New Reagents on the Horizon for Immune Tolerance

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Annual Review of Medicine (Impact Factor: 12.93). 02/2007; 58(1):329-46. DOI: 10.1146/
Source: PubMed

ABSTRACT Recent advances in immunology and a growing arsenal of new drugs are bringing the focus of tolerance research from animal models into the clinical setting. The conceptual framework for therapeutic tolerance induction has shifted from a "sledgehammer" approach that relies solely on cellular depletion and cytokine targeting, to a strategy directed toward restoring a functional balance across the immune system, namely the different populations of naive cells, effector and memory cells, and regulatory cells. Unlocking the key to tolerance induction in the future will likely depend on our ability to harness the functions of T regulatory cells. Also, dendritic cells are strategically positioned at the interface between innate and adaptive immunity and may be subject to deliberate medical intervention in a way that can control a chronic inflammatory response. Many reagents with tolerance-inducing potential are currently undergoing clinical testing in transplantation, autoimmune diseases, and allergic diseases, and even more that are on the horizon promise to offer enormous benefits to human health.

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Available from: Jeffrey Bluestone, Dec 26, 2013
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    • "A klasszikus antigén-bemutató sejtek is toleranciát hoznak létre, ha a felszínükön nincs aktivált kostimuláló molekula , ami szükséges az MHC-vel komplexet képző antigén mellett a CD4 T-sejtek aktivációjához. Ugyancsak toleranciát okoz, ha a T-sejten a kostimuláló molekula , a CTLA-4, ami kapcsolódva az antigén-prezentáló sejten elhelyezkedő CD80 (B7-1) és CD86 (B7-2) ligandhoz kötődve csökkenti a T-sejt aktivációját [8]. Az orális tolerancia kialakításában, mai ismereteink szerint, a regulátor T-sejteken kívül a CD103+ dendritikus sejteknek van kiemelkedően fontos szerepük. "
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    ABSTRACT: In the last decades our knowledge has been enormously broadened about the structure and function of the gut associated lymphoid system. It was recognized how intricate and finely tuned connection exists between the gut bacterial flora and the intestinal mucosa. This subtle balance ensures mucosal homeostasis, which has a key role in organ defence against pathogens. However, at the same time this system makes possible the development of oral tolerance toward the commensals and the food antigens. In case of any disturbances in this finely tuned process, immunmediated intestinal disorders may easily develop. The first part of this paper reviews the structure and function of the mucosal immune system, while the second part surveys the pathogenesis, diagnosis and therapy of coeliac disease, inflammatory bowel disease and cow's milk allergy induced enteropathy. Orv. Hetil., 2013, 154, 1512-1523.
    Orvosi Hetilap 09/2013; 154(38):1512-23. DOI:10.1556/OH.2013.29710
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    • "Tolerance is achieved in part by selecting against self-reactive T lymphocytes during ontogeny in the thymus, a powerful mechanism termed as central tolerance (Gershon and Kondo, 1971; Bonomo et al., 1995; Zheng et al., 2003; Kyewski and Klein, 2006; St Clair et al., 2007). However, there are " peripheral " tolerance mechanisms that divert immune responses away from self and toward appropriate pathogens (Miller and Morahan, 1992; Arnold et al., 1993; Anderson and Chan, 2004; Anderson et al., 2005; St Clair et al., 2007; Moraes-Vasconcelos et al., 2008). "
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    ABSTRACT: CD4⁺CD25⁺Foxp3⁺ T lymphocytes, known as regulatory T cells or T(regs), have been proposed to be a lineage of professional immune suppressive cells that exclusively counteract the effects of the immunoprotective "helper" and "cytotoxic" lineages of T lymphocytes. Here we discuss new concepts on the mechanisms and functions of T(regs). There are several key points we emphasize: 1. Tregs exert suppressive effects both directly on effector T cells and indirectly through antigen-presenting cells; 2. Regulation can occur through a novel mechanism of cytokine consumption to regulate as opposed to the usual mechanism of cytokine/chemokine production; 3. In cases where CD4⁺ effector T cells are directly inhibited by T(regs), it is chiefly through a mechanism of lymphokine withdrawal apoptosis leading to polyclonal deletion; and 4. Contrary to the current view, we discuss new evidence that T(regs), similar to other T-cells lineages, can promote protective immune responses in certain infectious contexts (Chen et al., 2011; Pandiyan et al., 2011). Although these points are at variance to varying degrees with the standard model of T(reg) behavior, we will recount developing findings that support these new concepts.
    Frontiers in Immunology 11/2011; 2:60. DOI:10.3389/fimmu.2011.00060
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    • "First, short term modulation of T cells can elicit long-term effects on immune tolerance [5]. Second, many of these agents thought to provide long-lived efficacy are considered to do so through promoting Treg subsets [6]. "
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    ABSTRACT: Therapies directed at augmenting regulatory T cell (Treg) activities in vivo as a systemic treatment for autoimmune disorders and transplantation may be associated with significant off-target effects, including a generalized immunosuppression that may compromise beneficial immune responses to infections and cancer cells. Adoptive cellular therapies using purified expanded Tregs represents an attractive alternative to systemic treatments, with results from animal studies noting increased therapeutic potency of antigen-specific Tregs over polyclonal populations. However, current methodologies are limited in terms of the capacity to isolate and expand a sufficient quantity of endogenous antigen-specific Tregs for therapeutic intervention. Moreover, FOXP3+ Tregs fall largely within the CD4+ T cell subset and are thus routinely MHC class II-specific, whereas class I-specific Tregs may function optimally in vivo by facilitating direct tissue recognition. To overcome these limitations, we have developed a novel means for generating large numbers of antigen-specific Tregs involving lentiviral T cell receptor (TCR) gene transfer into in vitro expanded polyclonal natural Treg populations. Tregs redirected with a high-avidity class I-specific TCR were capable of recognizing the melanoma antigen tyrosinase in the context of HLA-A*0201 and could be further enriched during the expansion process by antigen-specific reactivation with peptide loaded artificial antigen presenting cells. These in vitro expanded Tregs continued to express FOXP3 and functional TCRs, and maintained the capacity to suppress conventional T cell responses directed against tyrosinase, as well as bystander T cell responses. Using this methodology in a model tumor system, murine Tregs designed to express the tyrosinase TCR effectively blocked antigen-specific effector T cell (Teff) activity as determined by tumor cell growth and luciferase reporter-based imaging. These results support the feasibility of class I-restricted TCR transfer as a promising strategy to redirect the functional properties of Tregs and provide for a more efficacious adoptive cell therapy.
    PLoS ONE 07/2010; 5(7):e11726. DOI:10.1371/journal.pone.0011726 · 3.23 Impact Factor
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