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Viral infection: a potent barrier to transplantation tolerance.

Miller DM, Thornley TB, Greiner DL, Rossini AA - Clin. Dev. Immunol. (2008)

Bottom Line: Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade.However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection.In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.

ABSTRACT
Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance.

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Related in: MedlinePlus

Pathogen recognition systems. The innate immune system senses viral pathogens by recognizing distinct pathogen-associated molecular patterns (PAMPs) using various pattern recognition receptors (PRRs). Two of the best-characterized virus-sensing PRRs include member of the Toll-like receptors (TLRs) and retinoic acid inducible gene-I- (RIG-I-) like receptors (RLRs) families. These PRRs couple the recognition of viral PAMPs to the induction of proinflammatory cytokines through various signaling cascades. The cytosolic RNA helicase receptors MDA5 and RIG-I initiate the cascade by recruiting the Cardif/TBK1 complex after sensing viral RNA. This activates the kinase TBK1 to phosphorylate interferon regulatory factor (IRF)-3 and IRF7, resulting in their nuclear translocation and the transcription of IFNα/β. The cell surface receptor TLR4, in partnership with CD14, couples the recognition of respiratory syncytial virus fusion protein [78] to cytokine induction by signaling through the MyD88-dependent as well as the MyD88-independent pathways. The endosomal TLRs, TLR7, TLR8, and TLR9 also signal through MyD88 to activate inflammatory cytokines such as TNF, IL-6, and IFN-α/β. The other endosomal TLR (TLR3) signals through the MyD88-independent pathway via the TIR domain-containing adaptor molecule TRIF. Via TRIF, TLR3 signaling can activate NF-kB using TRAF6, and in addition, can induce type I IFN expression probably via TRAF3, TBK1, and IRF3.
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fig2: Pathogen recognition systems. The innate immune system senses viral pathogens by recognizing distinct pathogen-associated molecular patterns (PAMPs) using various pattern recognition receptors (PRRs). Two of the best-characterized virus-sensing PRRs include member of the Toll-like receptors (TLRs) and retinoic acid inducible gene-I- (RIG-I-) like receptors (RLRs) families. These PRRs couple the recognition of viral PAMPs to the induction of proinflammatory cytokines through various signaling cascades. The cytosolic RNA helicase receptors MDA5 and RIG-I initiate the cascade by recruiting the Cardif/TBK1 complex after sensing viral RNA. This activates the kinase TBK1 to phosphorylate interferon regulatory factor (IRF)-3 and IRF7, resulting in their nuclear translocation and the transcription of IFNα/β. The cell surface receptor TLR4, in partnership with CD14, couples the recognition of respiratory syncytial virus fusion protein [78] to cytokine induction by signaling through the MyD88-dependent as well as the MyD88-independent pathways. The endosomal TLRs, TLR7, TLR8, and TLR9 also signal through MyD88 to activate inflammatory cytokines such as TNF, IL-6, and IFN-α/β. The other endosomal TLR (TLR3) signals through the MyD88-independent pathway via the TIR domain-containing adaptor molecule TRIF. Via TRIF, TLR3 signaling can activate NF-kB using TRAF6, and in addition, can induce type I IFN expression probably via TRAF3, TBK1, and IRF3.

Mentions: Howdoes virus-mediated activation of innate immunity lead to the production of IFN-α/β?At present, the two best-characterized IFN-α/β-inducingviral recognition systems are members of the TLR and the retinoic acidinducible gene-I- (RIG-I-) like receptor (RLR) families (Figure 2). These receptors are activated by sensing viral nucleicacids either in the cytosol (RLR) or in endosomes (TLR) of cells [76]. Cytosolic receptors thatdetect nucleic acids upon viral infection are expressed ubiquitously bynucleated cells, while endosomal receptors, which detect viral particles thatare engulfed from outside rather than from direct infection, are expressed inspecialized cells of the innate immune system such as macrophages and dendriticcells [77].


Viral infection: a potent barrier to transplantation tolerance.

Miller DM, Thornley TB, Greiner DL, Rossini AA - Clin. Dev. Immunol. (2008)

Pathogen recognition systems. The innate immune system senses viral pathogens by recognizing distinct pathogen-associated molecular patterns (PAMPs) using various pattern recognition receptors (PRRs). Two of the best-characterized virus-sensing PRRs include member of the Toll-like receptors (TLRs) and retinoic acid inducible gene-I- (RIG-I-) like receptors (RLRs) families. These PRRs couple the recognition of viral PAMPs to the induction of proinflammatory cytokines through various signaling cascades. The cytosolic RNA helicase receptors MDA5 and RIG-I initiate the cascade by recruiting the Cardif/TBK1 complex after sensing viral RNA. This activates the kinase TBK1 to phosphorylate interferon regulatory factor (IRF)-3 and IRF7, resulting in their nuclear translocation and the transcription of IFNα/β. The cell surface receptor TLR4, in partnership with CD14, couples the recognition of respiratory syncytial virus fusion protein [78] to cytokine induction by signaling through the MyD88-dependent as well as the MyD88-independent pathways. The endosomal TLRs, TLR7, TLR8, and TLR9 also signal through MyD88 to activate inflammatory cytokines such as TNF, IL-6, and IFN-α/β. The other endosomal TLR (TLR3) signals through the MyD88-independent pathway via the TIR domain-containing adaptor molecule TRIF. Via TRIF, TLR3 signaling can activate NF-kB using TRAF6, and in addition, can induce type I IFN expression probably via TRAF3, TBK1, and IRF3.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2536507&req=5

fig2: Pathogen recognition systems. The innate immune system senses viral pathogens by recognizing distinct pathogen-associated molecular patterns (PAMPs) using various pattern recognition receptors (PRRs). Two of the best-characterized virus-sensing PRRs include member of the Toll-like receptors (TLRs) and retinoic acid inducible gene-I- (RIG-I-) like receptors (RLRs) families. These PRRs couple the recognition of viral PAMPs to the induction of proinflammatory cytokines through various signaling cascades. The cytosolic RNA helicase receptors MDA5 and RIG-I initiate the cascade by recruiting the Cardif/TBK1 complex after sensing viral RNA. This activates the kinase TBK1 to phosphorylate interferon regulatory factor (IRF)-3 and IRF7, resulting in their nuclear translocation and the transcription of IFNα/β. The cell surface receptor TLR4, in partnership with CD14, couples the recognition of respiratory syncytial virus fusion protein [78] to cytokine induction by signaling through the MyD88-dependent as well as the MyD88-independent pathways. The endosomal TLRs, TLR7, TLR8, and TLR9 also signal through MyD88 to activate inflammatory cytokines such as TNF, IL-6, and IFN-α/β. The other endosomal TLR (TLR3) signals through the MyD88-independent pathway via the TIR domain-containing adaptor molecule TRIF. Via TRIF, TLR3 signaling can activate NF-kB using TRAF6, and in addition, can induce type I IFN expression probably via TRAF3, TBK1, and IRF3.
Mentions: Howdoes virus-mediated activation of innate immunity lead to the production of IFN-α/β?At present, the two best-characterized IFN-α/β-inducingviral recognition systems are members of the TLR and the retinoic acidinducible gene-I- (RIG-I-) like receptor (RLR) families (Figure 2). These receptors are activated by sensing viral nucleicacids either in the cytosol (RLR) or in endosomes (TLR) of cells [76]. Cytosolic receptors thatdetect nucleic acids upon viral infection are expressed ubiquitously bynucleated cells, while endosomal receptors, which detect viral particles thatare engulfed from outside rather than from direct infection, are expressed inspecialized cells of the innate immune system such as macrophages and dendriticcells [77].

Bottom Line: Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade.However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection.In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.

ABSTRACT
Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance.

Show MeSH
Related in: MedlinePlus