IL-6 Induced by Staphylococcus aureus Infection Prevents the Induction of Skin Allograft Acceptance in Mice

Department of Surgery Medicine, The University of Chicago, Chicago, IL, USA.
American Journal of Transplantation (Impact Factor: 5.68). 03/2011; 11(5):936-46. DOI: 10.1111/j.1600-6143.2011.03476.x
Source: PubMed


Clinical correlations between bacterial infections and rejection suggest a hypothesis that innate immune stimulation by bacterial infections results in the production of inflammatory cytokine that facilitate bystander T-cell activation, increased alloreactivity and inhibition of tolerance induction. Previous studies demonstrated that IFNβ produced during an infection with a model bacterium, Listeria monocytogenes, prevented the induction of transplantation tolerance in mice with anti-CD154 and donor-specific transfusion (DST) (1). We investigated the impact of two clinically relevant bacterial infections at the time of transplantation on the ability of anti-CD154 and DST to induce skin allograft acceptance in mice. Staphylococcus aureus (SA) infection prevented skin allograft acceptance whereas maximally tolerated doses of Pseudomonas aeruginosa infection had no effect. SA induced an acute production of IL-6, which was necessary and sufficient for the prevention of skin allograft acceptance. Furthermore, a single pulse of methylprednisolone modulated IL-6 production during SA infection and facilitated skin allograft acceptance in SA-infected recipients. Taken together, our results suggest that bacterial infections elicit specific proinflammatory cytokines signatures that can serve as barriers to tolerance induction, and that inhibiting the production of or neutralizing these inflammatory cytokines can synergize with costimulatory blockade-based therapies to facilitate the development of transplantation tolerance.

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Available from: Anita Chong, Jan 16, 2015
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    • "Donor-specific tolerance means that, in the absence of immunosuppression, potential graft-threatening alloreactivity is controlled while other immune responses remain intact (i.e. against cancers or infections) [4]. However, a body of evidence demonstrates that tolerance is often fragile and easily reversed, particularly in the context of tissue damage or infection [5], [6], [7], [8], [9], [10]. By interacting with “danger” receptors such as Toll-like receptors (TLRs), pathogen-associated molecular patterns (PAMPs) or endogenous damage-associated molecular patterns (DAMPs) trigger innate immune response, dendritic cell maturation and alloreactive T cell priming ultimately leading to allograft rejection. "
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    ABSTRACT: Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "From the immunological point of view, bacterial infection (i.g. Staphylococcus aureus, Streptococcus pyogenes) strongly induces proinflammatory cytokines, including IL-1β, IL-6, IL-17 and PGE2 [6, 7]. These proinflammatory cytokines induce myeloid-derived suppressor cells, which, together with regulatory T cells (Tregs), are known to play a central role in the induction of peripheral tolerance [4]. "
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    ABSTRACT: We describe a 49-year-old Japanese woman with cutaneous squamous cell carcinoma (SCC) developing from recessive dystrophic epidermolysis bullosa (RDEB). Interestingly, immunohistochemical staining revealed dense infiltration of CD163(+) M2 macrophages and numerous Foxp3(+) regulatory T cells (Tregs) around the tumor. Since the contribution of immunosuppressive factors (e.g. TGFβ) to the carcinogenesis of SCC from RDEB was recently reported, our present findings suggest one of the possible contributions of immunosuppressive cells, such as CD163(+) M2 macrophages and Tregs, to the carcinogenesis of SCC from RDEB.
    Full-text · Article · Sep 2012 · Case Reports in Dermatology
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    • "Overall, these findings indicate that the inflammatory milieu of a particular viral or bacterial infection can impact the priming and/or recall of alloimmune responses (Ahmed et al., 2011a). The mechanisms underlying this phenomenon involve the ability of a particular infectious agent to induce the adjuvant effects of IL-6 and type I interferons (Wang et al., 2010; Ahmed et al., 2011b), and also likely the ability of pathogen infections to license dendritic cells that may also be presenting alloepitopes (Alegre et al., 2008a,b), either through the direct or indirect pathway. "
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    ABSTRACT: Adaptive immunity in both mouse and man results in the generation of immunological memory. Memory T cells are both friend and foe to transplant recipients, as they are intimately involved and in many cases absolutely required for the maintenance of protective immunity in the face immunosuppression, yet from the evidence presented herein they clearly constitute a formidable barrier for the successful implementation of tolerance induction strategies in transplantation. This review describes the experimental evidence demonstrating the increased resistance of memory T cells to many distinct tolerance induction strategies, and outlines recent advances in our knowledge of the ways in which alloreactive memory T cells arise in previously untransplanted individuals. Understanding the impact of alloreactive memory T cell specificity, frequency, and quality might allow for better donor selection in order to minimize the donor-reactive memory T cell barrier in an individual transplant recipient, thus allowing stratification of relative risk of alloreactive memory T cell mediated rejection, and conversely increase the likelihood of successful establishment of tolerance. However, further research into the molecular and cellular pathways involved in alloreactive memory T cell-mediated rejection is required in order to design new strategies to overcome the memory T cell barrier, without critically impairing protective immunity.
    Preview · Article · Mar 2012 · Frontiers in Immunology
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