guidance to the goals of the clinical project (#3, Herold). ..

..Aim 1: Importance of IP-10 in the pathogenesis of T1D - therapeutic blockade and mechanistic analyses. Aim 2: Importance of IP-10 during islet allograft rejection - therapeutic blockade and mechanistic analyses. ..

..In order to assure that our findings reach those groups working on HIV and HCV, cooperations have been established with leading groups in the field. ..

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..We believe that these two goals will greatly improve our understanding of how autoantigens are driving an autoaggressive process and during which phases of the diabetogenic response the initiating antigen(s) are important. ..

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..Therefore, the direct comparison of three autoimmune models will enable us to define, which in vivo consequences of costimulation blockade occur more commonly and which are restricted to a given experimental situation. ..

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..In order to assure that our findings reach those groups working on HIV and HCV, cooperations have been established with leading groups in the field. ..