REVIEW ARTICLE published: 19 April 2012 doi: 10.3389/fimmu.2012.00073 Innate and resistance to tolerogenesis in allotransplantation

Gilles Benichou 1,2, MakotoTonsho1,2, GeorgesTocco1,2, Ognjenka Nadazdin1,2 and Joren C. Madsen1,2*

1 Transplant Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 2 Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Edited by: The development of immunosuppressive drugs to control adaptive immune responses has Xian Chang Li, Brigham and Women’s led to the success of transplantation as a therapy for end-stage organ failure. However, Hospital, USA these agents are largely ineffective in suppressing components of the innate immune sys- Reviewed by: Joan Stein-Streilein, Schepens Eye tem.This distinction has gained in clinical significance as mounting evidence now indicates Research Institute, USA that innate immune responses play important roles in the acute and chronic rejection of Zhibin Chen, University of Miami whole organ allografts. For instance, whereas clinical interest in natural killer (NK) cells was Miller School of Medicine, USA once largely confined to the field of bone marrow transplantation, recent findings suggest *Correspondence: that these cells can also participate in the acute rejection of cardiac allografts and prevent Joren C. Madsen, Massachusetts General Hospital, Cox 654, 55 Fruit tolerance induction. Stimulation ofToll-like receptors (TLRs), another important component Street, Boston, MA 02114, USA. of innate immunity, by endogenous ligands released in response to ischemia/reperfusion e-mail: [email protected] is now known to cause an inflammatory milieu favorable to graft rejection and abrogation of tolerance. Emerging data suggest that activation of complement is linked to acute rejec- tion and interferes with tolerance. In summary, the conventional wisdom that the innate is of little importance in whole organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, complement, and other components of the innate immune system will be necessary to eventually achieve long-term tolerance to human allograft recipients.

Keywords: innate immunity, tolerance, transplantation, allografts, rejection

INTRODUCTION barrier to transplant tolerance induction (Adams et al., 2003a; Tay- Colossal advances over the past decades with the use of immuno- lor et al., 2004; Valujskikh, 2006; Koyama et al., 2007; Weaver et al., suppressive drugs have significantly enhanced the early survival of 2009; Nadazdin et al., 2010, 2011; Yamada et al., 2011). Indeed, allogeneic organs and tissues in clinical transplantation (Cecka, much effort is currently devoted to the elimination or inhibition 1998; Opelz et al., 1999; Opelz and Dohler, 2008a,b). Never- of donor-specific memory T cells (TMEM) in primates, which, theless, longer term success rates remain disappointing due to unlike laboratory mice, display high frequencies of alloreactive treatment-related complications and chronic allograft rejection, a TMEM prior to transplantation (Nadazdin et al., 2010, 2011). process characterized by perivascular inflammation, tissue fibro- Altogether, the majority of transplant immunologists have focused sis, and luminal occlusion of graft blood vessels (Hayry et al., their efforts on the deletion and/or inactivation of alloreactive T 1993; Hosenpud et al., 1997; Russell et al., 1997; Kean et al., 2006). and B cells, pre-transplantation. On the other hand, recent studies This stresses the need for the development of selective immune- have proven beyond doubt that innate immunity is also an essential therapies designed to achieve transplantation tolerance defined element of both acute and chronic rejection of allo- and xenografts as indefinite graft survival in the absence of immunosuppres- (LaRosa et al., 2007; Alegre et al., 2008a,b; Alegre and Chong, 2009; sion and graft vasculopathy (Billingham et al., 1953; Owen et al., Li, 2010; Goldstein, 2011; Murphy et al., 2011). Innate immune 1954). While tolerance to some solid organ allografts has been responses are initiated as a consequence of reperfusion injury, accomplished in several experimental rodent models, consistent inflammation, tissue damage, and presumably microbial infec- establishment of tolerance in patients still remains an elusive goal. tions occurring at the time of transplantation (Figure 1). Different It is firmly established that the potent adaptive immune responses cells of the innate immune system can contribute to the rejection initiated by pro-inflammatory T cells activated via direct and indi- process both directly via secretion of soluble factors and destruc- rect pathways in the host’s secondary lymphoid organs are both tion of donor grafted cells as well as indirectly by initiating or necessary and sufficient to ensure acute rejection of most allo- enhancing adaptive immune alloresponses while impairing the grafts (Benichou et al., 1992, 1999; Fangmann et al., 1993; Sayegh activation/expansion of protective regulatory T cells (Figure 1). At et al., 1994; Auchincloss and Sultan, 1996; Lee et al., 1997; Waaga the same time,there is increasing evidence suggesting that different et al., 1997). At the same time, it is now firmly established that cells and molecules associated with innate immunity can hinder the presence of alloreactive memory T cells or donor-specific anti- tolerance induction to allografts and xenografts (LaRosa et al., bodies in so-called sensitized recipients represents a formidable 2007; Alegre et al., 2008b; Wang et al., 2008; Murphy et al., 2011).

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Medzhitov and Janeway, 2002). Among these pattern-recognition receptors (PRRs; Medzhitov, 2001; Elmaagacli et al., 2006; Uematsu and Akira, 2007), the Toll-like receptors (TLRs) have been extensively characterized and studied for their role in the ini- tiation and amplification of innate immune responses (Iwasaki and Medzhitov, 2004; Pasare and Medzhitov, 2005). In addi- tion, there is increasing evidence that tissue injury is associated with the delivery of signal delivered through TLRs by so-called damage-associated molecular patterns or DAMPs (Alegre et al., 2008a,b). Until now, 10 different TLRs have been identified in humans (13 in mice), including TLRs 1, 2, 4, 5, and 6 expressed on the cell surface and TLRs 3, 7, 8, and 9 found in endosomal compartments (Rehli, 2002; Akira and Takeda, 2004; Akira et al., 2006). TLR1 is ubiquitously expressed while the other TLRs exhibit different expression patterns depending upon the type of leukocyte (Muzio et al., 2000; McCurdy et al., 2001; Hornung et al., 2002; Zarember and Godowski, 2002; Bourke et al., 2003; Caramalho et al., 2003; Hayashi et al., 2003; Nagase et al., 2003; Hart et al., 2005; Liu et al., 2006). On the other hand, all TLRs are expressed by epithelial cells while TLRs 5–10 are found in endothelial cells (Frantz et al., 1999) and other graft parenchymal cells depending upon the nature of the organ. All TLRs transduce their signal though the adapter- protein MyD88 (Barton and Medzhitov, 2003; Akira and Takeda, 2004) with the exception of TLR3 which uses the Toll-IL-1R (TIR) inducing IFNβ protein, TRIF (Frantz et al., 1999, 2001; Faure et al., 2000; Tsuboi et al., 2002; Harada et al., 2003; Mempel et al., 2003; Sukkar et al., 2006). TLR4 uses both MyD88 and TRIF during cell activation (Sakaguchi et al., 2003; Goriely et al., 2006; Molle et al., 2007). While the primary functions of TLRs is to ensure early detection of microbes and their products, these receptors have been shown to recognize autologous molecules expressed during the course of inflammatory processes such as nucleic acids released by necrotic cells, products of degraded extracellular matrices, heat FIGURE 1 | Leukocytes and major involved in the innate shock proteins (HSP60 and HSP70 via TLR2 and TLR4; Asea, immune response after allotransplantation. 2008), high mobility group box chromosomal protein 1 (TLRs 2, 4, and 9), and hyaluronan (TLR signaling via TIRAP; Mollen et al., 2006; Tesaret al., 2006; Ivanov et al., 2007; Kanzler et al., 2007; Tian At first glance, it can be speculated that all cells and molecules et al., 2007). Transplant surgical procedures, which are associated mediating graft rejection can potentially prevent tolerogenesis. with tissue damage and reperfusion injury trigger inflammatory However, immune rejection and tolerance resistance do not nec- reactions engaging the delivery of signals through TLRs and sub- essarily involve the same mechanisms and these two processes are sequent initiation of potent innate immune responses at the graft likely to differ in nature and magnitude. This article reviews some site. In addition, maturation and activation of donor and recipient of the mechanisms by which innate immunity can interfere with dendritic cells (DCs) and other cells of the innate immune system establishment or maintenance of tolerance to allogeneic trans- via TLR ligation is essential to their ability to initiate and amplify plants, an issue that is essential to the design of novel tolerance adaptive immunity. This process involves the secretion of pro- strategies in transplantation. inflammatory cytokines and chemokines (Shimamoto et al., 2006; Wu et al., 2007a) and subsequent activation of processing RECEPTORS AND SOLUBLE MEDIATORS OF THE INNATE pathways and the expression of costimulation and MHC molecules IMMUNE SYSTEM by APCs involved in to T and B lympho- TOLL-LIKE RECEPTORS cytes (Bluestone, 1996). Therefore, TLRs are considered to be an recognize exquisitely a vast array of molecular motifs essential link between innate and adaptive immunity. These obser- via their antigen receptors generated through somatic recombina- vations suggest that TLRs play a key role in the initiation of innate tion of gene segments during development. In contrast, cells of immune responses and the recruitment and activation of alloreac- the innate immune system interact with a few conserved mol- tive lymphocytes associated with allograft rejection. In support of ecules expressed by microorganisms referred to as pathogen- this view, absence of MyD88 adaptor-protein in both donor and associated molecular patterns (PAMPs; Medzhitov, 2001; recipient mice has led to acceptance of minor antigen-mismatched

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skin allografts and prolonged survival of fully allogeneic heart and epidermis where its secretion by keratinocytes is thought to play a skin transplants (Goldstein et al., 2003; Tesaret al., 2004). Further- key role in the immune defense against microorganisms (Palmer more, combined deficiencies of MyD88 and TRIF and expressions et al., 2007; Arend et al., 2008; Dinarello, 2009; Gabay et al., in donors have been shown to significantly extend the survival of 2010). In addition, during inflammation and sepsis, activated MHC-mismatched allografts. At the same time, there is accumu- , and polymorphonuclear neutrophils (PMNs) pro- lating evidence showing that TLR-mediated responses can hinder duce large amounts of IL-1α which is known to cause smooth mus- tolerance induction to allotransplants. First, it has been reported cle cell proliferation, secretion of TNFα by endothelial cells, the that long-term survival of skin allografts can be achieved in mice synthesis of acute phase proteins, and amplify antigen-specific and through costimulation blockade but only upon inhibition of TLR alloreactive T and responses (Rao et al., 2007, 2008; Rao and signaling in both donors and recipient mice (Chen et al., 2006; Pober, 2008; Dinarello, 2011a). IL-1β, also called acti- Walker et al.,2006). In another study,tolerance to cardiac allografts vating factor (LAF),is primarily released by activated macrophages induced via donor-specific transfusion (DST) combined with anti- during inflammation (Rao et al.,2007; Netea et al.,2010; Dinarello, CD40L mAb-mediated costimulation blockade was prevented by 2011b,c). It is involved in a variety of cellular activities, including injection of the TLR9 agonist, CpG as well as the TLR2 ligand, cell proliferation, differentiation, and apoptosis. The induction Pam3CysK. In this study, tolerance resistance was attributed to of cyclooxygenase 2 (PTGS2/COX2) by this in various increased γIFN production and inhibition of graft infiltration by tissues including the central nervous system (CNS) is found to regulatory T cells (Chen et al., 2006). Similarly, administration contribute to reactions and pain. IL-1α and β of CpG, LPS, or poly I:C which activate TLR 9, 4, and 3, respec- play a role in mediating acute inflammation during ischemia– tively, prevented tolerance induction to skin allografts induced via reperfusion (I/R) injury after transplantation (Suzuki et al., 2001). DST + anti-CD40L mAbs. In this model, it was observed that TLR Ischemia and hyperoxia/anoxia both contributes to the release engagement prevented the deletion of some effector donor-specific of IL-1 by macrophages (from the NALP-3 inflammasome), a CD8+ T cells (Thornley et al., 2006), a process relying on type process leading to both necrosis and apoptosis of transplanted I interferon production (Thornley et al., 2007). Finally, Turka’s cells, neutrophilic inflammation and initiation, and amplifica- group recently reported that spontaneous tolerance to MHC class tion of adaptive immune responses (Wanderer, 2010). Indeed, II-mismatched skin heart allografts as well as long-term acceptance it has been shown that overexpression of IL-1R antagonist (IL- of skin allografts mediated via anti-CD40L mAb and rapamycin 1Ra) can confer cardioprotection against I/R injury associated cotreatment in the B6-bm12 mouse combination were both pre- with reduction in cardiomyocyte apoptosis and decrease of neu- vented by CpG administration (Porrett et al., 2008). In this study, trophil infiltration and myocardial myeloperoxidase activity in prevention of tolerance was dependent on IL-12 production by heart-transplanted rats (Suzuki et al., 2001). APCs, which is critical to the differentiation of pro-inflammatory There are a few reports showing that IL-1 can prevent toler- type 1 (Th1/CT1) immunity. Therefore, engagement of certain ance induction to allografts. IL-1β is known to contribute to the TLRs at the time of transplantation can hinder tolerance induction breakdown of self-tolerance to pancreatic autoantigens resulting to allografts via concomitant enhancement of pro-inflammatory in type 1 diabetes in NOD mice (Bertin-Maghit et al., 2011). This responses and impairment of regulatory T cell functions. effect is mediated via both induction of TH17 and concomitant impairment of Treg differentiation and functions. INFLAMMATORY CYTOKINES Likewise, it has been shown that IL-1 can prevent the induction Certain pro-inflammatory cytokines produced by cells of the of tolerance to islet allografts (Sandberg et al., 1993). This is sup- innate immune system can prevent tolerance induction to alloanti- ported by studies showing that continuous infusion of diabetic gens or abrogate established tolerance of an allograft. For instance, mice with an IL-1 antagonist (IL-1Ra) can restore nor- IL-6 and TNFα deficiency has been shown to render mice suscep- moglycemia and facilitate tolerance to islet allografts (Sandberg tible to transplant tolerance induction via costimulation blockade et al.,1993). Similarly,alpha-1 anti-trypsin therapy (AAT) has been (Walker et al., 2006; Shen and Goldstein, 2009). Apparently, IL- shown to promote donor-specific tolerance to islet allografts in 6 and TNFα contributed to prevent tolerogenesis by enhancing mice via a process relying on the presence of immature DCs (iDCs) pro-inflammatory immunity while rendering T cells resistant to and Tregs in the graft associated with the presence of IL-1Ra (Lewis suppression by Tregs (Walker et al., 2006; Shen and Goldstein, et al., 2008; Shahaf et al., 2011). In another set of studies by Holan 2009). Likewise, type 1 interferons have been shown to confer tol- (1988), it was observed that transplantation tolerance induced via erance resistance of skin allografts mediated via anti-CD154 mAb inoculation of newborn mice with semi-allogeneic hematopoietic treatment in mouse models (Thornley et al.,2007). Tolerance resis- cells was abolished via administration of IL-1 given at the time tance to vascularized allografts induced via costimulation blockade of placement of skin allografts (Holan, 1988). Finally, a series of following Listeria monocytogenes infection has been shown to rely studies from Dana and Streilein’s groups have shown that IL-1Ra- on IFN α and β productions. In another study, evidence was based therapy can restore anterior chamber-associated immune provided that IL-6 could prevent transplant tolerance to cardiac deviation (ACAID) type tolerance associated with immune priv- allografts induced through the disruption of CD40/CD40L inter- ilege in the eye and acceptance of allogeneic corneal transplants actions, by promoting the differentiation and activation of CD8+ (Dana et al., 1997, 1998; Yamada et al., 1998, 2000; Dekaris et al., TH17 cells (Burrell et al., 2008). 1999). Interestingly, IL-1Ra treatment in this model was shown IL-1α is produced constitutively and at low levels by many to abolish donor-specific DTH, reduce corneal graft infiltration epithelial cells but it is found in substantial amounts in the by recipient Langerhans cells and abrogate second set rejection of

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skin allografts suggesting an impaired antigen presentation and a the inflammatory process as well as the immune response associ- lack of systemic priming of alloreactive T cells through the indi- ated with the rejection of allogeneic transplants (Zhou et al., 2007; rect allorecognition pathway in draining lymph nodes (Dana et al., Raedler et al., 2009; Raedler and Heeger, 2010; Vieyra and Heeger, 1997, 1998; Yamada et al., 1998, 2000; Dekaris et al., 1999). 2010). First, many studies have demonstrated the contribution of the complement to I/R injury following transplantation of a vari- CHEMOKINES ety of organs including liver, kidney, and lungs (Weisman et al., Chemokines represent an extensive family of proteins whose 1990; Ikai et al., 1996; Eppinger et al., 1997; Huang et al., 1999; function was initially associated with leukocyte . It Zhou et al., 2000; Chan et al., 2006; Farrar et al., 2006; Patel et al., is now clear that these molecules are also involved in a variety 2006). Remarkably, mice lacking complement have been shown to of biological processes including angiogenesis and hematopoiesis be unable to make high affinity anti-MHC after skin (Sallusto et al., 2000). There is ample evidence showing that transplantation. This was due to the lack of CR2 expression, a chemokines play a key role in the initiation of alloantigen- coreceptor that is required for antigen retention by follicular DCs dependent and alloantigen-independent reactions associated with (Fearon and Carroll, 2000; Marsh et al., 2001; Pratt et al., 2002). transplant injury as well as acute and chronic rejection of allo- On the other hand, the complement plays an important role in the grafts (DeVries et al., 2003). Likewise, many studies have shown antigen processing presentation by DCs and controls their ability that absence (KO mouse models) or in vivo neutralization of var- to activate T cells in antigen-specific fashion. Finally, elegant stud- ious chemokines or chemokine receptors, usually combined with ies from the Heeger’s group and others have demonstrated the role short-term or suboptimal calcineurin inhibitory treatment, results of C3 in the activation and expansion of both CD4+ and CD8+ in prolonged and sometimes indefinite survival of allografts in T cells presumably by limiting antigen-induced apoptosis (Fearon animal models (Gao et al., 2000, 2001; Hancock et al., 2000a,b; Fis- and Carroll, 2000; Marsh et al., 2001; Pratt et al., 2002; Peng et al., chereder et al., 2001; Abdi et al., 2002). These observations suggest 2006, 2008; Zhou et al., 2006; Lalli et al., 2008; Strainic et al., 2008). that chemokine release as well as leukocyte activation and migra- Altogether, these studies suggest that activation of the complement tion following chemokine receptor signaling should represent a cascade following transplantation should render tolerance difficult barrier to transplant tolerance induction and/or maintenance. On to induce. In support of this view, it has been shown that blockade the other hand,a number of chemokines have been associated with of complement activation on DCs results in an increase of Treg Treg activation and graft infiltration and are clearly necessary for expansion and favors tolerance induction (Sacks et al., 2009). tolerance induction in transplantation (DeVries et al., 2003). CELLS OF THE INNATE IMMUNE SYSTEM THE NK CELLS The complement system is comprised of a variety of small proteins Natural killer (NK) cells contribute to the innate immune response including serum proteins, serosal proteins, and cell surface recep- through their ability to recognize and destroy foreign cells in the tors (over 25 proteins and protein fragments,5% of serum globulin absence of antigen-specific recognition (Hamerman et al., 2005). fraction) present in the blood, generally synthesized by the liver, However, although NK cells lack expression of germline-encoded and normally circulating as inactive precursors (pro-proteins; antigen receptors, they can discriminate between self- and for- Carroll, 1998; Kang et al., 2009). eign cells via clonotypic receptors recognizing self-MHC class I When stimulated, the proteases in the system cleave specific molecules. NK cell interacting with self-MHC class I expressed proteins and subsequent cytokine release thus initiating an ampli- on autologous cells become inactivated while lack or suboptimal fying cascade of further cleavages. The end-result of this activation recognition of self-MHC class I molecules (missing self phenom- cascade is a massive amplification of the response and activation enon) on allogeneic cells results in NK cell stimulation associ- of the cell-killing membrane attack complex or MAC (Peitsch and ated with release of pro-inflammatory cytokines and cytotoxicity Tschopp, 1991). Three distinct pathways are involved in comple- (Karre et al., 1986; Ljunggren and Karre, 1990; Ljunggren et al., ment activation: the classical pathway, the alternative pathway, and 1990). This type of allorecognition has been shown to ensure the mannose-binding lectin pathway (Sacks et al., 2009). All of the destruction of skin grafts from donors lacking self-MHC these pathways converge on C3 whose cleavage leads to the release class I expression (b2m KO) as well as bone marrow transplants of soluble and C5a. It is noteworthy that while 80% of C3 is from semi-allogeneic donors and parental donors to F1 recipi- synthesized in the liver, 20% of C3 is of extra hepatic origin and ents (hybrid resistance; Karlhofer et al., 1992, 2006). In addition, produced by resident parenchymal cells and infiltrating leuko- recent evidence has been provided showing that NK cells also con- cytes (Naughton et al., 1996; Tang et al., 1999; Li et al., 2007). tribute to the rejection of solid organs transplants (Oertel et al., C3a and C5a have anaphylatoxin properties and trigger directly 2000, 2001; Kitchens et al., 2006; McNerney et al., 2006; van der and increase vascular permeability and Touw and Bromberg, 2010). NK cells participate in acute allograft smooth muscle contraction. Most importantly, the complement rejection either directly by killing donor cells through perforin, has opsonizing and chemotactic functions in that it enhances anti- granzymes, FasL, and TRAIL pathways (Biron et al., 1999; Smyth gen phagocytosis and attracts macrophages and PMNs at the site et al., 2001; Takeda et al., 2001; Trapani and Smyth, 2002) or indi- of inflammation. The complement system represents an essential rectly by promoting alloantigen processing and presentation by component of the inflammatory cascade and a major link between DCs and B cells (Boehm et al., 1997) and by enhancing Type innate and adaptive immunity. Likewise, there is now a body of 1 T cell adaptive primarily though their secretion evidence showing that the complement is an essential element of of γIFN and TNFα (Martin-Fontecha et al., 2004; Yoshida et al.,

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2008). Furthermore, NK cells have been shown to contribute to and endothelial through a process called trogocytosis (Joly and the rejection process by killing regulatory T cells (Roy et al., 2008). Hudrisier, 2003; Aucher et al., 2008). Theoretically, presentation Finally, some recent studies have demonstrated the pivotal role of intact allo-MHC molecules by host professional APCs could of NK cells in chronic rejection of cardiac allografts through a activate some alloreactive T cells, a mechanism referred to as semi- process involving CD4+ Tcellactivation(Uehara et al., 2005a,b). direct allorecognition. While, it has been shown that DCs having Altogether, these studies support the view that NK cells represent acquired donor-MHC molecules can activate T cells in vitro and an essential link between innate and adaptive immune responses in vivo, the actual contribution of semi-direct alloreactivity to the leading to acute and chronic rejection of allogeneic transplants. On alloresponse and allograft rejection is still unknown (Herrera et al., the other hand, a study from Szot et al. (2001) has demonstrated 2004; Smyth et al., 2006, 2007). that NK cells can also impair tolerance induction to a solid organ Dendritic cells consist of a diverse population of cells charac- transplant. In this model, injection of recipient CD28-deficient terized by a few common surface markers and some functional mice with anti-CD154 antibodies failed to accomplish indefinite characteristics (Banchereau and Steinman, 1998; Liu et al., 2009). survival of cardiac allografts. However, tolerance to heart allo- In addition, DC functions can differ dramatically depending upon grafts was restored upon in vivo depletion of NK cells or inhibition their degree of maturation (Steinman et al., 2003; Wilson and Vil- of the NK activating receptor, NKGD. Apparently, NK cells acti- ladangos, 2004). Myeloid iDCs, which have not yet encountered vated consequently to the absence of self-MHC class I molecules or become activated via PAMPs or cytokine exposure, on transplanted cells could provide help (otherwise missing in express low levels of MHC class II and costimulatory receptors CD28KO mice) to CD8+ T cells and thereby prevented tolerance and are poor APCs. Presentation of alloantigens by these iDCs induction (Maier et al., 2001; Kim et al., 2007). has been associated with induction (Fu et al., 1996; Dhodapkar et al., 2001; Roncarolo et al., 2001) and immune DENDRITIC CELLS privilege (Stein-Streilein and Streilein, 2002; Streilein et al., 2002; Dendritic cells are considered as the primary link between innate Masli et al., 2006) presumably via T cell anergy (Fu et al., 1996; and adaptive immunity based on their ability to prime naïve T Dhodapkar et al., 2001; Roncarolo et al., 2001). In contrast, DCs cells owing to: (1) efficient processing and presentation of anti- (mDCS) which underwent maturation following antigen uptake gen peptides in association with self-MHC molecules and, (2) the and processing in an inflammatory cytokine environment or expo- delivery of key costimulation signals (Steinman and Cohn, 1973; sure to PAMPs and presumably DAMPs express high levels of Austyn et al., 1983, 1988; Banchereau and Steinman, 1998; Lanza- MHC class II and costimulation receptors are potent inducers of vecchia and Sallusto, 2000, 2001; Steinman et al., 2000). Actually, type 1 alloimmunity after transplantation (Rogers and Lechler, the T cell alloresponse is primarily initiated through the recogni- 2001). Alternatively, plasmocytoid DCs (pDCs), which represent tion of intact donor-MHC molecules on donor DCs infiltrating a small population of DCs mostly located in the peripheral blood, the recipient’s secondary lymphoid organs (direct allorecognition; are thought to contribute to tolerance induction via IL-10 secre- Steinman and Witmer, 1978; Lechler and Batchelor, 1982; Larsen tion following ICOS costimulation and presumably induction of et al., 1990a,b,c,d; Lechler et al., 1990; Larsen and Austyn, 1991). regulatory T cell responses (Abe et al., 2005; Liu, 2005; Ochando The direct alloresponse is believed to represent the driving force et al., 2006; Ito et al., 2007; Tokita et al., 2008; Matta et al., 2010). behind acute allograft rejection. Alternatively, some alloreactive T Finally, seminal studies by Thomson and others have shown that cells become activated after recognition of donor peptides (MHC physical or chemical modifications of DCs can render them tolero- and minor antigens) presented by self-MHC molecules on recip- genic (Bacci et al., 1996; Kurimoto et al., 2000; Lu and Thomson, ient DCs (indirect allorecognition; Benichou et al., 1992, 1999; 2002; Thomson, 2002; Morelli and Thomson, 2003; Turnquist Dalchau et al., 1992; Fangmann et al., 1992; Liu et al., 1996; Sayegh et al., 2007) and ensure long-term survival to allografts upon their and Carpenter, 1996). The mechanisms by which recipient DCs in vivo transfer to recipients (Lu and Thomson, 2002; Thomson, acquire donor alloantigens are still unknown. The direct allore- 2002; Morelli and Thomson, 2003; Turnquist et al., 2007). sponse is believed to be short-lived due to the rapid elimination Altogether, these studies emphasize that DCs represent an of donor DCs, while the indirect alloresponse may be perpetuated essential link between innate and adaptive alloimmunity by serv- by continuous presentation of donor peptides by recipient APCs. ing as APCs for alloantigen presentation to T cells, by providing While it is clear that indirect alloreactivity is sufficient to trigger critical costimulation signals, and by secreting cytokines both at vigorous rejection of skin allografts, whether this response plays a the site of grafting and in the host’s lymphoid tissues and organs. significant role in acute rejection of vascularized solid organ trans- At the same time, it has become evident that the role of DCs in plants is still open to question (Auchincloss et al., 1993; Lee et al., the alloimmune response and rejection process is extremely com- 1994, 1997; Illigens et al., 2002). On the other hand, maintenance plex and depends on many factors including the origin (recipient of indirect alloresponses via continuous presentation of allopep- or donor) of the DCs, the nature of the DCs, their level of mat- tides by recipient DCs and endothelial cells is clearly associated uration, and the environment in which they become activated. with alloantibody production, chronic inflammation, and allo- It was initially assumed that donor or recipient DCs might hin- graft vasculopathy (Suciu-Foca et al., 1996, 1998; Shirwan, 1999; der tolerance induction to allografts owing to their contribution Baker et al., 2001; Lee et al., 2001; Najafian et al., 2002; Shirwan to the priming of alloreactive T cells and the secretion of pro- et al., 2003; Yamada et al., 2003; Illigens et al., 2009). Finally, some inflammatory cytokines. Based upon this principle,many attempts recent studies show that recipient DCs can capture donor-MHC have been made to deplete DCs from transplanted tissues or from molecules and presumably other donor proteins from donor DCs the host prior to tolerance induction. Actually, DC depletion has

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led to various and sometimes opposite outcomes depending upon window of opportunity that permitted Treg-mediated suppression the nature of the tissue transplanted, the site of graft placement, of graft rejection. Indeed, it well established that early activation the method utilized to induce tolerance. For instance, depletion of pre-existing alloreactive memory T cells represents a formida- of different DCs from skin transplants such as Langerhans cells ble barrier to tolerance induction in transplantation (Valujskikh or dermal DCs can lead to opposite effects on allograft rejection et al., 2002; Adams et al., 2003b; Valujskikh and Heeger, 2003; (Bobr et al., 2010; Igyarto and Kaplan, 2010; Igyarto et al., 2011). Weaver et al., 2009; Nadazdin et al., 2011). In the model described On the overall, most studies showed that absence of DCs, either above, PMNs did not prevent tolerance induction directly but from recipients or donors in studies using CD11C KO mice, graft indirectly by hindering the suppression of memory T cells by parking protocols, or -mediated cell depletion, not only Tregs. It is possible that this phenomenon represents a general regularly failed to significantly prolong graft survival but it often mechanism by which innate immunity prevent transplant toler- prevented tolerance induction. This further supports the view that ance induction through the potentiation of alloreactive memory DCs are necessary for antigen presentation during tolerogenesis T cells. This implies that blocking innate immune responses at the via their ability to trigger some regulatory mechanisms resulting time of graft placement may impair the development of anamnes- in graft protection. Further studies will be needed to discriminate tic alloresponses by T cells and render allograft susceptible to between the DCs, which promote or hinder tolerance to allografts tolerogenesis by regulatory responses induced after costimula- and the mechanisms by which they determine the fate of regu- tion blockade or mixed hematopoietic chimerism induction, a latory T cell responses. Gaining insights into these questions will hypothesis that requires further investigation. be necessary to delete or inactivate selectively the DCs associated Eosinophils play a key role in the pathogenesis associated with tolerance resistance in transplantation. with allergic reactions through their production of inflammatory cytokines and cationic proteins (Capron and Goldman, 2001). GRANULOCYTES, MASTOCYTES, AND MONOCYTES/MACROPHAGES These cells can drive the differentiation of T cells to TH2 immu- Granulocytes, mastocytes, and monocytes/macrophages are tradi- nity essentially via IL-4 and IL-5 cytokine release (Sanderson, tionally considered as key players in both early innate alloimmune 1992; Kay et al., 1997). TH2 cells that exert antagonist properties response and in the actual destruction of donor cells after trans- toward their pro-inflammatory TH1 counterparts were initially plantation. However, the mechanisms by which they contribute to thought to be potential contributors to tolerogenesis in autoim- alloimmunity and the actual nature of their contribution to allo- mune diseases and transplantation (Charlton and Lafferty, 1995; graft rejection have not been thoroughly investigated. Likewise, Goldman et al., 2001). Indeed, TH2 polarization has been demon- little is known regarding the impact of these cells in transplanta- strated to be essential in neonatal tolerance induction and in some tion tolerance. This section reviews some of the few studies that allotransplant models (Hancock et al., 1993; Forsthuber et al., have tackled these questions. 1996; Onodera et al., 1997; Yamada et al., 1999; Kishimoto et al., Granulocytes are the most abundant leukocytes in the blood 2000; Waaga et al., 2001; Fedoseyeva et al., 2002). However, it of mammals and an essential part of the innate immune sys- became rapidly evident that this concept is over simplistic and tem. Among them, PMNs migrate within hours to the site of that eosinophils either directly or via the activation of TH2 cells acute inflammation after transplantation following chemical sig- can trigger the rejection of allografts in various models (Illigens nals such as IL-8, C5a, and Leukotriene B4 in a process called et al., 2009). First, there is ample evidence showing that adop- chemotaxis. However, they survive only 1–3 days at the graft site tively transferred allospecific TH2 cells can ensure on their own where they undergo degranulation and release reactive oxygen the rejection of skin and cardiac allogeneic transplants (Piccotti species (ROS), a process involving the activation of NADPH oxi- et al., 1996, 1997; VanBuskirk et al., 1996; Shirwan, 1999). Second, dase and the production of superoxide anions and other highly IL-4 and IL-5 neutralization has been shown to delay the rejection reactive oxygen metabolites which cause tissue damage (Jaeschke of allografts in several models (Chan et al., 1995; Simeonovic et al., et al., 1990). There is ample evidence showing that PMNs con- 1997; Matesic et al., 1998; Le Moine et al., 1999; Braun et al., 2000; tribute to donor tissue destruction and graft rejection in skin Honjo et al., 2000; Goldman et al., 2001; Surquin et al., 2005). transplantation, solid organ transplantation, and bone marrow In the B6-bm12 MHC class II classical skin graft model, rejec- transplantation (Buonocore et al., 2004; Surquin et al., 2005). tion has been associated with a massive infiltration by eosinophils Studies from the Fairchild’s group have demonstrated that Abs (Le Moine et al., 1999; Goldman et al., 2001). IL-5 blockade directed to KC/CXCL1 can prolong cardiac allograft survival by delayed the rejection process by preventing eosinophilic infiltra- preventing PMNs from graft infiltrating the graft (Morita et al., tion, but these allografts were ultimately rejected via a mechanism 2001; LaRosa et al., 2007). Additionally, the potential role of PMNs involving PMNs (Le Moine et al., 1999; Goldman et al., 2001). in the prevention of tolerance induction has been examined in two In another study from the Martinez’s group, the existence of a recent studies, only. First, it has been reported that peritransplant non-classical pathway of liver allograft rejection was shown to elimination of PMNs facilitated tolerance to fully mismatched car- involve IL-5 and graft infiltrating eosinophils secreting a series of diac allografts induced via costimulation blockade (El-Sawy et al., cytotoxic mediators including eosinophil peroxidase, eosinophil- 2005; Mollen et al., 2006; LaRosa et al., 2007). Most interestingly, derived neurotoxin, eosinophil cationic protein, and major basic another study from Wood’s group shows that prevention of accel- protein (MB; Martinez et al., 1993). In addition, a number of erated rejection of skin allografts by CD8+ effector memory T cells studies from us and others have provided direct evidence demon- could be achieved by Tregs but only following depletion of PMNs strating that alloreactive TH2 cells activated through the indirect (Jones et al., 2010). It is likely that elimination of PMNs created a allorecognition pathway can trigger chronic allograft vasculopathy

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and tissue fibrosis in MHC class I-mismatched transplanted hearts tolerance induction in a skin allograft model (de Vries et al., 2009a; (Shirwan, 1999; Mhoyan et al., 2003; Koksoy et al., 2004; Illigens Murphy et al., 2011). While Tregs can induce the maturation and et al., 2009). At the same time, it has been reported that, in models growth of mastocytes through IL-9 production, this process seems in which acute rejection had been suppressed, eosinophilic graft rather to contribute to tolerance induction (Lu et al.,2006; Murphy infiltration could induce fibrosis through their production of TGF- et al., 2011). In addition, sequestration of pro-inflammatory IL-6 β, a key mediator of extracellular matrix remodeling (Goldman cytokines by mastocytes through MCP6 receptors has also been et al., 2001). It is noteworthy that eosinophils are likely to play a shown to promote establishment of tolerance to lung and car- prominent role in heart and lung transplantation through their diac allografts via costimulation blockade (de Vries et al., 2009a,b, cooperation with activated mast cells associated with IL-9 release 2010; de Vries and Noelle, 2010; Murphy et al., 2011). Therefore, (Dong et al., 1999; Marone et al., 2000; Suzuki et al., 2000; Cohn the role of mastocytes in alloimmunity is more complex than ini- et al., 2002; Poulin et al., 2003; Steenwinckel et al., 2007). Inter- tially anticipated and further studies will be required to determine estingly, it has been observed that depletion of CD8+ CT1 cells how these cells can prevent or promote tolerance induction in skin and subsequent deprivation of γIFN production or IL-12 antago- and presumably lung transplantation. nism can result in a polarization of the T cell response toward TH2 Different macrophages derived from monocyte differentiation alloimmunity and cause eosinophilic rejection of cardiac allografts are present in various tissues and organs including Kupffer cells primarily driven by IL-4 and IL-5 cytokines (Noble et al., 1998; in the liver, microglial cells in the CNS, alveolar macrophages in Foucras et al., 2000; Goldman et al., 2001). This further illustrates the lungs, and intraglomerular mesangial cells in the kidney (Lu the complexity of the alloimmune response and the multiplicity and Unanue, 1982; Unanue, 1984; Yan and Hansson, 2007; Varol of the mechanisms potentially involved in the rejection process. et al., 2009; Geissmann et al., 2010; Yona and Jung, 2010). These Indeed, as often observed in autoimmune disease models, block- cells are characterized by the surface expression of CD14, CD11b, ing a known deleterious type of alloimmunity can often uncover F4/80 (mice)/EMR1 (humans) as well as MAC1/3 and CD68. a different type of response also leading to allograft rejection. Macrophages and monocytes rapidly infiltrate inflammation sites Mastocytes were originally described by Paul Ehrlich in his and are typically found in large numbers within allografts (Geiss- 1878 doctoral thesis on the basis of their unique staining char- mann et al., 2010). Upon activation, they release large amounts acteristics and large granules (Alvarez-Errico et al., 2009; Barnes, of pro-inflammatory cytokines such as TNFα, IL-12 IL-1, and IL- 2011). These cells typically found in mucosal and connective tis- 6, which promote both innate and adaptive immune responses sues (skin, lungs, and intestines) are characterized by their high (Geissmann et al., 2010). Macrophages play a key role in the induc- expression of IgE high affinity Fc receptor (FcR) and IgG1 (in tion of antibody dependent cellular cytotoxic (ADCC) reactions mice) FcR. Mast cells are known for their pivotal role in immunity leading to the phagocytosis of opsonized allogeneic target cells against parasitic worms and their contribution to allergic reac- (Unanue and Allen, 1986; Rocha et al., 2003; Li, 2010). During tions (asthma, eczema, allergic rhinitis, and conjunctivitis). This acute inflammation, while PMNs are typically the first phenomenon is mediated mainly through degranulation of ser- infiltrating allografts, macrophages are usually involved in sec- ine proteases, histamine, and serotonin and through recruitment ondary stages of inflammation during which they remove aged of eosinophils at the site of inflammation via the secretion of PMNs via a mechanism involving PECAM-1 (CD31) as well as eosinophil chemotactic factors (Alvarez-Errico et al., 2009; Barnes, necrotic cells and cellular debris (Davies et al., 1993; Wu et al., 2011). Mast cells are also essential to the recruitment of T cells to 2007b; Roh et al., 2010; Wu and Madri, 2010). Macrophages have the skin and joints in autoimmune disorders including rheuma- also been shown to be essential to the maintenance of chronic toid arthritis, bullous pemphigoid, and multiple sclerosis (Sayed inflammatory processes (Yan and Hansson, 2007; Geissmann et al., and Brown, 2007; Sayed et al., 2008; Schneider et al., 2010). The 2010). Likewise, some evidence has been provided suggesting that role of mastocytes in allotransplantation was actually described in macrophages contribute to transplant vasculopathy and fibrosis seminal studies for the Voisin’s laboratory more than 40 years ago. (Davies et al., 1993; Kitchens et al., 2007; Yan and Hansson, 2007; It was observed that non-complement fixing anaphylactic IgG1 Bani-Hani et al., 2009; Dinarello, 2011b; Kamari et al., 2011). In and IgE antibodies directed to donor-MHC molecules can cause addition to their role in innate immunity, macrophages process, rejection of skin allografts through a process called alloantibody- and present alloantigens to CD4+ T cells in a MHC class II context induced anaphylactic degranulation (DAAD; Daeron et al., 1972, thus initiating T cell-mediated responses and rejection (Beller and 1975, 1980; Le Bouteiller et al., 1976; Daeron and Voisin, 1978, Unanue, 1980; Lu et al., 1981; Unanue and Allen, 1986; Unanue, 1979; Benichou and Voisin, 1987). Hyperacute rejection of skin 2002; Calderon et al., 2006). Some observations indicate that, in allografts was induced through bipolar bridging of mastocytes stable transplants, macrophages can convert otherwise harmless (through their FcR) and donor-MHC molecules on grafted cells, lymphocytes into aggressive ones and cause rejection, thereby a process leading to a massive anaphylactic reaction leading to controlling the cytopathic features of cellular infiltrates in solid allograft rejection (Daeron et al., 1972, 1975, 1980; Le Bouteiller organ transplants (Li, 2010). Likewise, some studies have shown et al., 1976; Daeron and Voisin, 1978, 1979). This type of “allergic the beneficial effects of blockage of the -migration transplant rejection” discovered during the 1960s has been largely inhibitory factor (MIF) on the pathogenesis of allografts including forgotten through the years and would deserve to be revisited the reduction of obstructive bronchiolitis after lung transplanta- using newly developed immunological models. More recently, it tion (Fukuyama et al., 2005; Javeed and Zhao, 2008). A study from has been shown that degranulating mastocytes can contribute to Heeger’s group has shown that in vivo blockade of MIF could allograft rejection by causing the loss of Tregs and thereby prevent prevent the rejection of MHC class II KO skin allografts in mice

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mediated through the indirect allorecognition pathway (Hou et al., regulatory mechanisms. In addition, innate immune responses 2001; Demir et al., 2003). In this model, neutralization of MIF can alter the immune privileged nature of the tissue transplanted resulted in reduced DTH response while it did not affect γIFN pro- or the site of graft placement as evidenced by studies in corneal duction by activated T cells (Hou et al., 2001; Demir et al., 2003). It transplantation. While,it is clear that innate immunity represents a is, however, noteworthy that different types of macrophages can be major barrier to tolerogenesis in allotransplantation,this phenom- found in kidney allografts,some of which being involved in attenu- enon is presumably even more relevant to xenotransplantation due ation of inflammation,activation of Tregs,and tolerance induction to the involvement of natural antibodies, CD47/SIRPα-mediated (Lu et al., 2006; Brem-Exner et al., 2008; Hutchinson et al., 2011). interactions, and presumably many other still unknown factors. Recently,macrophages have been shown to be involved in self-non- In addition, it is likely that activation of innate type of immu- self discrimination, i.e., self-awareness via interaction between the nity can abrogate formerly established tolerance to an allograft as innate inhibitory receptor SIRPα expressed on their surface and suggested by some studies involving microbial infections (Miller CD47. This type of recognition, which is reminiscent of the miss- et al., 2008; Ahmed et al., 2011a,b). Taken together, these studies ing self-model described with NK cells, has been shown to play a imply that the design of future successful tolerance protocols in role in xenograft rejection by macrophages (Ide et al., 2007; Wang transplantation will require the administration of agents capable et al., 2007; van den Berg and van der Schoot, 2008). However, of suppressing innate immunity. However, a number of cells of the it is still unclear whether some degree of CD47 polymorphism innate immune system such as NK cells and DCs have been shown within a given species exists and whether it could be involved in to be required for transplant tolerance induction. This apparent allorecognition. contradiction may be explained by the fact that different cell sub- sets and mediators of the innate immune system are involved in CONCLUDING REMARKS tolerance vs. rejection. Alternatively certain cells or mediators may It is now firmly established that innate immune responses trig- play opposite roles depending upon the context in which they are gered after transplantation as a consequence of tissue damage, activated. For instance, γIFN and IL-2 have been shown to be infections, and reperfusion injury are an essential element of the essential cytokines in both rejection and tolerance of allografts. It inflammatory process leading to early rejection of allografts. In is likely that their dual role depends upon their concentration at addition, there is accumulating evidence showing the contribution a given time point and the cells they are activating in a particular of innate immunity to chronic rejection of allogeneic transplants. physiological context. These observations illustrate the complex- On the other hand, this review supports the view that activation of ity of the cellular and molecular mechanisms by which innate virtually any of the cells of the innate immune system can prevent immunity can influence alloimmunity toward rejection or tol- transplant tolerance induction. This process is essentially medi- erance. Further dissection of the innate immune response will ated via signaling of various receptors including TLRs (via DAMPS be required to grasp some of this complexity, at least enough and PAMPS) and the secretion of several key pro-inflammatory to be able to manipulate this type of immune response to our cytokines (primarily IL-1, IL-6, TNFα, and type I interferons) advantage. and chemokines. Activated cells of the innate immune system can prevent tolerogenesis directly via cytokine secretion, activation of ACKNOWLEDGMENTS the complement cascade, and killing of donor cells or indirectly This work was supported by grants from the MGH ECOR and by promoting and amplifying deleterious inflammatory adaptive NIAID AI066705 grants to Gilles Benichou and NIH U191066705, immune responses while preventing the activation of protective PO1HL18646, and ROTRF 313867044 to Joren C. Madsen.

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Zhou, W., Patel, H., Li, K., Peng, conducted in the absence of any Citation: Benichou G, Tonsho M, Copyright © 2012 Benichou, Tonsho, Q., Villiers, M. B., and Sacks, commercial or financial relationships Tocco G, Nadazdin O and Mad- Tocco, Nadazdin and Madsen. This is an S. H. (2006). Macrophages from that could be construed as a potential sen JC (2012) Innate immunity and open-access article distributed under the C3-deficient mice have impaired conflict of interest. resistance to tolerogenesis in allotrans- terms of the Creative Commons Attribu- potency to stimulate alloreactive T plantation. Front. Immun. 3:73. doi: tion Non Commercial License, which per- cells. Blood 107, 2461–2469. Received: 29 December 2011; paper 10.3389/fimmu.2012.00073 mits non-commercial use, distribution, pending published: 09 February 2012; This article was submitted to Frontiers in and reproduction in other forums, pro- Conflict of Interest Statement: The accepted: 22 March 2012; published Immunological Tolerance, a specialty of vided the original authors and source are authors declare that the research was online: 19 April 2012. Frontiers in Immunology. credited.

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