|Viral infection: a potent barrier to transplantation tolerance.|
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|PMID: 18815618 Owner: NLM Status: MEDLINE|
|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.|
|David M Miller; Thomas B Thornley; Dale L Greiner; Aldo A Rossini|
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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review|
|Title: Clinical & developmental immunology Volume: 2008 ISSN: 1740-2530 ISO Abbreviation: Clin. Dev. Immunol. Publication Date: 2008|
|Created Date: 2008-09-25 Completed Date: 2009-01-02 Revised Date: 2013-06-05|
Medline Journal Info:
|Nlm Unique ID: 101183692 Medline TA: Clin Dev Immunol Country: United States|
|Languages: eng Pagination: 742810 Citation Subset: IM|
|Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.|
|APA/MLA Format Download EndNote Download BibTex|
Graft Rejection / immunology, virology
Immunity, Innate / immunology
Immunosuppression / methods
Signal Transduction / immunology
Transplantation Tolerance / immunology*
Virus Diseases / immunology*
|AI42669/AI/NIAID NIH HHS; DK32520/DK/NIDDK NIH HHS|
Journal ID (nlm-ta): Clin Dev Immunol
Journal ID (publisher-id): CDI
Publisher: Hindawi Publishing Corporation
Copyright ? 2008 David M. Miller et al.
open-access: This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received Day: 8 Month: 4 Year: 2008
Accepted Day: 26 Month: 6 Year: 2008
Print publication date: Year: 2008
Electronic publication date: Day: 14 Month: 9 Year: 2008
Volume: 2008E-location ID: 742810
PubMed Id: 18815618
|Viral Infection: A Potent Barrier to Transplantation Tolerance|
|David M. Miller1|
|Thomas B. Thornley1|
|Dale L. Greiner1|
|Aldo A. Rossini1,2I2*|
1Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
2Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
|Correspondence: *Aldo A. Rossini: firstname.lastname@example.org
[other] Recommended by Eiji Matsuura
Organ transplantation in the clinic became a reality in 1954 when Merrill, Murray, and Harrison performed the first successful human vascular organ graft, a kidney transplant [1, 2]. However, the donor and recipient were monozygotic twins, obviating the need for immunosuppression for organ graft survival. With the development of immunosuppressive regimens, the same group 5 years later performed the first kidney allograft transplantation between unrelated individuals; that graft survived for 20 years . Although successful graft survival was achieved, it rapidly became clear that all immunosuppressive drugs, even the newer generations of immunosuppressive regimens, are toxic [4, 5]. Immunosuppressive drugs are also known to increase the risk of infection and neoplasia [6, 7], and their associated side effects often lead to patient noncompliance . Since most patients eventually reject transplanted allografts either acutely or through a process of chronic rejection [9?11], these deleterious side effects make organ transplantation a therapy in which the risk/benefit ratio must be carefully weighed.
To overcome issues associated with chronic immunosuppression, investigators have focused on approaches that lead to the induction of tolerance to transplanted organ allografts . Operationally, transplantation tolerance is defined as the survival of a donor allogeneic graft in the absence of immunosuppression. Most transplantation tolerance induction protocols take advantage of information resulting from studies on the natural mechanisms by which the immune system prevents self-reactivity and autoimmune disease. Two major forms of natural tolerance have been identified: central tolerance and peripheral tolerance.
In 1953, Peter Medawar et al. obtained the first experimental evidence that the establishment of allogeneic hematopoietic chimerism leads to the induction of central tolerance and permits permanent acceptance of skin allografts . Inspired by the work done in freemartin cattle by Owen in 1945  and the clonal selection theory subsequently proposed by Burnet and Fenner , Medawar demonstrated in mice that the transfer of allogeneic hematopoietic cells in utero could induce tolerance to skin transplanted from the original donor later in life .
Medawar's observation led Main and Prehn to experimentally induce hematopoietic chimerism by treating mice with whole-body irradiation (WBI) and allogeneic bone marrow cells, followed by transplantation with donor-strain-matched skin allografts . This protocol successfully induced tolerance to skin allografts, conclusively linking the establishment of hematopoietic chimerism with subsequent allograft survival. However, despite the long-term survival of skin allografts on mice treated with WBI and allogeneic bone marrow, animals eventually develop lethal graft-versus-host disease (GVHD), a reaction where passenger leukocytes in the donor bone marrow or graft mount an immune response against the host. Therefore, modern conditioning protocols to induce central tolerance have been designed to address the common objectives of (1) establishing hematopoietic chimerism using a relatively benign preconditioning protocol that (2) prevents the development of GVHD.
Despite these common objectives, modern conditioning regimens can differ quite significantly in their methodology. In preclinical models of hematopoietic chimerism, conditioning regimens span the spectrum from myeloablative protocols, which often entail lethal irradiation and subsequent stem cell rescue, to noncytoreductive treatments that do not require irradiation, for example, costimulation blockade [17?19]. Between these two extremes are protocols that significantly weaken the recipient's immune system through selective antibody-mediated elimination of specific immune populations (e.g., CD4+ and CD8+ T cells) coupled with targeted irradiation (e.g., thymic irradiation) . These latter protocols are often considered nonmyeloablative. In clinical trials, successful nonmyeloablative approaches have recently been described [21, 22]. Stable renal allograft function in recipients for as long as five years after complete withdrawal of immunosuppressive drugs was observed in recipients in which hematopoietic chimerism was established [21, 22]. These reports document that in humans, as in rodents, establishment of hematopoietic chimerism is a robust approach for the development of central tolerance and the permanent survival of donor-specific allografts.
The second major form of tolerance is peripheral tolerance. Different from central tolerance in which hematopoietic chimerism leads to the clonal deletion of antigen-specific cells during development, peripheral tolerance targets pre-existing cells that have already been generated. To induce tolerance in this population, fundamental insights into how naive antigen-specific T cells become activated have led to protocols designed to prevent this process. Naive T cell activation is initiated by the interaction of the antigen-specific T cell receptor (TCR) with a peptide presented by the MHC. This interaction conveys specificity leading to the activation of only antigen-specific T cells. This signal is often termed as ?signal 1? (Figure 1). Following TCR-peptide/MHC ligation, a T cell then receives a number of costimulatory signals [23?25]. A key costimulatory signal in this pathway that permits the activated naive T cells to become functional effector/memory T cells is provided by CD28-CD80/86 interaction , which has often been referred to as ?signal 2.? In early studies, it was shown in vitro that T cells that receive signals through their TCR in the absence of engagement of the CD28-CD80/86 costimulation pathway became nonresponsive, a state of T cell nonresponsiveness often referred to as anergy [12, 27]. Following induction of signal 2, cytokines are produced that impart the final signal for T cell activation, and this is termed as ?signal 3? [24, 28, 29]. Although these three critical signals are required for the full activation of T cells, additional signals such as those derived from CD40-CD154 interaction can have potent effects on the activation of naive T cells (Figure 1).
The existence of a comparable in vivo state of T cell nonresponsiveness has been debated for years until it was independently shown to exist by Ohashi et al.  and Oldstone et al.  using two very similar experimental systems. These investigators generated double-transgenic mice that expressed (1) lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP)  or nucleoprotein (NP)  under the control of the rat insulin promoter, and (2) a transgenic TCR that recognizes a peptide from the transgenic LCMV protein. In unmanipulated mice, the transgenic T cells migrate from the thymus into the peripheral tissues and encounter their cognate antigen, but they remain nonresponsive to islets expressing GP or NP. However, LCMV infection reverses this state of nonresponsiveness, leading to a diabetic phenotype resulting from the destruction of pancreatic islets expressing the transgenic protein [30, 31]. These data support a mechanism where the LCMV-reactive T cells in naive mice encounter antigen in the absence of costimulation and become nonresponsive (tolerant), and further show that environmental perturbation can break this nonresponsive state. This model serves as the conceptual basis for the induction of peripheral transplantation tolerance, where the in vivo disruption of the costimulatory process?referred to as costimulation blockade?leads to the induction of tolerance in an antigen-specific manner .
Costimulation blockade therapies can target several different steps in the process of T cell activation. However, the CD40-CD154 pathway linking signal 1 to signal 2 has been identified to be a critical step in the activation of naive T cells. Anti-CD154 mAb blocks the interaction between CD154 on the T cell and CD40 on the APC [32, 33], and prevents the differentiation between naive T cells and effector/memory T cells  (Figure 1).
In peripheral tolerance induction protocols, anti-CD154 monotherapy significantly improves islet  and cardiac  allograft survival in mice and islet allograft survival in nonhuman primates [36?39]. In combination with a donor-specific transfusion (DST), anti-CD154 monoclonal antibody (mAb) induces permanent islet  and prolonged skin  allograft survival in mice. DST provides selective activation of the alloantigen-specific T cells, and we have shown that the subsequent blockade of costimulation by anti-CD154 mAb leads to selective depletion of only the specific alloantigen-reactive CD8+ T cells [41, 42]. Another reagent, CTLA4-Ig, binds to the costimulatory molecules CD80/86 on the APC. This blocks its interaction with CD28 on the T cell, preventing signal 2. CTLA4-Ig monotherapy induces the survival of xenogeneic islets  and allogeneic cardiac grafts . Not surprisingly, the combination of anti-CD154 mAb and CTLA4-Ig has shown great potential in prolonging skin and cardiac allograft survival in mice .
Effective as a peripheral tolerance induction protocol, costimulation blockade protocols based on blockade of the CD40-CD154 pathway have also been used to establish hematopoietic chimerism leading to the generation of central tolerance [17?19]. By establishing multilineage hematopoietic chimerism, these noncytoreductive protocols have proven to promote robust transplantation tolerance to a variety of solid-organ allografts across fully allogeneic barriers when transplanted several weeks after bone marrow transplantation (BMT) [17, 18] or being concurrent with BMT [19, 46]. Furthermore, because donor-reactivity against the host is dependent on the CD40-CD154 pathway , costimulation blockade effectively establishes hematopoietic chimerism in the absence of GVHD [17, 18].
As costimulation blockade protocols move closer to clinical reality, there is concern that virus infection during tolerance induction may (1) induce tolerance to the virus, (2) prevent the induction or maintenance of tolerance to the organ allograft, or (3) increase risk to the host. Viruses are known to stimulate innate immunity by activating various pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and retinoic acid inducible gene-I- (RIG-I-) like receptors (RLRs) . Activation of innate immunity by virus infection leads to the modulation of adaptive immunity, and it has been shown to impair transplantation tolerance induction and allograft survival [49?57].
For example, infection with LCMV before , at the time of [51, 56], or shortly after costimulation blockade for the induction of peripheral tolerance  impairs allograft survival. Mice treated with costimulation blockade rapidly reject skin allografts if they are infected with LCMV shortly after skin transplantation . Interestingly, this effect appeared to be virus-specific, as infection with vaccinia virus (VV) and murine cytomegalovirus (MCMV) did not engender allograft rejection . Furthermore, skin allograft survival is significantly shortened in LCMV-immune mice treated with a peripheral tolerance induction protocol consisting of DST and anti-CD154 mAb combination therapies . Additionally, TLRs and their proinflammatory role in responding to infection and ischemia are being increasingly seen as a serious obstacle to solid-organ transplantation [58?60].
Barriers to the induction of hematopoietic chimerism and establishment of central tolerance in the setting of viral infection have also been reported. Anti-CD154 mAb, CTLA4-Ig, and busulfan treatment fails to induce bone marrow chimerism and tolerance to skin allografts in the setting of multiple viral infections . Moreover, using a nonmyeloablative protocol where anti-CD154 mAb treatment was coupled with sublethal irradiation, Forman et al. observed that infection with LCMV on the day of BM transplantation not only resulted in allograft rejection but also proved lethal to the recipient . Interestingly, conditioned recipients that were infected and given syngeneic BM grafts did not die. Recipients of allogeneic BM died by a type I interferon- (IFN-) dependent mechanism, whereas mice deficient in the type I IFN receptor survived. The recent deaths of a cluster of human transplant recipients of LCMV-infected organs make this finding particularly relevant to the safety and efficacy of tolerance induction protocols based on costimulation blockade [61, 62].
It has been shown that mice infected with LCMV concurrent to costimulation blockade treatment [56, 63] or persistently infected with LCMV clone 13 prior to costimulation blockade treatment  rapidly reject skin allografts. In a transgenic TCR model, LCMV prevents the deletion of alloreactive CD8+ T cells that is ordinarily induced by costimulation blockade [56, 63]. In this same model system, injection of a TLR agonist similarly prevents the deletion of host alloreactive CD8+ T cells which are required for skin allograft rejection .
Surprisingly, the TLR4 agonist LPS impairs CD8+ T cell deletion and shortens skin allograft survival by activating host cells  rather than donor cells [64, 65], even though the transgenic CD8 T cells recognize donor antigen via the direct pathway. Furthermore, LPS required the expression of the adaptor molecule myeloid differentiation primary response gene-88 (MyD88) on the recipient to shorten allograft survival [65, 66]. These findings are consistent with clinical data suggesting that TLR4 polymorphisms on the host, but not the donor, correlate with allograft survival . Together, these data suggest that TLR activation induces a soluble mediator that augments host T cell activation, perhaps through a process of bystander activation (see below).
Numerous cytokines are reported to be important in the activation of CD8+ T cells, including IL-12 , TNF? [68, 69], and IFN-?/? . While IL-12 and TNF? are dispensable for shortened allograft survival induced by LPS in costimulation blockade treatment protocols , IFN-?/? has been reported to be absolutely essential for LPS to prime CTLs and induce allograft rejection . Type I IFNs also proved indispensable for allograft rejection mediated by the dsRNA mimetic and TLR3 agonist poly I:C . Emerging data suggest that IFN-?/? can be induced by viruses through a growing number of pathogen recognition receptor systems [71?74]. Thus the induction of IFN-?/? by virus infection or TLR ligation has emerged as an important obstacle to the establishment of peripheral transplantation tolerance as well as to the maintenance of self-tolerance .
How does virus-mediated activation of innate immunity lead to the production of IFN-?/?? At present, the two best-characterized IFN-?/?-inducing viral recognition systems are members of the TLR and the retinoic acid inducible gene-I- (RIG-I-) like receptor (RLR) families (Figure 2). These receptors are activated by sensing viral nucleic acids either in the cytosol (RLR) or in endosomes (TLR) of cells . Cytosolic receptors that detect nucleic acids upon viral infection are expressed ubiquitously by nucleated cells, while endosomal receptors, which detect viral particles that are engulfed from outside rather than from direct infection, are expressed in specialized cells of the innate immune system such as macrophages and dendritic cells .
Cytosolic RLRs, exemplified by the proteins RIG-I and melanoma differentiation factor-5 (MDA5), recognize double stranded RNA (dsRNA) located in the cytosol following replication by an RNA virus, or infection by a dsRNA-genome virus, through interaction with their helicase domains . RLRs contain a caspase recruitment domain (CARD)  which links detection of viral dsRNA to transcription of IFN-?/? by forming homotypic interactions with the CARD-containing molecule interferon-? promoter stimulator (IPS-1, also known as mitochondrial antiviral signaling protein (MAVS), CARD adaptor inducing IFN-B (CARDIF), and virus-induced signaling adaptor (VISA)) [79?82]. Activation of IPS-1 triggers members of the I?B kinase (IKK) family, specifically TANK-binding kinase 1 (TBK-1) and IKK? (also known as inducible I?B kinase, IKK-i), to phosphorylate and activate interferon regulatory factory (IRF)-3 and/or IRF7 [83?88]. Once activated, IRF3 and IRF7 translocate to the nucleus and bind to interferon-stimulated response elements (ISREs) to induce the expression of IFN-? and IFN-?, as well as other IFN-inducible genes [48, 89, 90].
It has recently been recognized that cytoplasmic sensing of DNA can also trigger IFN-? and IFN-? production [91?93]. This pathway is thought to intersect with the RIG-I and MDA5 pathways at the level of TBK-1 and IKK-I , and it requires IRF3 for IFN-?/? induction . A candidate cytosolic recognition receptor that senses and is activated by DNA has been described . This receptor, known as DNA-dependent activator of IFN-regulatory factors (DAI), was reported to induce type I IFN upon recognition of bacterial and mammalian as well as viral DNAs .
With the exception of TLR4, all known TLRs that induce type I IFN recognize nucleic acids, and are found in the endosomal compartment of cells. These include TLR3, TLR7, TLR8, and TLR9. Unlike the cytoplasmic nucleic acid receptors, the cellular distribution of endosomal TLRs is much more restricted. TLR7 and TLR9, which recognize ssRNA [95, 96] and unmethylated DNA that contain CpG motifs , respectively, are expressed highly on both conventional (cDC) and plasmacytoid (pDC) dendritic cells. However, they can also be expressed on other hematopoietic cells, including B cells [98, 99]. TLR3, which recognizes dsRNA , has a broader distribution than TLR7 and TLR9, and can be found on nonhematopoietic cells such as astrocytes and epithelial cells of the cervix, airway, uterus, vagina, intestine, and cornea [76, 98?100]. Its expression, however, is thought to be highest in cDCs [76, 100].
Similar to the other non-IFN-?/?-inducing TLRs, TLR3, 7, 8, and 9 are capable of activating both NF-?B and MAPK cascades and triggering the transcription of scores of proinflammatory cytokines and chemokines [76, 99, 100]. However, the endosomal TLRs are also capable of signaling through additional cascades, which results in the expression of type I IFNs. Recognition of dsRNA by TLR3 results in the activation of the adaptor molecule Toll/interleukin-1 receptor (TIR) domain-containing adaptor protein inducing IFN-? (TRIF) . TRIF interacts with tumor necrosis factor receptor-associated factor (TRAF)-3 to activate TBK1  and, as described above, leads to the activation of IRF3 and IRF7 and induction of type I IFN. In contrast, the coupling of TLR7 and TLR9 to IFN-?/? production involves the adaptor molecule MyD88 [97, 102]. Following recognition of either ssRNA or unmethylated DNA, a large complex consisting of MyD88, TRAF3, TRAF6, IL-1 receptor-associated kinase (IRAK)-4, IRAK-1, IKK-?, and IRF-7 is recruited to the TLR [48, 87, 88, 103?105]. Following recruitment of the complex, cytokines downstream of NF-?B are stimulated, and type I IFN expression is induced in an osteopontin (OPN)  and IRF7-dependent fashion [48, 89]. Interestingly, stimulation of TLR7 and TLR9 in cDCs is capable of inducing the expression of cytokines that are downstream of the NF-?B pathway, such as IL-6 and IL-12. However, only pDCs are capable of producing IFN-? in response to ssRNA and CpG-containing DNA . As exemplified by the multitude of signaling pathways by which TLRs can activate innate immunity, it is clear that virus or microbial infection has multiple ways to active innate immunity and modulate the adaptive immune system during tolerance induction.
There are multiple mechanisms by which virus infection or TLR agonists may modulate tolerance induction and allograft survival. We will focus on three potential mechanisms. First, virus infection can mature APCs to prime non-cross-reactive T cells, a process called bystander activation [107, 108]. Second, virus infection may stimulate innate immune cells to produce cytokines that suppress tolerance-promoting regulatory T cells . Third, virus infection may lead to the generation of virus-specific T cells that can cross-react with alloantigens, a phenomenon known as heterologous immunity .
A mechanism by which virus infection may modulate tolerance induction is through bystander activation. As described above, virus infection activates innate immunity, and is able to mature APCs to ?license? them to activate non-cross-reactive T cells. CD4+ T cells are known to play a pivotal role in the licensing of antigen-presenting cells (APCs) . The intercourse between antigen-specific CD4+ T cells and antigen-presenting APCs is thought to be crucial for the generation of a full immune response. In the setting of viral infection, virus-specific CD4+ T cells facilitate the maturation of virus-presenting APCs via CD154-CD40 interactions. Consequently, the APC is stimulated to upregulate costimulatory molecules, as well as to secrete proinflammatory cytokines. These molecules then feed back on the T cell, stimulate it to become fully activated, and release additional inflammatory cytokines and growth factors. Allospecific T cells that have encountered cognate alloantigen can be activated in this inflammatory milieu even if they do not cross-react with viral antigens. This process is traditionally referred to as bystander activation .
Viruses have also been shown to mature APCs independently of the normally required CD154-CD40 interaction. LCMV infection stimulates the upregulation of MHC classes I and II, CD40, CD80, and CD86 in the presence of CTLA-4-Ig and anti-CD154 mAb . The molecular mechanisms that govern this process have not been fully elucidated; however, the induction of type I IFNs by virus-infected APCs is a likely candidate. IFN-?/? is known to directly induce the maturation of immature DCs, and it results in the upregulation of MHC and costimulatory molecules [112, 113]. Given that pDCs can produce up to a thousand-fold more type I IFN than other cells [113, 114], we propose that viral detection by pDCs triggers the release of IFN-?/? that can in turn act in a paracrine or autocrine fashion to mature alloantigen-presenting APCs (Figure 3). Thus, these ?IFN-?/?-licensed? alloantigen-presenting APCs could directly stimulate alloreactive T cells, even in the presence of costimulation blockade.
The induction and maintenance of CD4+ regulatory T cells (Tregs) are essential to allograft survival [115?117]. Therefore, a second mechanism by which viruses could impair tolerance induction is through modulation of the generation or activity of this important T cell subset. In addition to priming cells through an IFN-?/?-dependent mechanism, TLR activation also prevents the intragraft recruitment of regulatory T cells in an MyD88-dependent manner . This observation extended earlier work showing that the MyD88 pathway plays an important role in the rejection of minor antigens  and cardiac allografts .
IL-6 is an MyD88-dependent cytokine that has emerged as a candidate mediator for impairing regulatory T cell generation and function; its production is diminished in untreated ?as well as LCMV-infected ?mice deficient in MyD88. CD4+ T cells develop a FoxP3+ regulatory T cell phenotype when they are activated in the presence of TGF-?. However, when CD4+ T cells are activated in the presence of TGF-? and IL-6, this regulatory phenotype is suppressed and the cells develop a proinflammatory TH17 cell phenotype  (Figure 4). Therefore, virus infection may precipitate allograft rejection by preventing the generation of Tregs following costimulation blockade and instead favor development of proinflammatory effector T cells.
IL-6 has also been shown to be important in regulating antigen-specific adaptive immune responses via additional mechanisms. Pasare et al. demonstrated that microbial induction of the TLR pathway on DCs enabled effector T cells to overcome suppression by CD4+CD25+ regulatory cells  (Figure 4). They reported that secretion of soluble mediators (principally IL-6) by TLR-activated DCs could render effector T cells refractory to Treg-mediated regulation, permitting activation of antigen-specific T cells in the presence of regulatory T cells. Hence, virus infection may trigger allograft rejection by compromising key regulatory mechanisms such as preventing the generation of regulatory T cells by costimulation blockade as well as by enabling alloreactive T cells to escape Treg-mediated suppression.
The classic view of clonal T cell activation is that one TCR interacts with one cognate antigen. However, we now understand that TCR binding is degenerate, and can recognize multiple related and unrelated antigens. The ability of an antigen-specific T cell to cross-react with multiple antigens, known as heterologous immunity , can influence immunodominance, protective immunity, and immunopathology during subsequent viral infections [110, 123, 124].
In studies of peripheral tolerance induction, of particular interest to transplant scientists is the observation that virus-specific T cells cross-react with alloantigens (Figure 5) [125, 126]. Yang et al. have reported that acute infection with VV, MCMV, or arena viruses LCMV and pichinde virus (PV) resulted in the spontaneous generation of cytotoxic lymphocytes (CTLs) with cytolytic activity towards allogeneic cells [127, 128]. These results were further supported by Nahill and Welsh , who used limiting dilution analyses to demonstrate that T cell clones specific for virus-infected syngeneic cells also kill uninfected allogeneic targets. Our report using virus-specific tetramers and an intracellular cytokine assay confirmed the findings that LCMV infection led to the generation of virus-specific CD8 T cells that cross-react with alloantigens, and further showed that virus-immune mice were refractory to the induction of tolerance by costimulation blockade . Others have also reported that virus-immune mice are refractory to tolerance induction by costimulation blockade . Because memory T cells are resistant to the induction of tolerance by costimulation blockade [107, 108], our data suggest that the allo-cross-reactive virus-specific memory T cells may precipitate the rejection of allografts even in the presence of costimulation blockade.
Surprisingly, mice infected with LCMV one day after transplantation also exhibit shortened allograft survival . Interestingly, the longer time after transplantation is, the less impact LCMV infection has on allograft survival. The deletion of alloreactive CD8+ T cells is thought to be complete at this time [41, 42], making it improbable that LCMV is interfering with deletion. However, because costimulation blockade protocols are only implemented during the peritransplant period, it is possible that LCMV infection shortly after transplantation prevents the generation of regulatory T cells, which have been shown to require up to 30 days after costimulation blockade to develop . Further research is necessary to elucidate the mechanisms by which LCMV shortens allograft survival during the post-transplantation timeframe.
Viral infection presents a potent barrier to the induction of transplantation tolerance. In this review, we have discussed potential mechanisms by which viral infection modulates organ allograft survival in the setting of transplantation tolerance. We have briefly summarized data on three mechanisms by which viral infection may mediate these effects: bystander activation, modulation of Tregs, or heterologous immunity. Recognition of viruses by pattern recognition receptors on innate immune cells can also directly stimulate the maturation of APCs, and thus may lead to bystander activation and licensing of alloreactive T cells. Activation of APCs by viruses may trigger the release of cytokines such as IL-6 that can prevent the generation and/or function of regulatory T cells that are essential for transplantation tolerance. Finally, heterologous immunity may be responsible for the discrepancy that has been encountered when tolerance strategies that work in specific pathogen-free rodent models fail when translated to nonhuman primates and to humans , which have been exposed to a variety of pathogens and thus have large memory T cell pools. Understanding the cellular and molecular mechanisms by which viruses and other microbial organisms modulate transplantation tolerance may lead to novel approaches that improve the efficacy of allogeneic organ transplantation.
|APC:||Antigen presenting cell|
|BMT:||Bone marrow transplantation|
|CARD:||Caspase recruitment domain|
|CARDIF:||CARD adaptor inducing IFN-B|
|cDC:||Conventional dendritic cell|
|CTL:||Cytotoxic T lymphocytes|
|DAI:||DNA-dependent activator of IFN-regulatory factors|
|dsRNA:||Double stranded RNA|
|IKK-I:||Inducible I?B kinase|
|IPS-1:||Interferon-? promoter stimulator|
|IRAK:||IL-1 receptor-associated kinase|
|IRF:||Interferon regulatory factory|
|ISRE:||Interferon-stimulated response element|
|LCMV:||Lymphocytic choriomeningitis virus|
|MAVS:||Mitochondrial antiviral signaling protein|
|MDA5:||Melanoma differentiation factor-5|
|MyD88:||Myeloid differentiation primary response gene-88|
|PRR:||Pattern recognition receptor|
|RIG-I:||Retinoic acid inducible gene I|
|pDC:||Plasmacytoid dendritic cell|
|TBK-1:||TANK-binding kinase 1|
|TCR:||T cell receptor|
|TRAF:||Tumor necrosis factor receptor-associated factor|
|Treg:||Regulatory T cell|
|TRIF:||TIR-domain-containing adaptor protein inducing IFN-?|
|VISA:||Virus-induced signaling adaptor|
This work is supported in part by the National Institutes of Health Research Grant no. AI42669, the American Diabetes Association Grant no. 7-05-PST-02, the Juvenile Diabetes Research Foundation, and a Diabetes Endocrinology Center Research Grant DK32520 from the National Institutes of Health. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. D. M. Miller and T. B. Thornley contributed equally to this work.
|1.||Merrill JP,Murray JE,Harrison JH,Guild WR. Successful homotransplantation of the human kidney between identical twinsThe Journal of the American Medical Association 1956;160(4):277–282.|
|2.||Merrill JP,Murray JE,Harrison JH,Guild WR. Landmark article Jan 28, 1956: successful homotransplantation of the human kidney between identical twins. By John P. Merrill, Joseph E. Murray, J. Hartwell Harrison, and Warren R. GuildThe Journal of the American Medical Association 1984;251(19):2566–2571.|
|3.||Merrill JP. Transplantation immunology 1957?1975Annales d'Immunologie 1978;129(2-3):347–352.|
|4.||Habwe VQ. Posttransplantation quality of life: more than graft functionAmerican Journal of Kidney Diseases 2006;47(4, supplement 2):S98–S110. [pmid: 16567244]|
|5.||Cantarovich D,Vistoli F,Soulillou J-P. Immunosuppression minimization in kidney transplantationFrontiers in Bioscience 2008;13(4):1413–1432. [pmid: 17981639]|
|6.||Ferry C,Soci? G. Busulfan-cyclophosphamide versus total body irradiation-cyclophosphamide as preparative regimen before allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia: what have we learned?Experimental Hematology 2003;31(12):1182–1186. [pmid: 14662323]|
|7.||Soulillou J,Giral M. Controlling the incidence of infection and malignancy by modifying immunosuppressionTransplantation 2001;72(supplement 12):S89–S93. [pmid: 11833147]|
|8.||Laederach-Hofmann K,Bunzel B. Noncompliance in organ transplant recipients: a literature reviewGeneral Hospital Psychiatry 2000;22(6):412–424. [pmid: 11072057]|
|9.||Paul LC. Immunobiology of chronic renal transplant rejectionBlood Purification 1995;13(3-4):206–218. [pmid: 7619392]|
|10.||Kreis HA,Ponticelli C. Causes of late renal allograft loss: chronic allograft dysfunction, death, and other factorsTransplantation 2001;71(supplement 11):SS5–SS9. [pmid: 11583489]|
|11.||Kamoun M. Mechanisms of chronic allograft dysfunctionTherapeutic Drug Monitoring 2006;28(1):14–18. [pmid: 16418687]|
|12.||Rossini AA,Greiner DL,Mordes JP. Induction of immunologic tolerance for transplantationPhysiological Reviews 1999;79(1):99–141. [pmid: 9922369]|
|13.||Billingham RE,Brent L,Medawar PB. ?Actively acquired tolerance? of foreign cellsNature 1953;172(4379):603–606. [pmid: 13099277]|
|14.||Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twinsScience 1945;102(2651):400–401. [pmid: 17755278]|
|15.||Burnet F,Fenner F. The Production of Antibodies. 1949Melbourne, Australia: MacMillan;|
|16.||Main JM,Prehn RT. Successful skin homografts after the administration of high dosage X radiation and homologous bone marrowJournal of the National Cancer Institute 1955;15(4):1023–1029. [pmid: 13233946]|
|17.||Wekerle T,Kurtz J,Ito H,et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatmentNature Medicine 2000;6(4):464–469. [pmid: 10742157]|
|18.||Seung E,Mordes JP,Rossini AA,Greiner DL. Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioningJournal of Clinical Investigation 2003;112(5):795–808. [pmid: 12952928]|
|19.||Durham MM,Bingaman AW,Adams AB,et al. Cutting edge: administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioningThe Journal of Immunology 2000;165(1):1–4. [pmid: 10861026]|
|20.||Sharabi Y,Sachs DH. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimenThe Journal of Experimental Medicine 1989;169(2):493–502. [pmid: 2562984]|
|21.||Scandling JD,Busque S,Dejbakhsh-Jones S,et al. Tolerance and chimerism after renal and hematopoietic-cell transplantationThe New England Journal of Medicine 2008;358(4):362–368. [pmid: 18216356]|
|22.||Kawai T,Cosimi AB,Spitzer TR,et al. HLA-mismatched renal transplantation without maintenance immunosuppressionThe New England Journal of Medicine 2008;358(4):353–361. [pmid: 18216355]|
|23.||Larsen CP,Knechtle SJ,Adams A,Pearson T,Kirk AD. A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppressionAmerican Journal of Transplantation 2006;6(5, part 1):876–883. [pmid: 16611323]|
|24.||Mescher MF,Curtsinger JM,Agarwal P,et al. Signals required for programming effector and memory development by CD8+ T cellsImmunological Reviews 2006;211(1):81–92. [pmid: 16824119]|
|25.||Snanoudj R,de Pr?neuf H,Cr?put C,et al. Costimulation blockade and its possible future use in clinical transplantationTransplant International 2006;19(9):693–704. [pmid: 16918529]|
|26.||Greenwald RJ,Freeman GJ,Sharpe AH. The B7 family revisitedAnnual Review of Immunology 2005;23:515–548.|
|27.||Schwartz RH. T cell anergyAnnual Review of Immunology 2003;21:305–334.|
|28.||Curtsinger JM,Gerner MY,Lins DC,Mescher MF. Signal 3 availability limits the CD8 T cell response to a solid tumorThe Journal of Immunology 2007;178(11):6752–6760. [pmid: 17513722]|
|29.||Curtsinger JM,Lins DC,Mescher MF. Signal 3 determines tolerance versus full activation of naive CD8 T cells: dissociating proliferation and development of effector functionThe Journal of Experimental Medicine 2003;197(9):1141–1151. [pmid: 12732656]|
|30.||Ohashi PS,Oehen S,Buerki K,et al. Ablation of ?tolerance? and induction of diabetes by virus infection in viral antigen transgenic miceCell 1991;65(2):305–317. [pmid: 1901764]|
|31.||Oldstone MBA,Nerenberg M,Southern P,Price J,Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune responseCell 1991;65(2):319–331. [pmid: 1901765]|
|32.||Larsen CP,Pearson TC. The CD40 pathway in allograft rejection, acceptance, and toleranceCurrent Opinion in Immunology 1997;9(5):641–647. [pmid: 9368772]|
|33.||Foy TM,Aruffo A,Bajorath J,Buhlmann JE,Noelle RJ. Immune regulation by CD40 and its ligand GP39Annual Review of Immunology 1996;14:591–617.|
|34.||Parker DC,Greiner DL,Phillips NE,et al. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligandProceedings of the National Academy of Sciences of the United States of America 1995;92(21):9560–9564. [pmid: 7568172]|
|35.||Larsen CP,Alexander DZ,Hollenbaugh D,et al. CD40-gp39 interactions play a critical role during allograft rejection: suppression of allograft rejection by blockade of the CD40-gp39 pathwayTransplantation 1996;61(1):4–9. [pmid: 8560571]|
|36.||Elster EA,Xu H,Tadaki DK,et al. Treatment with the humanized CD154-specific monoclonal antibody, hu5c8, prevents acute rejection of primary skin allografts in nonhuman primatesTransplantation 2001;72(9):1473–1478. [pmid: 11707732]|
|37.||Kenyon NS,Fernandez LA,Lehmann R,et al. Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154Diabetes 1999;48(7):1473–1481. [pmid: 10389857]|
|38.||Kenyon NS,Chatzipetrou M,Masetti M,et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154Proceedings of the National Academy of Sciences of the United States of America 1999;96(14):8132–8137. [pmid: 10393960]|
|39.||Preston EH,Xu H,Dhanireddy KK,et al. IDEC-131 (anti-CD154), sirolimus and donor-specific transfusion facilitate operational tolerance in non-human primatesAmerican Journal of Transplantation 2005;5(5):1032–1041. [pmid: 15816883]|
|40.||Markees TG,Phillips NE,Noelle RJ,et al. Prolonged survival of mouse skin allografts in recipients treated with donor splenocytes and antibody to CD40 ligandTransplantation 1997;64(2):329–335. [pmid: 9256196]|
|41.||Iwakoshi NN,Markees TG,Turgeon N,et al. Skin allograft maintenance in a new synchimeric model system of toleranceThe Journal of Immunology 2001;167(11):6623–6630. [pmid: 11714833]|
|42.||Iwakoshi NN,Mordes JP,Markees TG,Phillips NE,Rossini AA,Greiner DL. Treatment of allograft recipients with donor-specific transfusion and anti-CD154 antibody leads to deletion of alloreactive CD8+ T cells and prolonged graft survival in a CTLA4-dependent mannerThe Journal of Immunology 2000;164(1):512–521. [pmid: 10605049]|
|43.||Lenschow DJ,Zeng Y,Thistlethwaite JR,et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lgScience 1992;257(5071):789–792. [pmid: 1323143]|
|44.||Lin H,Bolling SF,Linsley PS,et al. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusionThe Journal of Experimental Medicine 1993;178(5):1801–1806. [pmid: 8228826]|
|45.||Larsen CP,Elwood ET,Alexander DZ,et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathwaysNature 1996;381(6581):434–438. [pmid: 8632801]|
|46.||Yamazaki M,Pearson T,Brehm MA,et al. Different mechanisms control peripheral and central tolerance in hematopoietic chimeric miceAmerican Journal of Transplantation 2007;7(7):1710–1721. [pmid: 17564635]|
|47.||Durie FH,Aruffo A,Ledbetter J,et al. Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host diseaseJournal of Clinical Investigation 1994;94(3):1333–1338. [pmid: 7521888]|
|48.||Takeuchi O,Akira S. Recognition of viruses by innate immunityImmunological Reviews 2007;220(1):214–224. [pmid: 17979849]|
|49.||Pascher A,Proesch S,Pratschke J,et al. Rat cytomegalovirus infection interferes with anti-CD4 mAb-(RIB 5/2) mediated tolerance and induces chronic allograft damageAmerican Journal of Transplantation 2006;6(9):2035–2045. [pmid: 16869800]|
|50.||Stapler D,Lee ED,Selvaraj SA,et al. Expansion of effector memory TCR V?4+CD8+ T cells is associated with latent infection-mediated resistance to transplantation toleranceThe Journal of Immunology 2008;180(5):3190–3200. [pmid: 18292543]|
|51.||Williams MA,Tan JT,Adams AB,et al. Characterization of virus-mediated inhibition of mixed chimerism and allospecific toleranceThe Journal of Immunology 2001;167(9):4987–4995. [pmid: 11673506]|
|52.||Williams MA,Onami TM,Adams AB,et al. Cutting edge: persistent viral infection prevents tolerance induction and escapes immune control following CD28/CD40 blockade-based regimenThe Journal of Immunology 2002;169(10):5387–5391. [pmid: 12421910]|
|53.||Adams AB,Williams MA,Jones TR,et al. Heterologous immunity provides a potent barrier to transplantation toleranceJournal of Clinical Investigation 2003;111(12):1887–1895. [pmid: 12813024]|
|54.||Brehm MA,Markees TG,Daniels KA,Greiner DL,Rossini AA,Welsh RM. Direct visualization of cross-reactive effector and memory allo-specific CD8 T cells generated in response to viral infectionsThe Journal of Immunology 2003;170(8):4077–4086. [pmid: 12682237]|
|55.||Forman D,Welsh RM,Markees TG,et al. Viral abrogation of stem cell transplantation tolerance causes graft rejection and host death by different mechanismsThe Journal of Immunology 2002;168(12):6047–6056. [pmid: 12055213]|
|56.||Turgeon NA,Iwakoshi NN,Phillips NE,et al. Viral infection abrogates CD8+ T-cell deletion induced by costimulation blockadeJournal of Surgical Research 2000;93(1):63–69. [pmid: 10945944]|
|57.||Welsh RM,Markees TG,Woda BA,et al. Virus-induced abrogation of transplantation tolerance induced by donor- specific transfusion and anti-CD154 antibodyJournal of Virology 2000;74(5):2210–2218. [pmid: 10666251]|
|58.||Obhrai J,Goldstein DR. The role of toll-like receptors in solid organ transplantationTransplantation 2006;81(4):497–502. [pmid: 16495791]|
|59.||Kupiec-Weglinski JW,Busuttil RW. Ischemia and reperfusion injury in liver transplantationTransplantation Proceedings 2005;37(4):1653–1656. [pmid: 15919422]|
|60.||Romics L Jr.,Szabo G,Coffey JC,Jiang HW,Redmond HP. The emerging role of toll-like receptor pathways in surgical diseasesArchives of Surgery 2006;141(6):595–601. [pmid: 16785361]|
|61.||Fischer SA,Graham MB,Kuehnert MJ,et al. Transmission of lymphocytic choriomeningitis virus by organ transplantationThe New England Journal of Medicine 2006;354(21):2235–2249. [pmid: 16723615]|
|62.||Palacios G,Druce J,Du L,et al. A new arenavirus in a cluster of fatal transplant-associated diseasesThe New England Journal of Medicine 2008;358(10):991–998. [pmid: 18256387]|
|63.||Turgeon NA,Iwakoshi NN,Meyers WC,et al. Virus infection abrogates cd8+ t cell deletion induced by donor-specific transfusion and anti-cd154 monoclonal antibodyCurrent Surgery 2000;57(5):505–506. [pmid: 11064087]|
|64.||Thornley TB,Brehm MA,Markees TG,et al. TLR agonists abrogate costimulation blockade-induced prolongation of skin allograftsThe Journal of Immunology 2006;176(3):1561–1570. [pmid: 16424185]|
|65.||Thornley TB,Phillips NE,Beaudette-Zlatanova BC,et al. Type 1 IFN mediates cross-talk between innate and adaptive immunity that abrogates transplantation toleranceThe Journal of Immunology 2007;179(10):6620–6629. [pmid: 17982052]|
|66.||Chen L,Wang T,Zhou P,et al. TLR engagement prevents transplantation toleranceAmerican Journal of Transplantation 2006;6(10):2282–2291. [pmid: 16970798]|
|67.||Palmer SM,Burch LH,Davis RD,et al. The role of innate immunity in acute allograft rejection after lung transplantationAmerican Journal of Respiratory and Critical Care Medicine 2003;168(6):628–632. [pmid: 12773319]|
|68.||Kim EY,Teh H-S. TNF type 2 receptor (p75) lowers the threshold of T cell activationThe Journal of Immunology 2001;167(12):6812–6820. [pmid: 11739497]|
|69.||Kim EY,Teh H-S. Critical role of TNF receptor type-2 (p75) as a costimulator for IL-2 induction and T cell survival: a functional link to CD28The Journal of Immunology 2004;173(7):4500–4509. [pmid: 15383581]|
|70.||Curtsinger JM,Valenzuela JO,Agarwal P,Lins D,Mescher MF. Cutting edge: type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiationThe Journal of Immunology 2005;174(8):4465–4469. [pmid: 15814665]|
|71.||Alexopoulou L,Holt AC,Medzhitov R,Flavell RA. Recognition of double-stranded RNA and activation of NF-?B by Toll-like receptor 3Nature 2001;413(6857):732–738. [pmid: 11607032]|
|72.||Yoneyama M,Kikuchi M,Natsukawa T,et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responsesNature Immunology 2004;5(7):730–737. [pmid: 15208624]|
|73.||Kang D-C,Gopalkrishnan RV,Wu Q,Jankowsky E,Pyle AM,Fisher PB. mda-5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive propertiesProceedings of the National Academy of Sciences of the United States of America 2002;99(2):637–642. [pmid: 11805321]|
|74.||Saunders LR,Barber GN. The dsRNA binding protein family: critical roles, diverse cellular functionsThe FASEB Journal 2003;17(9):961–983. [pmid: 12773480]|
|75.||Gottenberg J-E,Chiocchia G. Dendritic cells and interferon-mediated autoimmunityBiochimie 2007;89(6-7):856–871. [pmid: 17562353]|
|76.||Pichlmair A,Reis e Sousa C. Innate recognition of virusesImmunity 2007;27(3):370–383. [pmid: 17892846]|
|77.||Stetson DB,Medzhitov R. Type I interferons in host defenseImmunity 2006;25(3):373–381. [pmid: 16979569]|
|78.||Kurt-Jones EA,Popova L,Kwinn L,et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virusNature Immunology 2000;1(5):398–401. [pmid: 11062499]|
|79.||Kawai T,Takahashi K,Sato S,et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon inductionNature Immunology 2005;6(10):981–988. [pmid: 16127453]|
|80.||Meylan E,Curran J,Hofmann K,et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virusNature 2005;437(7062):1167–1172. [pmid: 16177806]|
|81.||Seth RB,Sun L,Ea C-K,Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-?B and IRF3Cell 2005;122(5):669–682. [pmid: 16125763]|
|82.||Xu L-G,Wang Y-Y,Han K-J,Li L-Y,Zhai Z,Shu H-B. VISA is an adapter protein required for virus-triggered IFN-? signalingMolecular Cell 2005;19(6):727–740. [pmid: 16153868]|
|83.||Sun Q,Sun L,Liu H-H,et al. The specific and essential role of MAVS in antiviral innate immune responsesImmunity 2006;24(5):633–642. [pmid: 16713980]|
|84.||Fitzgerald KA,McWhirter SM,Faia KL,et al. IKK? and TBK1 are essential components of the IRF3 signaling pathwayNature Immunology 2003;4:491–496. [pmid: 12692549]|
|85.||Sharma S,TenOever BR,Grandvaux N,Zhou G-P,Lin R,Hiscott J. Triggering the interferon antiviral response through an IKK-related pathwayScience 2003;300(5622):1148–1151. [pmid: 12702806]|
|86.||Kumar H,Kawai T,Kato H,et al. Essential role of IPS-1 in innate immune responses against RNA virusesThe Journal of Experimental Medicine 2006;203(7):1795–1803. [pmid: 16785313]|
|87.||Oganesyan G,Saha SK,Guo B,et al. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral responseNature 2006;439(7073):208–211. [pmid: 16306936]|
|88.||H?cker H,Redecke V,Blagoev B,et al. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6Nature 2006;439(7073):204–207. [pmid: 16306937]|
|89.||Honda K,Yanai H,Negishi H,et al. IRF-7 is the master regulator of type-I interferon-dependent immune responsesNature 2005;434(7034):772–777. [pmid: 15800576]|
|90.||Honda K,Taniguchi T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptorsNature Reviews Immunology 2006;6(9):644–658. [pmid: 16932750]|
|91.||Ishii KJ,Coban C,Kato H,et al. A toll-like receptor-independent antiviral response induced by double-stranded B-form DNANature Immunology 2006;7(1):40–48. [pmid: 16286919]|
|92.||Stetson DB,Medzhitov R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune responseImmunity 2006;24(1):93–103. [pmid: 16413926]|
|93.||Okabe Y,Kawane K,Akira S,Taniguchi T,Nagata S. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradationThe Journal of Experimental Medicine 2005;202(10):1333–1339. [pmid: 16301743]|
|94.||Takaoka A,Wang Z,Choi MK,et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune responseNature 2007;448(7152):501–505. [pmid: 17618271]|
|95.||Heil F,Hemmi H,Hochrein H,et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8Science 2004;303(5663):1526–1529. [pmid: 14976262]|
|96.||Diebold SS,Kaisho T,Hemmi H,Akira S,Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNAScience 2004;303(5663):1529–1531. [pmid: 14976261]|
|97.||Hemmi H,Takeuchi O,Kawai T,et al. A Toll-like receptor recognizes bacterial DNANature 2000;408(6813):740–745. [pmid: 11130078]|
|98.||Iwasaki A,Medzhitov R. Toll-like receptor control of the adaptive immune responsesNature Immunology 2004;5(10):987–995. [pmid: 15454922]|
|99.||Reis e Sousa C. Toll-like receptors and dendritic cells: for whom the bug tollsSeminars in Immunology 2004;16(1):27–34. [pmid: 14751761]|
|100.||Akira S,Uematsu S,Takeuchi O. Pathogen recognition and innate immunityCell 2006;124(4):783–801. [pmid: 16497588]|
|101.||Oshiumi H,Matsumoto M,Funami K,Akazawa T,Seya T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-? inductionNature Immunology 2003;4(2):161–167. [pmid: 12539043]|
|102.||Hemmi H,Kaisho T,Takeuchi O,et al. Small-antiviral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathwayNature Immunology 2002;3(2):196–200. [pmid: 11812998]|
|103.||Kawai T,Sato S,Ishii KJ,et al. Interferon-? induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6Nature Immunology 2004;5(10):1061–1068. [pmid: 15361868]|
|104.||Uematsu S,Sato S,Yamamoto M,et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-? inductionThe Journal of Experimental Medicine 2005;201(6):915–923. [pmid: 15767370]|
|105.||Hoshino K,Sugiyama T,Matsumoto M,et al. I?B kinase-? is critical for interferon-? production induced by Toll-like receptors 7 and 9Nature 2006;440(7086):949–953. [pmid: 16612387]|
|106.||Shinohara ML,Lu L,Bu J,et al. Osteopontin expression is essential for interferon-? production by plasmacytoid dendritic cellsNature Immunology 2006;7(5):498–506. [pmid: 16604075]|
|107.||Wickham S,Carr DJJ. Molecular mimicry versus bystander activation: herpetic stromal keratitisAutoimmunity 2004;37(5):393–397. [pmid: 15621563]|
|108.||Fujinami RS,von Herrath MG,Christen U,Whitton JL. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune diseaseClinical Microbiology Reviews 2006;19(1):80–94. [pmid: 16418524]|
|109.||Lu L-F,Lind EF,Gondek DC,et al. Mast cells are essential intermediaries in regulatory T-cell toleranceNature 2006;442(7106):997–1002. [pmid: 16921386]|
|110.||Selin LK,Brehm MA,Naumov YN,et al. Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunityImmunological Reviews 2006;211(1):164–181. [pmid: 16824126]|
|111.||Lee BO,Hartson L,Randall TD. CD40-deficient, influenza-specific CD8 memory T cells develop and function normally in a CD40-sufficient environmentThe Journal of Experimental Medicine 2003;198(11):1759–1764. [pmid: 14657225]|
|112.||Luft T,Pang KC,Thomas E,et al. Type I IFNs enhance the terminal differentiation of dendritic cellsThe Journal of Immunology 1998;161(4):1947–1953. [pmid: 9712065]|
|113.||Theofilopoulos AN,Baccala R,Beutler B,Kono DH. Type I interferons (?/?) in immunity and autoimmunityAnnual Review of Immunology 2005;23:307–336.|
|114.||Coccia EM,Severa M,Giacomini E,et al. Viral infection and toll-like receptor agonists induce a differential expression of type I and ? interferons in humans plasmacytoid and monocyte-derived dendritic cellsEuropean Journal of Immunology 2004;34(3):796–805. [pmid: 14991609]|
|115.||Markees TG,Phillips NE,Gordon EJ,et al. Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4+ T cells, interferon-gamma, and CTLA4Journal of Clinical Investigation 1998;101(11):2446–2455. [pmid: 9616216]|
|116.||Graca L,Honey K,Adams E,Cobbold SP,Waldmann H. Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation toleranceThe Journal of Immunology 2000;165(9):4783–4786. [pmid: 11045999]|
|117.||Banuelos SJ,Markees TG,Phillips NE,et al. Regulation of skin and islet allograft survival in mice treated with costimulation blockade is mediated by different CD4+ cell subsets and different mechanismsTransplantation 2004;78(5):660–667. [pmid: 15371665]|
|118.||Goldstein DR,Tesar BM,Akira S,Lakkis FG. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejectionJournal of Clinical Investigation 2003;111(10):1571–1578. [pmid: 12750407]|
|119.||Walker WE,Nasr IW,Camirand G,Tesar BM,Booth CJ,Goldstein DR. Absence of innate MyD88 signaling promotes inducible allograft acceptanceThe Journal of Immunology 2006;177(8):5307–5316. [pmid: 17015716]|
|120.||Zhou S,Kurt-Jones EA,Mandell L,et al. MyD88 is critical for the development of innate and adaptive immunity during acute lymphocytic choriomeningitis virus infectionEuropean Journal of Immunology 2005;35(3):822–830. [pmid: 15724245]|
|121.||Bettelli E,Carrier Y,Gao W,et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cellsNature 2006;441(7090):235–238. [pmid: 16648838]|
|122.||Pasare C,Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cellsScience 2003;299(5609):1033–1036. [pmid: 12532024]|
|123.||Welsh RM,Selin LK. No one is naive: the significance of heterologous T-cell immunityNature Reviews Immunology 2002;2(6):417–426. [pmid: 12093008]|
|124.||Selin LK,Cornberg M,Brehm MA,et al. CD8 memory T cells: cross-reactivity and heterologous immunitySeminars in Immunology 2004;16(5):335–347. [pmid: 15528078]|
|125.||Yang H,Welsh RM. Induction of alloreactive cytotoxic T cells by acute virus infection of miceThe Journal of Immunology 1986;136(4):1186–1193. [pmid: 2418107]|
|126.||Nahill SR,Welsh RM. High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte responseThe Journal of Experimental Medicine 1993;177(2):317–327. [pmid: 8093891]|
|127.||Yang H,Welsh RM. Induction of allospecific and virus-specific memory cytotoxic T cells during acute arenavirus infectionsMedical Microbiology and Immunology 1986;175(2-3):137–139. [pmid: 3487705]|
|128.||Yang H,Dundon PL,Nahill SR,Welsh RM. Virus-induced polyclonal cytotoxic T lymphocyte stimulationThe Journal of Immunology 1989;142(5):1710–1718. [pmid: 2537363]|
|129.||Kingsley CI,Karim M,Bushell AR,Wood KJ. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponsesThe Journal of Immunology 2002;168(3):1080–1086. [pmid: 11801641]|
|130.||Brook MO,Wood KJ,Jones ND. The impact of memory T cells on rejection and the induction of toleranceTransplantation 2006;82(1):1–9. [pmid: 16861933]|
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