NEUROVASCULAR MEDICINE - Pursuing Cellular Longevity for Healthy Aging Part 7 ppsx

ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 348 Table 14.1 Regulatory T-cell Populations Cell Type Generation/Location Markers Properties and Function References Natural Tregs Generated in the thymus, predominantly located in lymphoid organs, migrate toward sites of in ammation CD4, CD25, Foxp3, CD45RB low , CD62L, CTLA-4 or CD152, GITR, ±CD127, ±CD38 Antigen speci c, secrete IL-10 and/or TGF-β, suppressive activity, inhibit effector T-cell functions, contact dependent, require CD80 and CD86 ligands on target T cells Hsieh et al. 2004; Fontenot, Rudensky 2005; Ziegler 2006; Scalzo et al. 2006 Inducible or adaptive Tregs: (1) Tr1 (2) Th3 Generated in the periphery, migrate toward sites of in ammation CD4, CD25, CD45RO Target APC and T cells; prevent autoimmune colitis and in ammation of the digestive track mainly the gut, and are mainly involved in oral tolerance Groux et al. 1997; Graca et al. 2002; Chen et al. 2003; Apostolou et al. 2004; Cottrez, Groux 2004 Tr1 From naive CD4 T cells in the presence of IL-10 and IFN-α Secrete mainly IL-10, but also TGF-β, IL-5, and IFN-γ; do not secrete IL-2 or IL-4; inhibit Th1 and Th2 cell responses, regulate both naive and memory T cells, inhibit T-cell-mediated responses to pathogens and alloantigens and cancer; target APC Groux et al. 1997; Foussat et al. 2003; Roncarolo et al. 2003; Scalzo et al. 2006 Th3 Through oral antigen administration Produce mainly TGF- β but also IL-10; suppress APC and T-cells, mainly Th2 Weiner 1997; Scalzo et al. 2006 T helper 1 cells (Th1) Generated in the periphery from Th0 or Th2 cells mainly in the presence of IL-12 CD4, CD25, STAT-4, T-bet Produce IL-2, IFN-γ, lymphotoxin-α; target Th2 cells; activate phagocytosis, opsonization, and complement protection against intracellular antigens; responsible for autoimmunity and in ammation Mosmann, Coffman 1989; Boom et al. 1990; Le Gros et al. 1990; Romagnani 1991, 1994, 1997; Hsieh et al. 1993 T helper 2 cells (Th2) Generated in the periphery from Th0 cells or Th1 mainly in the presence of IL-4 CD4, CD25, STAT-6, GATA-3, c-maf Secrete IL-4, IL-5, IL-9, IL-13; target Th1 cells; induce B-cell function and eosinophil activation; participate in allergic disorders Abbas et al. 1996; Annunziato et al. 2001; Smits et al. 2001; Ghoreschi et al. 2003; Szabo et al. 2003; Skapenko et al. 2004; Scalzo et al. 2006 T helper 17 cells (Th17) Generated in the periphery from naive T cells mainly in the absence of IFN-γ, IL-4, and IL-6 and in the presence of IL-β or TNF-α; IL-23 promotes their survival CD4 Secrete IL-17A, F, IL-6, TNF-α, IL-22; protect against extracellular microbes, responsible for autoimmune disorders, in ammation, downregulate Treg function Ye et al. 2001; Murphy et al. 2003; Nakae et al. 2003; Langrish et al. 2005; Bettelli et al. 2006; Harrington et al. 2006; Iwakura, Ishigame 2006; Liang et al. 2006; Reinhardt et al. 2006; Tato, O’Shea 2006; Annunziato et al. 2007 CD8 regulatory T cells Generated in the thymus and also in the periphery (?), predominantly located in lymphoid organs, migrate toward sites of in ammation CD8, Foxp3, CD28 − , γδ subgroup Induction of tolerance; inhibit T cells; antigen-speci c (MHC class Ib APC-dependent) subgroup and IFN-γ-secreting, nonantigen-speci c subgroup; CD8gdT cells secrete IFN-γ and IL-4 and inhibit APC and Th cells Jiang et al. 1992; Hu et al. 2004; Scalzo et al. 2006 Natural Killer T cells (NKT) Periphery CD3, CD56 Secrete IFN-γ and IL-4; inhibit Th1/Th2 responses and DCs; tolerogenic but also proin ammatory in different pathological conditions Boyson et al. 2002; Scalzo et al. 2006; Godfrey, Berzins 2007; Novak et al. 2007; Nowak, Stein-Streilein 2007 APC, antigen presenting cell; DC, dendritic cell; IL, interleukin; IFN, interferon; TGF, transforming growth factor; (?), not clear. Chapter 14: Immunomodulation: Role of T Regulatory Cells 349 suppressive potential that are not able to accumulate and proliferate in the lymph nodes cannot suppress or prevent disease (Tang, Henriksen, Bi et al. 2004; Tarbell, Yamazaki, Olson et al. 2004; Jaeckel, von Boehmer, Manns 2005). Therefore, it seems that in vivo homing and proliferation of Tregs in the lymph nodes are important for these cells to exert their suppressive activity in the early phase of the immune response. The migration of Tregs toward sites of in ammation is essential for their suppression of T effector cells, and it has been shown that activated Tregs change their homing receptors to accomplish this task (Huehn, Siegmund, Lehmann et al. 2004). It has also been demonstrated that natural Tregs are predominantly located in lymphoid organs, whereas another group of Tregs, Tr1 cells, tends to migrate toward sites of in ammation (Graca, Cobbold, Waldmann 2002; Cottrez, Groux 2004). Antigen exposure is very important for Tregs to initiate suppressive activity. Interestingly, in vitro studies have also shown that activated Tregs can inhibit the immune response, regardless of the antigen that causes it (Thornton, Shevach 2000). Furthermore, there is strong evidence that Foxp3-transduced CD4 + T cells speci c for the OVA antigen are able to protect OVA-speci c TCR-transgenic mice from GVHD (Albert, Liu, Anasetti et al. 2005). There seems to be antigen speci city during the activation phase and a bystander suppression phenomenon in the effector suppressor phase. Although the exact suppression mechanism remains largely unknown, in vitro and in vivo research has shown a relative contribution of both cell-to-cell contact and soluble cytokine mechanisms. Accessory molecules such as CTLA-4 and its ligands CD80, CD86, and GITR, which are expressed on the surface of Tregs, have been implicated (Takahashi, Kuniyasu, Toda et al. 1998; Takahashi, Tagami, Yamazaki et al. 2000; Suri-Payer, Cantor 2001; Piccirillo, Letterio, Thornton et al. 2002; Shimizu, Yamazaki, Takahashi et al. 2002). In the GVHD murine model, CD4 + CD25 + or CD4 + CD25 – T cells were unable to inhibit the development of disease caused by effector T cells de cient in CD80 or CD86 ligands, indicating that suppression of T-cell activation functions through CD80 and CD86 molecules on activated T cells and CTLA-4 on Tregs (Paust, Lu, McCarty et al. 2004). Furthermore, studies have implicated cell surface TGF-β1 in the immunosuppressive effect of Tregs (Nakamura, Kitani, Strober 2001). Inducible or Adaptive Tregs Another important group of regulatory T cells includes the T cells that can be induced by naive T cells in the periphery under low doses of antigenic stimulation or has also been detected in activated CD4 + CD25 + cells with no regulatory action (Seidel, Ernst, Printz et al. 2006). CD127 (IL-7 receptor α chain) has been shown to have a reverse relationship with the suppressive function of CD4 + Foxp3 T cells and is downregulated in human T cells after activation. Cells separated on the basis of CD4 and CD127 expression were shown to be anergic and to possess suppressive action compared to CD4 + CD25 + T cells (Huster, Busch, Schiemann et al. 2004; Fuller, Hildeman, Sabbaj et al. 2005; Boettler, Panther, Bengsch et al. 2006; Liu et al. 2006a; Seddiki, Santner-Nanan, Martinson et al. 2006). Natural Tregs develop in the thymus after positive selection on cortical medullary epithelial cells (Bensinger, Bandeira, Jordan et al. 2001). The selection of CD4 + CD25 + thymocytes requires an intermediate af nity of TCRs for self-peptides, since thymocytes with low-af nity TCRs do not yet undergo selection (Jordan, Boesteanu, Reed et al. 2001). However, a defect in this selection process contributes to the enrichment of autoreactive Tregs, as these precursors seem to be resistant to clonal deletion (van Santen, Benoist, Mathis et al. 2004; Romagnoli, Hudrisier, van Meerwijk 2005). Nevertheless, this enrichment could be due to both positive selection by self-ligands and the absence of negative selection. Antigen speci city is required for natural Treg activation. Studies with TCR-transgenic mice speci c for ovalbumin (OVA) have shown that protection from graft-versus-host-disease (GVHD) is realized only when the host T cells used for immunization recognize the antigen (Albert, Liu, Anasetti et al. 2005). Tregs also recognize pathogen antigens. Tregs from mice infected with Schistosoma or Leishmania produce IL-10 in response to the same parasite antigens but not other pathogens (Belkaid, Piccirillo, Mendez et al. 2002; Hesse, Piccirillo, Belkaid et al. 2004). In human studies of asymptomatic human immunode ciency virus–infected individuals, CD4 + CD25 + peripheral blood Tregs showed immunosuppressive properties in an antigen-speci c way (Kinter, Hennessey, Bell et al. 2004). The same phenomenon was observed in Helicobacter pylori–infected patients (Raghavan, Suri- Payer, Holmgren 2004). The in vivo suppressive activity of Tregs requires close contact with T effectors with certain antigen speci city. Tregs seem to require strong localiza- tion to parts of the body where antigenic stimulation occurs, like draining lymph nodes. Furthermore, it has been shown that suppression of activated T cells occurs when the ratio of Tregs to T effectors is one third. Since the percentage of Tregs is only 2 to 3% of total T cells, selective homing, as well as expansion, is very important for a suppressive effect to be achieved. It has been shown in animal models that cells with ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 350 Furthermore, desmoglein 3–speci c Tr1 cell induction requires the presence of IL-2; these cells function mainly through IL-10 and TGF-β secretion, indicating their critical involvement in tolerance homeostasis in response to the speci c antigen (Beissert, Schwarz, Schwarz 2006). TH3 It has been shown in an experimental allergic/ autoimmune encephalomyelitis (EAE) model that the oral delivery of myelin basic protein (MBP) antigen generates a T-cell population that inhibits the in ammatory reaction. This population was identi ed as the Th3 cell subgroup of T regulatory cells and produces high amounts of TGF-β and moderate amounts of IL-10, and has the ability to inhibit the development of autoimmunity (Weiner 1997). Anti-TGF-β monoclonal antibodies inhibit the suppressive effects of Th3 cells, indicating the importance of TGF-β in immunosuppression through Th3 cells. Th3 cells have been shown to inhibit the proliferation and cytokine production of MBP-speci c Th1 clones through TGF-β. This suppression is antigen nonspeci c and is mediated through TGF-β, indicating a bystander suppression–based mechanism (Weiner 1997). Furthermore, suppression of Th2, as well as Th2 clones, by Th3 cells has also been demonstrated, suggesting a unique role for this orally induced Treg population. Th1 and Th2 Regulation For the last 20 years, the classical concept of the immune response included two main branches of the T-cell group, Th1 and Th2 cells, based mainly on the type of cytokines produced. Th1 cells were found to produce IL-2, IFN-γ, and lymphotoxin-α, and Th2 cells were found to produce IL-4, IL-5, IL-9, and IL-13 (Mosmann, Coffman 1989; Romagnani 1991). These two cell groups also differ in the transcription factors used for their regulation. Th1 cells are regulated by transcription factors that include STAT-4 and T-bet, whereas Th2 development is regulated by factors such as STAT-6, GATA-3, and c-maf, which are also antagonistic to the transcription factors belonging to the Th1 branch (Hsieh, Macatonia, Tripp et al. 1993; Szabo, Sullivan, Peng et al. 2003). Th1 transcription factors STAT-4 and T-bet are usually activated in the presence of IL-12 or IFN-γ. IL-12 is produced by dendritic cells and IFN-γ is produced by NK cells when activation by highly conserved microbial products occurs. Th2 transcription factors are activated when IL-4, instead of IL-12 or IFN-γ, is present (Le Gros, Ben-Sasson, Seder et al. 1990). Cytokines produced by Th1 cells activate phagocytosis, opsonization, and complement protection against intracellular parasites, whereas Th2 cytokines induce mainly B-cell function and eosinophil activation (Romagnani 1994; Abbas, in the presence of immunosuppressive cytokines like TGF-β (Chen, Jin, Hardegen et al. 2003; Apostolou von Boehmer 2004; von Boehmer 2005). There are two subgroups of inducible Tregs, Tr1 and Th3, and they cannot be separated on the basis of their phenotype. In addition, they are better characterized on the basis of the cytokines they use as mediators. Tr1 and Th3 cells are similar—Tr1 cells are characterized by their large amount of IL-10 secretion and their role in preventing autoimmune colitis (Groux, O’Garra, Bigler et al. 1997) and Th3 cells play an important role in oral tolerance through the secretion of TGF-β (Chen, Kuchroo, Inobe et al. 1994). None of these subgroups expresses Foxp3, and the suppression effect on Th1 and Th2 cells mediated by TGF-β1 and IL-10 is MHC unrestricted and antigen nonspeci c (Vieira, Christensen, Minaee et al. 2004). TR1 Tr1 cells were  rst identi ed in a murine model in which CD4 + transgenic T cells generated Tr1 cells after repetitive stimulation by their cognate peptide in the presence of IL-10 (Groux O’Garra, Bigler et al. 1997). Tr1 cells are characterized by the secretion of large amounts of IL-10 and moderate amounts of TGF-β, IL-5, and interferon γ (IFN-γ). These cells do not secrete IL-2 or IL-4 (Groux O’Garra, Bigler et al. 1997). Although they show poor proliferative ability after polyclonal or antigen-speci c stimulation, they can inhibit T-cell responses in vitro and in vivo through mechanisms similar to bystander suppression, as has been shown in the case of colitis. Tr1 cells are capable of regulating the activation of naive and memory T cells and also inhibit T-cell–mediated responses to pathogens and alloantigens, as well as cancer (Foussat, Cottrez, Brun et al. 2003; Roncarolo, Gregori, Levings 2003). Neutralizing anti-IL-10 antibodies blocks most of the immunosuppressive effects of Tr1, demonstrating the importance of IL-10 in Tr1’s immunosuppressive function (Roncarolo, Bacchetta, Bordignon et al. 2001). It has also been shown that complement can play a role in Tr1 induction. Resting CD4 + T cells treated with anti-CD3 and anti-CD46 antibodies in the presence of IL-2 resulted in the induction of Tr1 cells. CD46 is an important complement regulator that induces Tr1 through an endoge- nous receptor–mediated event (Kemper, Chan, Green et al. 2003). Tr1 cells have been shown to be important in controlling autoimmunity. In the case of pemphigus vulgaris, desmoglein 3–speci c Tr1 cells maintained and restored natural tolerance against the pemphigus vulgaris antigen (Veldman, Hohne, Dieckmann et al. 2004). Healthy individuals carrying the pemphigus- associated human leukocyte antigen (HLA) class II allele DRB1*0402 and DQB1*0503 were found to have desmoglein 3–responsive Tr1 cells that secreted IL-10 although these cells were rarely found in patients. Chapter 14: Immunomodulation: Role of T Regulatory Cells 351 by lack of T-bet (Harrington, Mangan, Weaver 2006). Furthermore, TGF-β secreted from Tregs in the presence of IL-6 was responsible for the differentiation of Th17 cells, and IL-1β or TNF-α addition signi cantly increased the percentage of naïve T cells that differ- entiated into Th17. The presence of IL-23 seems to be important for the maintenance and survival of Th17 cells, although it was not necessary for their generation (Reinhardt, Kang, Liang et al. 2006). Th17 cells are induced through the production of IL-23 from dendritic cells and are involved in the pathogenesis of in ammatory and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and EAE (Murphy, Langrish, Chen et al. 2003; Nakae, Nambu, Sudo et al. 2003; Langrish, Chen, Blumenschein et al. 2005). Th17 cells produce IL-17 and IL-22, which is a member of the IL-10 family (Ye, Rodriguez, Kanaly et al. 2001; Tato, O’Shea 2006; Liang, Tan, Luxenberg et al. 2006). These cytokines induce  broblasts and endothelial and epithelial cells, as well as macrophages, to produce chemokines that result in the recruitment of polymorphonu- clear leukocytes and the induction of in ammation (Ye, Rodriguez, Kanaly et al. 2001). Thus, IL-17 may play a protective role against extracellular bacteria, although, under certain circumstances, in ammation is induced by macrophages through the production of IL-1, IL-6, and metalloproteinases (Cua, Sherlock, Chen et al. 2003; Park, Li, Yang et al. 2005). Th17 cells do not express Th1 or Th2 transcription factors such as T-bet or GATA-3 (Dong 2006). Therefore, clari ca- tion of the pathogenetic role of Th17 cells may provide more information on the role of other Th cell groups in protecting against different pathogens. Murine model experiments have suggested that Th17 cells are involved in autoimmune phenomena like in ammatory bowel disease and EAE. Th17 originate through the production of IL-23 by dendritic cells, which has been shown to be due to the combined activity of IL-6 and TGF-β. TGF-β is also involved in the generation of Tregs. Furthermore, there is evidence for a functional antagonism between Th17 and Foxp3 Tregs (Bettelli, Carrier, Gao et al. 2006). Since the production of Th17 cells is inhibited by IL-6, IL-4, and IFN-γ, there must be a regulatory point that separates the generation of Th17 cells, which are pathogenic and induce autoimmunity, from Foxp3 Tregs, which inhibit autoimmunity (Iwakura, Ishigame 2006). CD8 + and NK T cells (or NKT cells) CD8 + T cells have also been shown to possess immunosuppressive activity; this also results in the inhibition of EAE (Jiang, Zhang, Pernis 1992) by inhibiting Th1 encephalitogenic cells. These CD8 + T cells exert their suppressive activity only after being primed during Murphy, Sher et al. 1996). Currently, the Th1 branch is considered to be mainly responsible for phenomena such as autoimmunity, whereas the Th2 branch par- ticipates in allergic disorders (Romagnani 1997). A process known as immune deviation re ects the mutual regulation between the Th1 and Th2 responses. The presence of IL-12, IL-18, IFN-γ, and IFN-α induces the development of Th1 cells while at the same time inhibiting the development of Th2 cells. Microbial products induce the secretion of IL-12 and IFNs, leading Th2 responses toward a Th0 or Th1 type of response (Maggi, Parronchi, Manetti et al. 1992; Parronchi, De Carli, Manetti et al. 1992; Manetti, Parronchi, Giudizi et al. 1993; Kips, Brusselle, Joos et al. 1996; Lack, Bradley, Hamelmann et al. 1996; Li, Chopra, Chou et al. 1996). The presence of IL-12 is important in the polarization of immune responses, since it can shift even established Th2 responses toward a Th1 response (Annunziato, Cosmi, Manetti et al. 2001; Smits, van Rietschoten, Hilkens et al. 2001). On the other hand, the presence of IL-4 inhibits Th1- cell type development and can in turn shift established Th1 responses toward a Th2 phenotype, although the opposite phenomenon can occur just as easily (Boom, Liebster, Abbas et al. 1990; Ghoreschi, Thomas, Breit et al. 2003; Skapenko, Niedobitek, Kalden et al. 2004). Furthermore, some chemokines can interact with Th1 or Th2 cells and shift their balance in either direc- tion, thus inducing the production of certain cytokines (Karpus, Lujacs, Kennedy et al. 1997). Th17: Treg Antagonists? Beyond the initially polarized forms of Th effector T cells (Th1 and Th2, as well as Th0 CD4 + cells), another subset has been identi ed. This subset, called Th17, is distinct from Th1, Th2, and Th0 cells. Th17 cells secrete IL-17A, IL-17F, IL-6, and tumor necrosis factor α (TNF-α . ) cytokines. Th17 cells are protective against extracellular microbes but also seem to be responsible for autoimmune disorders in mice (Annunziato, Cosmi, Santarlasci et al. 2007). Recent studies show that these cells are probably a separate lineage of Th cells and that they do not represent just another Th1 population that has undergone further differentiation (Harrington, Mangan, Weaver 2006; Reinhardt, Kang, Liang et al. 2006). When naive CD4 + T cells were cultured in the presence of anti-IFN-γ monoclonal antibody, induction of Th17 population was observed. This observation was stronger with IL-4 inhibition, which is an indication of Th17 inhibition in the presence of IFN-γ and IL-4 (Reinhardt, Kang, Liang et al. 2006). The T-bet transcription factor seems to play an important role in Th1 cell differentiation, but Th17 cell growth is not in uenced ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 352 function of autoreactive cells or a decrease in the function of regulatory mechanisms, leading to autoimmunity. However, a decrease in these regulatory mechanisms can lead to immunode ciency. Autoimmunity targeting the nervous system has been studied extensively in animal models and human subjects (Mouzaki, Tselios, Papathanassopoulos et al. 2004; Mouzaki, Deraos, Chatzantoni 2005; Owens, Babcock, Millward et al. 2005; Boscolo, Passoni, Baldas et al. 2006; Alaedini, Okamoto, Briani et al. 2007; Cabanlit, Wills, Goines et al. 2007; Cassan, Liblau 2007; Correa, Maccioni, Rivero et al. 2007; Krishnamoorthy, Holz, Wekerle 2007; Tschernatsch, Gross, Kneifel et al. 2007; Weber, Prod’homme, Youssef et al. 2007) and a plethora of experimental and clinical observations indicate that all major types of immune cells together with cells of the central nervous system (CNS) are involved in the resulting damage to the nervous system mediated through direct cell-to- cell cytotoxicity and/or soluble mediators that include cytokines, chemokines, and antibodies (Table 14.2). In the following paragraph immunomodulation in the nervous system in relation to T-cell regulation will be analytically discussed with the use of multiple sclerosis (MS) as a prototype autoimmune disease of the nervous system (Toy 2006). Immunomodulation in the Nervous System: The Paradigm of Multiple Sclerosis MS is considered to be a chronic autoimmune demy- elinating disease that results in axonal loss within the CNS. MS is characterized by T cell and macrophage in ltrates that are triggered by CNS-speci c CD4 the  rst episode of EAE. There are indications that these cells function through the nonclassical MHC class Ib pathway, since their suppressive function can be blocked by MHC class Ib Qa-1 antibodies. Qa-1 cells have the ability to present foreign and self-peptides to CD8 + T cells (Hu, Ikizawa, Lu et al. 2004). NK T cells are innate cells that can be induced to secrete both proin ammatory and anti-in ammatory cytokines immediately on exposure to activating signals and induced to regulate an ongoing immune response, usually in conjunction with other regulatory T-cell types. NK T cells recognize glycolipid antigens presented by a monomorphic glycoprotein CD1d. Numerous works have shown that NK T cells may serve as regulatory cells in autoimmune diseases and are tolerogenic in conditions of prolonged exposure to foreign antigen (e.g., in pregnancy) (Boyson, Rybalov, Koopman et al. 2002). However, recent studies have revealed that the presence of NK T cells accel- erates some in ammatory conditions, implying that their protective role against autoimmunity is not pre- determined (Godfrey, Berzins 2007; Novak, Griseri, Beaudoin et al. 2007; Nowak, Stein-Streilein 2007). AUTOIMMUNITY AND T REGULATION On the basis of what has been previously reported in this chapter, immune tolerance as a whole is the result of a very sensitive balance between naturally arising autoreactive cells and the regulatory mechanisms that regulate these autoreactive processes. In terms of immune regulation as discussed so far, autoimmunity can be considered to be manifested by a loss of balance among these functions. This lack of balance can result from either an increase in the number or Table 14.2 Immune Disorders that Affect the Nervous System Immune Disorder Implicated Cell Types Mediators References Leukocyte recruitment to the CNS, axon terminal degeneration, hippocampal lesions, MS, EAE CD4, CD8 T cells, NK cells, B cells, CD45CD11b MΦ, microglia IFN-γ, TNF-α, IL-1β, Abs, chemokine MCP-1/CCL2 expression by blood–brain barrier– associated glial cells Mouzaki et al. 2004; Owens et al. 2005; Toy 2006; Cassan, Liblau 2007 MS, EAE, reduced suppressive activity of Tregs Th1 and Th17 cells recognizing MBP, PLP, MOG self-peptides IFN-γ, TNF-α, IL-17 Mouzaki et al. 2004, 2005; Langrish et al. 2005; Haas et al. 2005; Huan et al. 2005; Bettelli et al. 2006; Cassan, Liblau 2007 In ammation, Alzheimer’s disease, MS, viral or bacterial infections, ischemia, stroke, encephalopathy Brain/hypothalamus Agonists: IL-1β, IFN-γ Antagonists: IL-4, TGF-β Toy 2006; Correa et al. 2007 Myasthenia gravis, Lambert— Eaton myasthenic syndrome, Guillain—Barre syndrome, paraneoplastic cerebellar degeneration, generalized neuropathies B cells Antibrain Abs, antigliadin Abs, Abs to glial antigens Boscolo et al. 2006; Alaedini et al. 2007; Cabanlit et al. 2007; Tschernatsch et al. 2007 CNS, central nervous system; MS, multiple sclerosis; EAE, experimentally induced autoimmune encephalomyelitis; MΦ, macrophage; Ab, antibody. Chapter 14: Immunomodulation: Role of T Regulatory Cells 353 organ system for the induction of immune responses based on the following facts: The limited renewal and mitotic nature of neurons • protect the CNS from immune pathology. The blood–brain barrier does not allow traf cking • of resting lymphocytes, whereas it does allow the entrance of activated cells (Hickey, Hsu, Kimura 1991). The fact that only a few cells within the CNS consti-• tutively express MHC molecules makes it dif cult for immune responses to develop (Perry 1998). A functional silencing or elimination of T cells • that manage to enter the CNS occurs through the expression of CNS Fas-ligand, TGF-β, and prosta- glandin E 2 (Zhu, Anderson, Schubart et al. 2005; Liu, Teige, Birnir et al. 2006b). Nevertheless, recent evidence has proved that there is access to the CNS, although limited, and naive T cells have been shown to traf c within the in amed tissue (Krakowski, Owens 2000; Aloisi, Pujol-Borrell 2006). Studies in animal models have also shown that naive CD4 + and CD8 + T cells are able to patrol nonlym- phoid tissues including the CNS (Brabb, von Dassow, Ordonez et al. 2000; Cose, Brammer, Khanna et al. 2006). Although these cells are allowed to circulate T cells. The prominent autoimmune etiology of MS is considered to be the aberrant activation of IFN- γ-producing Th1 cells that recognize self-peptides of the myelin sheath, such as MBP, proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) (Mouzaki, Tselios, Papathanassopoulos et al. 2004). There is a heterogeneous pathophysiology of this disease that remains unclear and includes an in ammatory response characterized by CD4 + CD8 + T cells and macrophages. MBP, PLP, and MOG components of the myelin sheath are the main speci c targets of T cells and B cells that are directed against these self- peptides (Olsson, Sun, Hillert et al. 1992; Genain, Cannella, Hauser et al. 1999; Bielekova, Goodwin, Richert et al. 2000; Berger, Rubner, Schautzer et al. 2003; Bielekova, Sung, Kadom et al. 2004; Sospedra, Martin 2005). The etiology for the immune system, triggering such an in ammatory response against self-antigens of the CNS, remains largely unknown, similar to most autoimmune diseases. The proposed mechanism for the pathophysiology of this disease based on what we know so far is described in Figure 14.2 and Table 14.3. Our knowledge of CNS dynamics and function so far gives the impression that the CNS is a privileged Figure 14.2 Treg implication in multiple sclerosis pathogenesis. BBB, blood brain barrier; CNS, central nervous system; MΦ, macrophage; APC, antigen presenting cell; IFN, interferon; TNF, tumor necrosis factor. Periphery T cells return to circulation Induction of autoreactive T-cell invasion Crossing of the BBB through diapedesis Peripheral activation by infectious or other factors Autoreactive T cells that have escaped central or peripheral tolerance Autoantigen presentation by an APC within the CNS Anergy IL-1, IL-4, IL-10 Activation proliferation Epitope spreading Release of new CNS ‘‘sequestered’’ antigens Inflammatory environment CNS injury B-cell and complement activation CNS 3 1 2 CTLA-4 costimulation costimulation CD28 Cytokine production IF N-γ TNF-α M activation IFN-γ TNF-α Central tolerance failure/T autoreactive toward Treg shift failure Treg-reduced suppressive activity3 1 2 ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 354 Another dendritic cell phenomenon that has been shown to occur within the CNS is epitope spreading, which leads to the induction of immune reactivity against more self-epitopes during chronic in ammation (McMahon, Bailey, Castenada et al. 2005; Miller, McMahon, Schreiner et al. 2007). These data, along with the fact that vessel-associated dendritic cells have also been found in active MS lesions, indicate that reactivation of incoming T cells is possible within the CNS (Kivisakk, Mahad, Callahan et al. 2004; Greter, Heppner, Lemos et al. 2005). TGF-β is known to play an important regulatory role and is now being implicated in pathogenic processes. TGF-β has been shown to promote, in an in ammatory cytokine environment, the differentiation of CD4 + T cells toward the pathogenic lineage Th17, which is characterized, as explained in the preceding text, by the secretion of IL-17 (Langrish, Chen, Blumenschein et al. 2005; Bettelli, Carrier, Gao et al. 2006). within the CNS without causing an unwanted effect, their entry requires more than the activation of myelin-speci c T cells, since additional signals are needed, such as those triggered by speci c microbial components through the Toll-like receptors (TLRs) (Brabb, Goldrath, von Dassow et al. 1997; Waldner, Collins, Kuchroo 2004). Although there are no professional APCs in the CNS, antigen presentation does occur in the CNS. There is evidence that MHC class I molecules are present on oligodendrocytes and neurons when they are exposed to an in ammatory environment that allows for antigen presentation to CD8 + T cells. Presentation to both CD8 + and CD4 + T cells can be realized by astrocytes and microglial cells, which have been shown to express both MHC class I and class II molecules. As has been shown in an EAE model, dendritic-like cells are needed to reactivate CD4 + T cells within the CNS (Greter, Heppner, Lemos et al. 2005). Table 14.3 Immune Cells and Soluble Mediators Involved in the Pathogenesis of Multiple Sclerosis Cell Type Mediator Effect References Th1 cells, CD8 T cells, NK cells IFN-γ MΦ and MN activation, disease exacerbation Mouzaki et al. 2004*; Chatzantoni et al. 2004; Scalzo et al. 2006; Cassan, Liblau 2007*; Krishamoorthy et al. 2007* Th1 cells, MΦ TNF-α MΦ and T-cell activation, disease exacerbation Th2 cells IL-4 Symptom alleviation, ±anaphylactic shock Th2 cells IL-13 Symptom alleviation MN, MF IL-1 EAE deterioration CD4CD25 ± Foxp3 T cells, Th3 cells TGF-β Th2 cell response, anti-in ammatory activity, differentiation of CD4 T-cells towards the Th17 lineage Ha er 2004; Sakaguchi 2004; Langrish et al. 2005; Lim et al. 2005; Bettelli et al. 2006 CD4CD25 ± Foxp3 T cells, Tr1 cells, MΦ IL-10 Th2 cell response, anti- in ammatory activity Ha er 2004; Sakaguchi 2004; Lim et al. 2005 CD11b(+)CD11c(+)CD45(hi) myeloid dendritic cells (mDCs) TGF-β1, IL-6, IL-23 Drive epitope spreading, enhance Th17 cell activity Miller et al. 2007 DC IL-23 Th17 cell production Langrish et al. 2005; Bettelli et al. 2006 Th17 cells IL-17 Disease exacerbation, anti-Foxp3 Treg activity In vivo and in vitro treatments anti-CD25 Ab Disease exacerbation in EAE, inactivation ±depletion of Tregs Stephens et al. 2005; Cassan et al. 2006 anti-CD3 Ab+anti- CD28 Ab+IL-2+IL-4, Ag-loaded DCs Expansion of Tregs Yamazaki et al. 2003; Thornton et al. 2004; Masteller et al. 2005; Fisson et al. 2006; Ochi et al. 2006; Tischner et al. 2006 Glatiramer acetate, other copolymers Expansion of Tregs Stern et al. 2004; Hong et al. 2005 Immature DCs+Ag+CD4 T cells +TGF-β; murine neurons + encephalitogenic CD4 T-cells; human CD4 T-cells. Conversion of CD4 T cells to Tregs Chen et al. 2003; Kretschmer et al. 2005; Weber et al. 2006; Liu et al. 2006a,b *Papers describing in detail the animal models used to study the pathogenesis of multiple sclerosis. Ab, antibody; DC, dendritic cell; MΦ, macrophage. Chapter 14: Immunomodulation: Role of T Regulatory Cells 355 the thymus of both mice and humans (Derbinski, Schulte, Kyewski et al. 2001). Recent results in mice indicate that there is very limited expression in the thymus, and this expression does not seem to be suf-  cient to induce tolerance (Delarasse, Daubas, Mars et al. 2003; Linares, Mana, Goodyear et al. 2003; Fazilleau, Delarasse, Sweenie et al. 2006). In addition to myelin oligodendrocyte antigens other CNS antigens are expressed in the thymus. For example, S100β, which is synthesized by astrocytes in the CNS, has been detected in the thymus of animal models (Kojima, Reindl, Lassmann et al. 1997). Thymic expression of αΒ-crystallin, a heat-shock protein expressed by astrocytes and oligodendrocytes, has been associated with the inability of peripheral lymphocytes to respond to autologous αΒ-crystallin (van Stipdonk, Willems, Plomp et al. 2000). Although there seems to be a negative selection process for CNS antigens in the thymus, there are circulating CNS autoreactive T cells in the periphery, both in healthy individuals and MS patients, that are related to MS pathogenesis. Therefore, there must be another level of regulation in the secondary lymphoid organs that limit the action of these autoreactive cells in healthy individuals. Experimental  ndings in the last few years have demonstrated the important role of Tregs in CNS autoimmunity (Ha er 2004; Sakaguchi 2004; Lim, Hillsamer, Banham et al. 2005). Recovery of EAE is accompanied by Treg accumulation within the CNS and, when isolated, these cells showed signi cant suppressive ability in vitro. Furthermore, transfer of these cells in low numbers reduced EAE (Kohm, Carpentier, Anger et al. 2002; McGeachy, Stephens, Anderton et al. 2005). Disease activity in Rag –/– MBP TCR-transgenic mice was reduced after the transfer of CD4 + or CD4 + CD25 + T cells from wild type animals (Hori, Haury, Coutinho et al. 2002). On the other hand, injection of anti-CD25 monoclonal antibody before EAE induction, which leads to the inactivation or depletion of Tregs, resulted in higher activation of autoaggressive T cells (Stephens, Gray, Anderton et al. 2005; Cassan, Piaggio, Zappulla et al. 2006). Typically resistant C57BL/6 mice become susceptible to reinduction of disease when depletion of Tregs is performed after the acute phase of EAE (McGeachy, Stephens, Anderton et al. 2005). The in uence of Tregs on disease progression is also indicated by the fact that depletion of Tregs in remitting-relapsing EAE models increases acute phase severity and prevents secondary remissions (Zhang, Reddy, Ochi et al. 2006). Research investigating the presence of a quanti- tative defect in the Treg population of MS patients has shown that there is no difference whatsoever, on the basis of CD4 CD25 expression, between the The  rst step in CNS self-reactive regulation occurs in the thymus during thymic ontogeny where T cells expressing high-af nity receptors for self-antigens undergo apoptosis (Siggs, Makaroff, Liston 2006). Until recently, it has been thought that thymocytes speci c for CNS-speci c self-antigens were spared during negative thymic selection, whereas eliminated T cells recognized only ubiquitous or blood-born antigens. Current research data indicate that many of these self-antigens, which were once believed to be tissue restricted, are expressed in the thymus and are therefore eliminated by negative selection. These antigens are expressed by cortical and medullary thymic epithelial APCs (Derbinski, Schulte, Keywski et al. 2001). There are a variety of CNS self-antigens expressed in the thymus, several of which are related to MS pathogenesis. Several thymic cell types have been shown to synthesize MBP mRNA and proteins (Feng, Givogri, Bongarzone et al. 2000; Liu, MacKenzie-Graham, Kim et al. 2001). Experiments in animal models have clearly shown that MBP +/+ mice demonstrate a strong negative selection of that particular self-antigen in the thymus, although it seems that bone marrow–derived cells play a more important role in this process (Huseby, Sather, Huseby et al. 2001; Perchellet, Stromnes, Pang et al. 2004). Expression of several MBP isoforms was shown to be associated with reduced development of EAE in animal models (Liu, MacKenzie-Graham, Kim et al. 2001). Nevertheless, MBP-speci c T cells are present in the periphery of both mice and humans, which is an indication of the importance of not only the presence of thymic expression but also the extent of that expression (Kuchroo, Anderson, Waldner et al. 2002; Sospedra, Martin 2005). DM20, a splice variant of PLP, was found to be con- stitutively expressed chie y by cortical and medullary thymic cells (Anderson, Nicholson, Legge et al. 2000; Klein, Klugmann, Nave et al. 2000; Derbinski, Schulte, Kyewski et al. 2001). In SLJ mice, an animal model with susceptibility to PLP-induced EAE, CD4 + encephalitogenic T cells are speci c for the PLP139–151 peptide, which is not transcribed in the thymus (Anderson, Nicholson, Legge et al. 2000). Nevertheless, it has been shown that thymic stromal cells expressing PLP can induce the tolerance of PLP-speci c T cells (Klein, Klugmann, Nave et al. 2000). Other experiments showing that the introduction of PLP peptides in the thymus can induce tolerance to these speci c peptides indicate that there can be tolerance to PLP peptides as long as they are expressed in the thymus (Anderson, Nicholson, Legge et al. 2000). Although MOG does not represent an important percentage of the myelin proteins, it seems to be a very important target in cases of EAE in experimental models and MS in humans (Adelman, Wood, Benzel et al. 1995). There was limited detection of MOG expression in ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 356 dendritic cells would be more useful and has already been achieved (Yamazaki, Iyoda, Tarbell et al. 2003; Masteller, Warner, Tang et al. 2005; Fisson, Djelti, Trenado et al. 2006). Another approach is aimed at the in vitro conversion of CD4 + T cells to Tregs, which requires cultures of immature dendritic cells in the presence of low doses of antigen. The presence of TGF-β in this culture system seems to be of great importance for the switching of one cell type to another (Chen, Jin, Hardegen et al. 2003; Kretschmer, Apostolou, Hawiger et al. 2005; Weber, Harbertson, Godebu et al. 2006). It has also been reported that co-culturing murine neurons with encephalitogenic CD4 + T cells can lead to their conversion to Tregs, which have been shown to be effective in controlling autoimmunity. The expression of TGF-β and CD80 CD86 costimulatory factors seems to be very important for this conversion, but the fact that neurons are able to produce factors that lead to such a conversion and thus induce a protective response is of great importance (Liu, Teige, Birnir et al. 2006b). There have also been attempts to induce the expression of Foxp3 on CD4 + T cells to convert them to Tregs. Such an attempt in mice using a retroviral vector encoding Foxp3 resulted in cells with regulatory properties and protective function against autoimmunity (Bettelli, Dastrange, Oukka 2005). In the last few years, many similar attempts have focused on the human system and expansion of natural Tregs has been achieved (Liu, Putnam, Xu-Yu et al. 2006a). Polyclonal, as well as antigen-speci c, conversion of CD4 + T cells to Tregs has also been achieved in the human system, but the extent of the suppressive activity of these Foxp3-expressing cells requires further investigation (Grossman, Verbsky, Barchet et al. 2004; Allan, Passerini, Bacchetta et al. 2005; Walker, Carson, Nepom et al. 2005). Despite the promising results of these attempts, the best way to use Treg properties as a possible therapeutic approach for autoimmunity is the direct expansion of Tregs in vivo. It has been observed that Tregs proliferate strongly when they encounter their speci c antigen in vivo (Fisson, Djelti, Trenado et al. 2003). Glatiramer acetate , a drug approved and largely used for MS, seems to have the ability to induce Tregs. The expansion of Tregs after injection of copolymers has been shown to occur in both mice and humans (Stern, Illes, Reddy et al. 2004; Hong, Zhang, Zheng et al. 2005). In animal models, oral administration of anti- CD3 monoclonal antibodies or treatment with anti- CD28 monoclonal antibodies led to prevention of EAE and induction of the Treg population, along with an increase in their regulatory properties (Ochi, Abraham, Ishikawa et al. 2006; Tischner, Weishaupt, van den Brandt et al. 2006). blood of MS patients and healthy individuals (Huan, Culbertson, Spencer et al. 2005; Venken, Hellings, Hensen et al. 2006). No difference has been shown for the proportion of Tregs in the peripheral blood and cerebrospinal  uid of MS patients (Haas, Hug, Viehover et al. 2005). Tregs from remitting-relapsing MS patients showed reduced suppressive activity in vitro (Haas, Hug, Viehover et al. 2005; Huan, Culbertson, Spencer et al. 2005). This reduction in Treg activity is associated with reduced Foxp3 mRNA and protein expression in MS CD4 + CD25 + peripheral blood T cells compared to those of healthy individuals (Huan, Culbertson, Spencer et al. 2005). It is not yet clear whether this defect is due to decreased expression at the cellular level or due to the lower incidence of Tregs among CD4 + CD25 + T cells. This phase of the disease seems to be of great importance in Treg function, since patients with secondary progressive MS show normal levels of Foxp3 expression among CD4 + CD25 high T cells, and normal suppressive activity in vitro (Venken, Hellings, Hensen et al. 2006). In contrast, there is no correlation between relapses and the defective suppressive activity of Tregs from remitting-relapsing MS patients (Haas, Hug, Viehover et al. 2005). As has been previously described and reported from experiments in animal models, the presence of self-antigen in the thymus is very important for the development and maintenance of Tregs for this antigen, as well as for the reduction of the ratio between T cells and Tregs (Kyewski, Klein 2006; Grajewski, Silver, Agarwal et al. 2006). It has been reported speci cally for CNS antigens that SJL mice, which have a greater susceptibility to EAE than the B10.S strain, have stronger thymic expression of the PLP antigen and a lower frequency of Tregs speci c for this antigen (Reddy, Illes, Zhang et al. 2004). This is an indication of the relationship between high thymic expression of an antigen and the generation of Tregs speci c for this antigen. It can be concluded that thymus plays an important role in immune tolerance against CNS-restricted self-antigens, not only through negative selection but also through the induction of Tregs. Although manipulation of the Treg population has proved to be quite dif cult, such an attempt could be useful for the manipulation of CNS autoimmune diseases based on what is known so far about the function of this T-cell population. Beyond the natural hyporesponsiveness of Tregs, their clonal expansion occurs upon stimulation with anti-CD3 and anti-CD28 monoclonal antibodies in the presence of IL-2 and IL-4 (Thornton, Piccirillo, Shevach 2004). Nevertheless, since antigen-speci c Tregs have been shown to be better able to control autoimmunity, their expansion with antigen-loaded Chapter 14: Immunomodulation: Role of T Regulatory Cells 357 also involved in shaping the size and composition of the atherosclerotic lesions (Xu, Dietrich, Steiner et al. 1992; Xu, Willeit, Marosi et al. 1993; George, Afek, Gilburd et al. 1998; George, Shoenfeld, Afek et al. 1999; Frangogiannis, Smith, Entman 2002; Kariko, Weissman, Welsh 2004; Hahn, Grossmana, Chena et al. 2007). Further evidence showed a considerable number of Th1 cells present in human and murine plaques, some of which were reactive with oxidized low-density lipoprotein (LDL) (Jonasson, Holm, Skalli et al. 1986; Zhou, Stemme, Hansson 1996). Attenuation of the induction of atherosclerosis has been shown to be possible through induction of Tregs; the extent of the disease can be reduced by induction of oral tolerance with proatherogenic antigens (Maron, Sukhova, Faria et al. 2002; Harats, Yacov, Gilburd et al. 2002; George, Yacov, Breitbart et al. 2004). Furthermore, cytokines secreted by Tregs are antiatherogenic (Hansson 2005). Ischemic stroke and cardiovascular disease are mainly caused by atherosclerosis, which involves plaques and lesions of the arteries. These plaques and lesions are composed of cell debris and lipids, mainly cholesterol, as well as in ammatory cells such as macrophages and T cells, collagen and smooth mus- cle cells, and sites of old hemorrhage, angiogenesis, and calcium deposits (Stary 2005). Acute ischemia is created when a thrombus is formed, a phenomenon precipitated by activation of these plaques (Falk, Shah, Fuster 1995). Together with risk factors such as Although selective induction and expansion of CNS-speci c human Tregs has a strong potential for controlling the manifestations of CNS autoimmunity based on our knowledge so far, a few obstacles must be considered. The  ne speci city of Tregs has an impact on their ef cacy, especially when this population is very limited and hardly identi ed on the basis of the markers known so far. Autoantigens vary among patients and in the same patient during different phases of the disease. As Tregs have been shown to be nonfunctional in an in ammatory environment, they cannot be used to block an already ongoing disease (Cassan, Liblau 2007). Immunomodulation in the Vascular System Diseases of the vascular system such as atherosclerosis have been proved by experimental evidence to impli- cate aspects of the immune system that are important for innate immunity and in ammatory mechanisms (see Table 14.4). These mechanisms are not only implicated in situations such as atherosclerosis, but can also initiate vascular ischemic damage to prevent and treat vascular disease and even induce ischemic tolerance. There is also evidence of autoimmune involvement in atherosclerotic individuals, since these patients have higher titers of autoantibodies against HSP60/65, which are related to ischemia. Such autoimmune situations are Table 14.4 Immune System Involvement in Vascular Disorders Immune Cells and Molecules Function References Th1 cells Reactive with oxidized LDL, Hsp, β2 glycoprotein 1; activation by speci c antigens, secretion of IFN-γ leading to further activation of MΦ, EC Jonasson et al. 1986; Zhou et al. 1996; Mach et al. 1998; Nicoletti et al. 1998; Stary 2005; Hahn et al. 2007 Tregs Induction of oral tolerance with proatherogenic antigens leading to disease inhibition Antiatherogenic cytokine secretion, atherosclerosis inhibition through IL-10 and TGF-β secretion Harats et al. 2002; Maron et al. 2002; Robertson et al. 2003; George et al. 2004; Hansson 2005 CD8 T cells, NK T cells Disease acceleration, CTL activity Shresta et al. 1998; Robertson et al. 2003 MΦ Transformation to foam cells in atherosclerotic lesions; promotion of in ammation in the arteries Schmitz, Drobnik 2002; Miller et al. 2003; Edfeldt et al. 2004; Stary 2005 MN Recruited by secreted chemokines, transformation to MΦ Schmitz, Drobnik 2002; Dai et al. 2004; Sheikine, Hansson 2004 EC Activation by phospholipids, leading to MN and lymphocyte activation Cybulsky, Gimbrone 1991; Witztum, Berliner 1998 B cells, systemic immunity Abs to Hsp65, OxLDL, cardiolipin, β2-glycoprotein 1, DNA, HDL, Apolipoprotein A1, lipoprotein lipase, Abs to CNS antigens, myocardial Abs, complement activation, induction of acute phase proteins, release of proin ammatory cytokines IL-1, IL-6, IL-8, activation of neutrophils, microglia Melguizo et al. 1997; Streit 2000; Hansson 2005; Hahn et al. 2007 MΦ, macrophage; MN, monocyte; EC, endothelial cell; Ab, antibody; Hsp, heat-shock protein. [...]... Cho, Hong et al 20 07) Insulin-like growth factor-I (IGF-I) regulates β-amyloid levels and displays protective effects against β-amyloid toxicity (Carro, Trejo, Gomez-Isla et al 2002; Aguado-Llera, Arilla-Ferreiro, Campos-Barros et al 2005) Fibroblast growth factor-2 (FGF-2) has common binding sites with β-amyloid fibrils in heparan sulfate from cerebral cortex (Lindahl, Westling, Gimenez-Gallego et al... Human T regulatory cells can use the perforin pathway to cause autologous target T-cell death Immunity 21:589–601 Groux H, O’Garra A, Bigler M et al 19 97 A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis Nature 389 :73 7 74 2 Haas J, Hug A, Viehover A et al 2005 Reduced suppressive effect of CD4+CD25high regulatory T-cells on the T-cell immune response against myelin oligodendrocyte... R, Finkelman FD, Paul WE 1990 Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL- 4- producing cells J Exp Med 172 :921–29 Le NT, Chao N 20 07 Regulating regulatory T-cells Bone Marrow Transplant 39:1–9 Levings MK, Sangregorio R, Galbiati F et al 2001 IFNalpha and IL-10 induce the differentiation of human type 1 T regulatory... Wills-Karp M, Huang SK 1996 Mucosal IFN-gamma gene transfer inhibits pulmonary allergic responses in mice J Immunol 1 57: 3216–3219 Liang SC, Tan XY, Luxenberg DP et al 2006 Interleukin (IL )-2 2 and IL- 17 are co-expressed by Th 17 cells and cooperatively enhance expression of antimicrobial peptides J Exp Med 203:2 271 –2 279 Lim HW, Hillsamer P, Banham AH, Kim CH 2005 Cutting edge: direct suppression of B-cells... release from LDL MN M-CSF Chemokines TNF-α, IL-1 T cells Vascular cell activation Foam cells M M iva tio n Recruitment LDL cholesterol Antigen activation Complement activation IL-1, IL-6, IL-8 Inflammatory cytokines EC activation VCAM-1 Activation of neutrophils IFN-γ A: Resting APC B: Activated APC Foxp3 expression TGF-β IL-10 Death by apoptosis or necrosis Induction of acute-phase proteins act Plaque... state J Exp Med 198 :73 7 74 6 Fisson S, Djelti F, Trenado A et al 2006 Therapeutic potential of self-antigen-specific CD4+ CD25+ regulatory T-cells selected in vitro from a polyclonal repertoire Eur J Immunol 36:8 17 8 27 Fontenot JD, Rudensky AY 2005 A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3 Nat Immunol 6:331–3 37 Foussat A, Cottrez... C 2006 Diverisification of T-helper-cell lineages: finding of the family root of IL- 1 7- producing cells Nat Rev Immunol 6:329–333 Edfeldt K, Bennet AM, Eriksson P et al 2004 Association of hypo-responsive Toll-like receptor 4 variants with risk of myocardial infarction Eur Heart J 25:14 47 1453 Falk E, Shah PK, Fuster V 1995 Coronary plaque disruption Circulation 92:6 57 671 Fazilleau N, Delarasse C,... stimulatory factor (interleukin-12) induces T helper type 1 (Th1 )- specific immune responses and inhibits the development of IL- 4- producing Th cells J Exp Med 177 :1199–204 Maron R, Sukhova G, Faria AM et al 2002 Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of lowdensity lipoprotein receptor-deficient mice Circulation 106: 170 8– 171 5 Masteller EL, Warner... cellular activity, Type-1/Type-2 cytokine secretion patterns and their modulation by therapeutic peptides Curr Med Chem 12:15 37 1550 Murphy CA, Langrish CL, Chen Y et al 2003 Divergent proand antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation J Exp Med 198:1951–19 57 Nakae S, Nambu A, Sudo K, Iwakura Y 2003 Suppression of immune induction of collagen-induced arthritis in IL- 1 7- deficient... Nakae S, Nambu A, Sudo K, Iwakura Y 2003 Suppression of immune induction of collagen-induced arthritis in IL- 1 7- deficient mice J Immunol 171 :6 173 –6 177 Nakamura K, Kitani A, Strober W 2001 Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T-cells is mediated by cell surface-bound transforming growth factor b J Exp Med 194:629–644 Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK 1998 . mainly in the presence of IL-4 CD4, CD25, STAT-6, GATA-3, c-maf Secrete IL-4, IL-5, IL-9, IL-13; target Th1 cells; induce B-cell function and eosinophil activation; participate in allergic. called Th 17, is distinct from Th1, Th2, and Th0 cells. Th 17 cells secrete IL-17A, IL-17F, IL-6, and tumor necrosis factor α (TNF-α . ) cytokines. Th 17 cells are protective against extracellular. of immune induction of collagen-induced arthritis in IL- 1 7- de cient mice. J Immunol. 171 :6 173 – 6 177 . Nakamura K, Kitani A, Strober W. 2001. Cell contact-dependent immunosuppression by CD4+CD25+

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