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Influence of immunosuppressive drugs on dendritic cells
Transplant Immunology 11 (2003) 357–365
Review
Influence of immunosuppressive drugs on dendritic cells Masanori Abea, Angus W. Thomsona,b,* a
Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA b Department of Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA Received 29 April 2003; accepted 21 May 2003
Abstract Immunosuppressive drugs used to control allograft rejection and in efforts to promote transplant tolerance are well recognized for their abilities to inhibit lymphocyte activation and proliferation. In recent years, evidence has accumulated that these diversely acting agents (anti-proliferative drugs, calcineurin inhibitors, rapamycin, deoxyspergualin and glucocorticoids) also affect the development and functional immunobiology of dendritic cells, in vitro and in vivo. Here we review the influence of immunosuppressive drugs on the differentiation and function of these important antigen-presenting cells. We also consider how these effects influence immune reactivity and tolerance induction, implications for furthermore understanding of dendritic cell biology and prospects for improving the outcome of organ transplantation and therapy of other immune-mediated disorders by impacting dendritic cell function. 䊚 2003 Elsevier B.V. All rights reserved. Keywords: Dendritic cells; Immunosuppressive drugs; Transplant tolerance
1. Introduction Remarkable advances have been made in clinical transplantation over the past two decades, largely because of major strides in understanding the immune mechanisms involved in transplant rejection and the development of more effective and safer immunosuppressive drugs. Nevertheless, the goal of specific and sustained inhibition of donor-specific immune responses in the absence of both graft pathology and dependence on anti-rejection therapy remains elusive. In keeping with the fundamental role of T cells in graft rejection, much emphasis in the development of immunosuppressive drugs has been focused on inhibition of T cell activation and proliferation. The mechanisms by which these drugs affect T cells have been investigated in great detail. However, induction of immune responses does not rely solely on T cells, but also on essential and complex interactions between *Corresponding author. Tel.: q1-412-624-6392; fax: q1-412-6241172. E-mail address: [email protected] (A.W. Thomson).
antigen-presenting cells (APC) and T cells. The immune response to organ grafts is believed to be initiated by the presentation of alloantigen by donor and self APC to host T cells, which then differentiate into effector and regulatory cells. Dendritic cells (DC) are rare, ubiquitously distributed, migratory APC, derived from CD34q bone marrow (BM) stem cells. In addition to ¨ T cells, DC having the unique capacity to prime naıve also regulate various effector cell functions and play central roles in modulating the immune response w1,2x. Donor-derived DC are commonly regarded as the principal instigators of transplant rejection, but considerable evidence also exists for DC tolerogenicity in the context of alloimmune responses w3–5x. In addition, immature DC and DC manipulated pharmacologically, biologically or genetically to enhance their tolerogenicity in vitro or in vivo can improve outcomes in cell or organ transplantation w3–5x. Thus, in order to comprehend the mechanism of action of immunosuppressive drugs and their potential for tolerance induction more fully, it is necessary to elucidate their influence on DC development, maturation and function.
0966-3274/03/$ - see front matter 䊚 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0966-3274(03)00050-9
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In this review, we discuss recently-accumulated information on the effects of currently used immunosuppressive drugs on DC both in vitro and in vivo. While most available information concerns classic (myeloidymonocytoid) DC, evidence is also emerging concerning the influence of immunosuppressive drugs on DC subsets that have been identified in humans and experimental animals. 2. Anti-proliferative drugs (purine nucleotide biosynthesis inhibitors) 2.1. Azathioprine (AZA) AZA was the most widely used immunosuppressive drug for prophylaxis of acute rejection in organ transplant recipients until the advent of cyclosporine in 1979. This agent has found increasing use in the treatment of autoimmune diseases. AZA is a pro-drug that is converted to 6-mercaptopurine, which is subsequently metabolized to the pharmacologically active 6-thioguanine nucleotides. These metabolites block the de novo and salvage pathways of purine nucleotide biosynthesis and subsequently, inhibit the proliferation of T- and Bcells. There have been few studies concerning effects of AZA on DC. Liu et al. w6x, however, reported that human epidermal Langerhans cells (LC) treated with pharmacological levels of AZA in vitro, exhibited decreased T cell allostimulatory capacity. 2.2. Mizoribine (MZB) MZB is an antibiotic agent produced by the soil fungus Eupenicillium brefeldianum w7x and is used as a clinical immunosuppressive agent in Japan. MZB is metabolized to the pharmacologically active mizoribine 59-monophosphate. This metabolite inhibits the enzyme inosine 59-monophosphate dehydrogenase (IMPDH) and guanosine 59-monophosphate synthetase. Thus, MZB blocks the de novo pathway of guanosine synthesis, without affecting the salvage pathway w8x. As a result of its inhibitory effects on nucleic acid synthesis, MZB suppresses T- and B-cell lymphocyte functions w9,10x. Although it is likely that this agent impacts on DC function, there are as yet no reports that address this issue. 2.3. Mycophenolate mofetil (MMF) MMF is the morpholinoethanol ester prodrug of its active metabolite mycophenolic acid (MPA) w11x, a fermentation product of several species of Penicillium. MPA is a non-competitive, reversible inhibitor of the enzyme IMPDH that, like MZB, plays a major role in the de novo synthesis of guanosine nucleotides w12x.
MMF inhibits both T- and B-cell proliferation in response to mitogenic and allogeneic stimulation w13x. Mehling et al. w14x reported that mouse BM-derived DC propagated in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 in the presence of MMF exhibited a dose-dependent impairment of T cell allostimulatory capacity, consistent with reduced costimulatory molecule expression and IL12p70 production in response to lipopolysaccharide (LPS) stimulation. They also demonstrated impairment of the antigen-presenting capacities of LC following chronic (30 days) MMF treatment in vivo w14x. These findings also point to a possible role of IMPDH in DC maturation. Gregori et al. w15x showed that a combination of 1a, 25-hydroxyvitamin D3 (1a,25(OH)2D3) and MMF in vivo could induce DC with a tolerogenic phenotype that enhanced the frequency of CD4qCD25q T regulatory (T reg) cells and promoted tolerance to allografts. 3. Calcineurin inhibitors 3.1. Cyclosporine A (CsA) CsA is a metabolite of the soil fungi Polysporium Rafti and Cylindrocarpon lucidum w16x. It potently inhibits Ca2q-dependent T-cell receptor (TCR)-mediated signal transduction leading to IL-2 production. After binding to its intracellular immunophilin receptor (cyclophilin), the drug–immunophilin complex decreases calcineurin phosphatase-dependent nuclear translocation of the cytosolic nuclear factor (NF) of activated T cells, its binding to the IL-2 enhancer and subsequent IL-2 gene transcription w17–20x. Thus, the immunosuppressive effect of CsA is believed to be due primarily to its direct suppression of T cell activation. Several effects of CsA on mouse, rat and human DC have been reported during the last 15 years. Lee et al. w21x showed that CsA inhibited the allostimulatory capacity of in vitro generated mouse BM-derived DC by downregulation of surface costimulatory molecule expression. They also showed clearly that NF-kB was a molecular target in the inhibitory action of CsA on DC. Recently, using mouse BM-derived DC and T cells from D11.10 TCR transgenic mice, Matsue et al. w22x reported that CsA blocked bi-directional DC-T cell interaction following antigen presentation. Thus, CsA inhibited DCtriggered production of interferon (IFN)-g, IL-2 and IL4 by T cells and IL-6, IL-12p40 and IL-12p70 by DC. However, CsA failed to inhibit cytokine production by LPS-stimulated DC. On the other hand, CsA suppressed DC-induced proliferation of primed T cells and inhibited cytokine production by both Th1 and Th2 cells. In addition, inhibitory effects of CsA on mouse spleen DC in vitro w23x and defective functions of DC from lymph nodes of CsA-treated mice w24x have been reported.
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With regard to mouse LC, CsA inhibits their antigenpresenting capacity in vitro w25,26x and inhibits their capacity to induce contact hypersensitivity reactions in vivo w27x. In the rat, numbers of thymic DC are decreased during CsA treatment w28,29x, however, the DC reveal an identical phenotype and function to controls w28x. In addition, inhibition of differentiation of epidermal LC precursors during systemic treatment with CsA has been reported w30x. With regard to human DC, the influence of CsA on monocyte-derived DC (Mo-DC) has mainly been investigated w31–37x. Most reports show that CsA does not affect DC development during DC differentiation from monocytes w31–33x. During their maturation promoted by TNFa or LPS, however, inhibition of augmented expression of costimulatory molecules, DC-lysosomalassociated-membrane protein (LAMP) or CD83 w33– 36x and T cell allostimulatory capacity by CsA w32–35x has been observed. On the other hand, Woltman et al. w31x reported that while treatment of Mo-DC with CsA resulted in a partial reduction in tumor necrosis factor (TNF)-a production, other functional activites of the cells, including allostimulatory capacity and expression of costimulatory molecules, were not affected. These effects appear to be dependent on the stimuli used to trigger DC maturation w33–37x. Thus, CsA does not inhibit human DC maturation induced by double-stranded RNA or CD40 ligand w33x. Recently, Tajima et al. w38x reported effects of CsA on human peripheral blood DC subsets. They demonstrated that CsA inhibited the stimulated upregulation of costimulatory molecules and the allostimulatory capacity of both CD11cq(monocytoid) and CD11cy (plasmacytoid) DC subsets. They also showed that CsA negatively regulated the endocytic activity of CD11cq DC while in the immature state. In addition, CsA inhibited IL-12p70 production, but augmented IL-10 production by the CD11cq subset, whereas it reduced IFN-a production by the CD11cy subset. Inhibitory effects of CsA on the antigen-presenting functions of human LC have also been reported w39,40x. 3.2. FK506 (tacrolimus) FK506 (tacrolimus) is a macrolide lactone antibiotic isolated from the soil fungus Streptomyces tsukubaensis w41x. FK506 binds to intracellular immunophilins termed FK506-binding proteins (FKBP). The FK506-FKBP complexes then bind to and inhibit the phosphatase activity of calcineurin, the same molecular target as CsA, thereby inhibiting TCR-mediated signal transduction in T lymphocytes w17–19x. Although T cells are the most widely recognized cellular target for this drug, as well as for CsA, direct effects of FK506 on DC have also been reported.
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Morelli et al. w42x observed that FK506 suppressed GM-CSF-stimulated growth of myeloid DC from mouse BM without affecting surface MHC class II or costimulatory molecule expression. They also showed that administration of FK506 to allogeneic recipients of fmslike tyrosine 3 kinase ligand (Flt-3L)-mobilized donor BM cells resulted in marked enhancement of DC chimerism in host lymphoid tissue with reduction in antidonor T cell proliferation responses w42–44x. Matsue et al. w22x reported that FK506 blocked all changes that resulted from mouse bi-directional DC-T cell interactions and that short-term exposure of BM-derived DC cultures to FK506 modestly reduced DC surface expression of MHC class II and costimulatory molecules. FK506 was significantly more potent than other immunosuppressive agents in inhibiting DC cytokine production (IL-6, IL-12p40 and p70) upon antigen-specific interaction with T cells. FK506 also inhibits costimulatory molecule expression on mouse epidermal LC in vitro w26x. Studies of the influence of FK506 on human Mo-DC have led to some discrepant observations, as with CsA. Most reports have shown that expression of key surface molecules on Mo-DC is not affected by FK506 at physiological concentrations when the drug is added to cultures during cell maturation w31,32,45x. However, Koski et al. w34x reported that expression of costimulatory molecules and CD83 on Mo-DC was reduced. In addition, some authors have shown decreased T cell stimulatory capacity and cytokine production by FK506treated human Mo-DC w32,34x. On the other hand, Woltman et al. w31x reported that FK506 treatment in vitro had no effect. In a study of CD34q hematopoietic progenitor-derived human DC w46x, FK506 promoted the development of DC, unlike observations with mouse BM-derived cells w42x. Despite no effect on costimulatory molecule expression, the human FK506-treated DC displayed a reduced allostimulatory capacity and IL-12 production w46x. In addition, when pulsed with exogenous antigen (keyhole limpet hemocyanin) these cells induced CD4q T cells towards a Th2-like response. The in vivo effect of FK506 on DC in humans was investigated with respect to epidermal DC following topical FK506 administration in atopic dermatitis w47,48x. Decreased expression of receptors for immunoglobulin E (IgE) on both LC and inflammatory dendritic epidermal cells was observed. Impaired function of human LC by FK506 has also been reported w49x. 4. Rapamycin (sirolimus) Rapamycin (RAPA; sirolimus) is a macrocyclic triene antibiotic produced by the actinomycete Streptomyces hygroscopicus w50x. The drug structurally resembles FK506 and binds to the same intracellular binding protein, FKBP12. RAPA-FKBP12 complexes act to
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inhibit the activity of the mammalian target of RAPA (mTOR) w51,52x. This results in inhibition of multiple biochemical pathways that are critical for cytokiney growth factor-induced cellular proliferation, ribosome synthesis, translation initiation and cell cycle progression into S phase w51,52x. T cells have been considered the principal targets of RAPA. Hackstein et al. w53x reported that, at clinicallyrelevant concentrations, RAPA inhibited endocytosis by mouse BM-derived DC, both in vitro and in vivo. This effect was not related to apoptotic cell death and the underlying mechanism remains uncertain. The authors also showed that RAPA suppressed the functional activation of BM-derived DC, both in vitro and in vivo w54x. Inhibition of DC maturation was IL-4-dependent and was antagonized by competition for FKBP12 binding. In addition, in vivo administration of RAPA suppressed DC generation and impaired costimulatory molecule upregulation, IL-12 production and T cell allostimulatory capacity. Impairment of T cell stimulatory ability of DC by RAPA has also been reported by other groups w22,55x. Chiang et al. w55x found that RAPA-treated BM-derived DC had markedly impaired ability to induce antigen-specific cytotoxic T cell activity and exhibited decreased IFN-g expression through inhibition of the Stat4 activation pathway, although RAPA did not alter costimulatory molecule expression on DC. Injection of RAPA-treated donor DC 7 days before transplant significantly prolonged heart allograft survival compared with untreated DC-injected controls. With respect to human cells, RAPA induces apoptosis of both Mo-DC and DC generated from CD34q precursors w56,57x. RAPA interferes with the GM-CSFyPI3Ky mTOR signaling pathway in DC and promotes apoptosis via increased p27KIP1 expression w58x. Monti et al. w57x reported that receptor-mediated endocytosis was impaired in RAPA-treated human DC. They further showed that allostimulatory ability, costimulatory molecule expression and IL-12 and IL-10 production were decreased by RAPA w57x. 5. Glucocorticoids (GC) GC are potent immunosuppressive and anti-inflammatory agents used to treat autoimmune diseases and to prevent graft rejection. Their immunosuppressive actions are focused mainly on T cells and monocytesymacrophages w59x. In addition, there have been more than 50 reports to date regarding the influence of GC on DC. Moser et al. w60x reported that GC reduced DC viability, downregulated the expression of costimulatory molecules on viable DC and strongly reduced the allostimulatory capacity of mouse spleen DC in vitro. They also showed that GC impaired the antigen-presenting function of DC in vivo. Dexamethasone (Dex) also downregulated costimulatory molecule expression and T
cell allostimulatory capacity of mouse BM-derived DC in vitro w22,61x and of a mouse epidermal DC line w62x. Matyszak et al. w61x reported that Dex-treated BMderived DC were unable to undergo full maturation and to prime Th1 cells efficiently. In addition, multiple restimulation of T cells with these DC gave rise to T reg cells (Tr1 cells; IFN-gy, IL-4y , IL-10q). The suppressive effect of Dex was not observed with DC pre-activated with LPS, indicating that the stage of DC maturation influenced the effect of GC. Inhibition of costimulatory molecule expression and the allostimulatory capacity on mouse LC has been reported w26,63x. Following topical administration of GC, the number of murine epidermal LC is reduced w63,64x. This effect has also been reported for rat, guinea pig and human LC and is associated with marked decrease in LC-induced T cell activation w65–67x. Decreased expression of MHC class II and loss of Birbeck granules in mouse LC was shown following systemic GC treatment w68x. Cumberbatch et al. w69x reported that systemically administered Dex inhibited mouse LC migration to draining lymph nodes following skin sensitization with contact allergen. In the rat, the effects of GC on thymic and lung DC have been reported w70–75x. Sacedon et al. w70x observed that thymic DC expressed GC receptors. Dextreated thymic DC showed impaired allostimulatory capacity and production of IL-1b and TNF-a, but not that of IL-6 or IL-10 was diminished in mixed leukocyte reaction (MLR) set up with Dex-treated thymic DC. These DC were resistant to GC-induced apoptosis w70x. The authors also showed that GC strongly influenced thymic DC maturation early in ontogeny w71x. Holt et al. w72–74x reported that exposure to inhaled GC rapidly and reversibly decreased the number of rat airway intraepithelial DC and their surface expression of MHC class II, whereas GC did not inhibit their antigenpresenting capacity. Brokaw et al. w75x showed that GCinduced apoptosis contributed to the rapid decrease of rat airway DC. In the rhesus macaque, topical GC treatment leads to a marked decrease in the number of skin CD1aq DC and to a shift in phenotype towards a more mature APC in the draining lymph nodes w76x. There have been numerous publications regarding effects of GC on human Mo-DC. Some of the data are conflicting. The reasons for these discrepancies between reports are largely unclear, but likely include the different maturation states of the DC used and different exposure times to different concentrations of GC. GC interfere strongly with the differentiation and function of human Mo-DC in vitro w31,77–79x. This inhibitory effect has also been reported for the development of dermal DC but not LC from CD34q hematopoietic progenitors w80x. Some reports have shown that GC induce DC apoptosis during their differentiation or maturation w77,80,81x. Expression of molecules involved in antigen presentation is impaired, while that of mole-
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cules involved in antigen uptake (mannose receptor; CD32) and adhesion molecules (CD11y18, CD54) is upregulated w78x. Whereas impairment of the T cell stimulating capacity of Mo-DC following treatment with GC during their w31,78,82,83x differentiation and maturation w35,77,83,84x has been reported, there are other accounts that GC do not affect the ability of Mo-DC to induce T cell proliferation w79,85,86x. Impairment of the allostimulatory capacities of lung DC by GC has been reported w87x. There are some discrepancies concerning the expression of costimulatory molecules or CD83 by DC exposed to GC. With regard to cytokine production, IL12p70, IL-6 and TNFa production by Mo-DC is decreased by GC w31,78,79,83–86,88,89x. In addition, some authors have shown increased IL-10 production by GC-treated DC w79,84x. There is also evidence that GC treatment impairs IFN-g secretion, but stimulates IL-10 and IL-5 production by CD4q Th cells w84– 86,88,89x. GC appear to transform CD40-triggered DC into APC with potential for suppression of adverse T cell response in vivo. Exposure of DC to GC during their differentiation from monocytes increases their endocytic activity w78,82x. However, failure of GC to affect antigen uptake by DC has also been described w85,88x. Vanderhyde et al. w89x reported that Mo-DC treated with methylprednisolone exhibited enhanced endocytic capacity. Recently, Schodell and Siegal w90x have shown that GC administration results in a decrease in IFN-a production by human peripheral blood mononuclear cells, accompanied by a reduction in circulating plasmacytoid DC numbers. Topical GC therapy reduces the number of human skin or mucosal CD1aq LC and their T cell stimulatory capacities w65,91–93x, whereas in vitro exposure of human LC to GC inhibits their antigenpresenting ability w94x. 6. Other drugs 6.1. Deoxyspergualin (DSG) and its novel analogue LF15-0195 (LF) DSG, a compound isolated from culture filtrates of Bacillus lacterosporus w95x, prolongs allograft survival in rodents. Although its mechanism of action is still poorly understood, DSG has been reported to inhibit NF-kB activation and antigen processing, T or B cell differentiation and antibody production w96–98x. Thomas et al. w99x have demonstrated in rhesus macaques that simultaneous targeting of both T cells (using anti-CD3 immunotoxin) and DC (using DSG) results in renal transplant tolerance. Mature DC (CD83q) were reduced markedly in lymph nodes of graft recipients and DSG inhibited rhesus DC maturation in vitro w99x. Inhibitory effects of the novel DSG
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analogue, 15-0195(LF) on mouse BM-derived DC maturation have also been reported w100x. Chiffoleau et al. w101x showed that LF treatment induced donor APCs to expand powerful T reg cells in a rat heart allograft model. Recently, Min et al. w100x reported that immature (tolerogenic) DC and T reg cells were increased using LF and anti-CD45RB antibody combination in a mouse cardiac transplantation tolerance model. In vitro study suggested that DC generated T reg cells ¨ T cells and that T reg cells (CD4qCD25q) from naıve generated tolerogenic DC, thus constituting a tolerogenic feedback loop. 6.2. Aspirin, vitamin D and N-acetyl-L-cysteine In addition, of these pharmacologic agents, a variety of other drugs have been shown to inhibit DC maturation and function. Among them are aspirin, vitamin D and N-acetyl-L-cysteine (NAC). Aspirin (salicylate) is the most commonly used analgesic and anti-inflammatory agent. At physiological concentrations, it inhibits the maturation of murine BMderived DC without impairing their generation from progenitor cells. Its inhibitory effect is cyclooxygenaseindependent and associated with suppressed activation of NF-kB p50. The T cell stimulatory activity of DC pre-exposed to aspirin is markedly diminished, both in vitro and in vivo, despite the ability of these cells to migrate to T cell areas of draining lymphoid tissue w102x. Suppression of maturation of human Mo-DC by aspirin has also been reported w103x. 1a, 25-(OH)2D3 (calcitrol), the biologically active metabolite of vitamin D3, is a secosteroid hormone that not only regulates bone and calciumyphosphate metabolism, but also exerts a number of biological activities, including modulation of immune responses. Penna and Adorini w104x showed that this agent could inhibit maturation and function of human Mo-DC in vitro and in vivo, leading to suppressed IL-12 and enhanced IL10 secretion upon CD40 ligation. 1a, 25-(OH)2D3 also promotes apoptosis of mature DC. These inhibitory effects 1a, 25-(OH)2D3 on DC have also been shown in murine BM-derived DC both in vitro and in vivo w105x and in murine LC in vitro w106x. NAC is classically used as a mucolytic agent, however, it has recently gained new interest in view of its immunologic effects. Verhasselt et al. w107x reported that NAC inhibited the activation of the NF-kB in human Mo-DC and inhibited their T cell allostimulatory capacity. The authors also demonstrated that NACtreated DC induced T reg cells in vitro w108x. 7. Conclusion Structurally diverse immunosuppressive drugs can exert strong inhibitory effects on DC maturation and
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Review
Influence of immunosuppressive drugs on dendritic cells Masanori Abea, Angus W. Thomsona,b,* a
Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA b Department of Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA Received 29 April 2003; accepted 21 May 2003
Abstract Immunosuppressive drugs used to control allograft rejection and in efforts to promote transplant tolerance are well recognized for their abilities to inhibit lymphocyte activation and proliferation. In recent years, evidence has accumulated that these diversely acting agents (anti-proliferative drugs, calcineurin inhibitors, rapamycin, deoxyspergualin and glucocorticoids) also affect the development and functional immunobiology of dendritic cells, in vitro and in vivo. Here we review the influence of immunosuppressive drugs on the differentiation and function of these important antigen-presenting cells. We also consider how these effects influence immune reactivity and tolerance induction, implications for furthermore understanding of dendritic cell biology and prospects for improving the outcome of organ transplantation and therapy of other immune-mediated disorders by impacting dendritic cell function. 䊚 2003 Elsevier B.V. All rights reserved. Keywords: Dendritic cells; Immunosuppressive drugs; Transplant tolerance
1. Introduction Remarkable advances have been made in clinical transplantation over the past two decades, largely because of major strides in understanding the immune mechanisms involved in transplant rejection and the development of more effective and safer immunosuppressive drugs. Nevertheless, the goal of specific and sustained inhibition of donor-specific immune responses in the absence of both graft pathology and dependence on anti-rejection therapy remains elusive. In keeping with the fundamental role of T cells in graft rejection, much emphasis in the development of immunosuppressive drugs has been focused on inhibition of T cell activation and proliferation. The mechanisms by which these drugs affect T cells have been investigated in great detail. However, induction of immune responses does not rely solely on T cells, but also on essential and complex interactions between *Corresponding author. Tel.: q1-412-624-6392; fax: q1-412-6241172. E-mail address: [email protected] (A.W. Thomson).
antigen-presenting cells (APC) and T cells. The immune response to organ grafts is believed to be initiated by the presentation of alloantigen by donor and self APC to host T cells, which then differentiate into effector and regulatory cells. Dendritic cells (DC) are rare, ubiquitously distributed, migratory APC, derived from CD34q bone marrow (BM) stem cells. In addition to ¨ T cells, DC having the unique capacity to prime naıve also regulate various effector cell functions and play central roles in modulating the immune response w1,2x. Donor-derived DC are commonly regarded as the principal instigators of transplant rejection, but considerable evidence also exists for DC tolerogenicity in the context of alloimmune responses w3–5x. In addition, immature DC and DC manipulated pharmacologically, biologically or genetically to enhance their tolerogenicity in vitro or in vivo can improve outcomes in cell or organ transplantation w3–5x. Thus, in order to comprehend the mechanism of action of immunosuppressive drugs and their potential for tolerance induction more fully, it is necessary to elucidate their influence on DC development, maturation and function.
0966-3274/03/$ - see front matter 䊚 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0966-3274(03)00050-9
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In this review, we discuss recently-accumulated information on the effects of currently used immunosuppressive drugs on DC both in vitro and in vivo. While most available information concerns classic (myeloidymonocytoid) DC, evidence is also emerging concerning the influence of immunosuppressive drugs on DC subsets that have been identified in humans and experimental animals. 2. Anti-proliferative drugs (purine nucleotide biosynthesis inhibitors) 2.1. Azathioprine (AZA) AZA was the most widely used immunosuppressive drug for prophylaxis of acute rejection in organ transplant recipients until the advent of cyclosporine in 1979. This agent has found increasing use in the treatment of autoimmune diseases. AZA is a pro-drug that is converted to 6-mercaptopurine, which is subsequently metabolized to the pharmacologically active 6-thioguanine nucleotides. These metabolites block the de novo and salvage pathways of purine nucleotide biosynthesis and subsequently, inhibit the proliferation of T- and Bcells. There have been few studies concerning effects of AZA on DC. Liu et al. w6x, however, reported that human epidermal Langerhans cells (LC) treated with pharmacological levels of AZA in vitro, exhibited decreased T cell allostimulatory capacity. 2.2. Mizoribine (MZB) MZB is an antibiotic agent produced by the soil fungus Eupenicillium brefeldianum w7x and is used as a clinical immunosuppressive agent in Japan. MZB is metabolized to the pharmacologically active mizoribine 59-monophosphate. This metabolite inhibits the enzyme inosine 59-monophosphate dehydrogenase (IMPDH) and guanosine 59-monophosphate synthetase. Thus, MZB blocks the de novo pathway of guanosine synthesis, without affecting the salvage pathway w8x. As a result of its inhibitory effects on nucleic acid synthesis, MZB suppresses T- and B-cell lymphocyte functions w9,10x. Although it is likely that this agent impacts on DC function, there are as yet no reports that address this issue. 2.3. Mycophenolate mofetil (MMF) MMF is the morpholinoethanol ester prodrug of its active metabolite mycophenolic acid (MPA) w11x, a fermentation product of several species of Penicillium. MPA is a non-competitive, reversible inhibitor of the enzyme IMPDH that, like MZB, plays a major role in the de novo synthesis of guanosine nucleotides w12x.
MMF inhibits both T- and B-cell proliferation in response to mitogenic and allogeneic stimulation w13x. Mehling et al. w14x reported that mouse BM-derived DC propagated in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 in the presence of MMF exhibited a dose-dependent impairment of T cell allostimulatory capacity, consistent with reduced costimulatory molecule expression and IL12p70 production in response to lipopolysaccharide (LPS) stimulation. They also demonstrated impairment of the antigen-presenting capacities of LC following chronic (30 days) MMF treatment in vivo w14x. These findings also point to a possible role of IMPDH in DC maturation. Gregori et al. w15x showed that a combination of 1a, 25-hydroxyvitamin D3 (1a,25(OH)2D3) and MMF in vivo could induce DC with a tolerogenic phenotype that enhanced the frequency of CD4qCD25q T regulatory (T reg) cells and promoted tolerance to allografts. 3. Calcineurin inhibitors 3.1. Cyclosporine A (CsA) CsA is a metabolite of the soil fungi Polysporium Rafti and Cylindrocarpon lucidum w16x. It potently inhibits Ca2q-dependent T-cell receptor (TCR)-mediated signal transduction leading to IL-2 production. After binding to its intracellular immunophilin receptor (cyclophilin), the drug–immunophilin complex decreases calcineurin phosphatase-dependent nuclear translocation of the cytosolic nuclear factor (NF) of activated T cells, its binding to the IL-2 enhancer and subsequent IL-2 gene transcription w17–20x. Thus, the immunosuppressive effect of CsA is believed to be due primarily to its direct suppression of T cell activation. Several effects of CsA on mouse, rat and human DC have been reported during the last 15 years. Lee et al. w21x showed that CsA inhibited the allostimulatory capacity of in vitro generated mouse BM-derived DC by downregulation of surface costimulatory molecule expression. They also showed clearly that NF-kB was a molecular target in the inhibitory action of CsA on DC. Recently, using mouse BM-derived DC and T cells from D11.10 TCR transgenic mice, Matsue et al. w22x reported that CsA blocked bi-directional DC-T cell interaction following antigen presentation. Thus, CsA inhibited DCtriggered production of interferon (IFN)-g, IL-2 and IL4 by T cells and IL-6, IL-12p40 and IL-12p70 by DC. However, CsA failed to inhibit cytokine production by LPS-stimulated DC. On the other hand, CsA suppressed DC-induced proliferation of primed T cells and inhibited cytokine production by both Th1 and Th2 cells. In addition, inhibitory effects of CsA on mouse spleen DC in vitro w23x and defective functions of DC from lymph nodes of CsA-treated mice w24x have been reported.
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With regard to mouse LC, CsA inhibits their antigenpresenting capacity in vitro w25,26x and inhibits their capacity to induce contact hypersensitivity reactions in vivo w27x. In the rat, numbers of thymic DC are decreased during CsA treatment w28,29x, however, the DC reveal an identical phenotype and function to controls w28x. In addition, inhibition of differentiation of epidermal LC precursors during systemic treatment with CsA has been reported w30x. With regard to human DC, the influence of CsA on monocyte-derived DC (Mo-DC) has mainly been investigated w31–37x. Most reports show that CsA does not affect DC development during DC differentiation from monocytes w31–33x. During their maturation promoted by TNFa or LPS, however, inhibition of augmented expression of costimulatory molecules, DC-lysosomalassociated-membrane protein (LAMP) or CD83 w33– 36x and T cell allostimulatory capacity by CsA w32–35x has been observed. On the other hand, Woltman et al. w31x reported that while treatment of Mo-DC with CsA resulted in a partial reduction in tumor necrosis factor (TNF)-a production, other functional activites of the cells, including allostimulatory capacity and expression of costimulatory molecules, were not affected. These effects appear to be dependent on the stimuli used to trigger DC maturation w33–37x. Thus, CsA does not inhibit human DC maturation induced by double-stranded RNA or CD40 ligand w33x. Recently, Tajima et al. w38x reported effects of CsA on human peripheral blood DC subsets. They demonstrated that CsA inhibited the stimulated upregulation of costimulatory molecules and the allostimulatory capacity of both CD11cq(monocytoid) and CD11cy (plasmacytoid) DC subsets. They also showed that CsA negatively regulated the endocytic activity of CD11cq DC while in the immature state. In addition, CsA inhibited IL-12p70 production, but augmented IL-10 production by the CD11cq subset, whereas it reduced IFN-a production by the CD11cy subset. Inhibitory effects of CsA on the antigen-presenting functions of human LC have also been reported w39,40x. 3.2. FK506 (tacrolimus) FK506 (tacrolimus) is a macrolide lactone antibiotic isolated from the soil fungus Streptomyces tsukubaensis w41x. FK506 binds to intracellular immunophilins termed FK506-binding proteins (FKBP). The FK506-FKBP complexes then bind to and inhibit the phosphatase activity of calcineurin, the same molecular target as CsA, thereby inhibiting TCR-mediated signal transduction in T lymphocytes w17–19x. Although T cells are the most widely recognized cellular target for this drug, as well as for CsA, direct effects of FK506 on DC have also been reported.
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Morelli et al. w42x observed that FK506 suppressed GM-CSF-stimulated growth of myeloid DC from mouse BM without affecting surface MHC class II or costimulatory molecule expression. They also showed that administration of FK506 to allogeneic recipients of fmslike tyrosine 3 kinase ligand (Flt-3L)-mobilized donor BM cells resulted in marked enhancement of DC chimerism in host lymphoid tissue with reduction in antidonor T cell proliferation responses w42–44x. Matsue et al. w22x reported that FK506 blocked all changes that resulted from mouse bi-directional DC-T cell interactions and that short-term exposure of BM-derived DC cultures to FK506 modestly reduced DC surface expression of MHC class II and costimulatory molecules. FK506 was significantly more potent than other immunosuppressive agents in inhibiting DC cytokine production (IL-6, IL-12p40 and p70) upon antigen-specific interaction with T cells. FK506 also inhibits costimulatory molecule expression on mouse epidermal LC in vitro w26x. Studies of the influence of FK506 on human Mo-DC have led to some discrepant observations, as with CsA. Most reports have shown that expression of key surface molecules on Mo-DC is not affected by FK506 at physiological concentrations when the drug is added to cultures during cell maturation w31,32,45x. However, Koski et al. w34x reported that expression of costimulatory molecules and CD83 on Mo-DC was reduced. In addition, some authors have shown decreased T cell stimulatory capacity and cytokine production by FK506treated human Mo-DC w32,34x. On the other hand, Woltman et al. w31x reported that FK506 treatment in vitro had no effect. In a study of CD34q hematopoietic progenitor-derived human DC w46x, FK506 promoted the development of DC, unlike observations with mouse BM-derived cells w42x. Despite no effect on costimulatory molecule expression, the human FK506-treated DC displayed a reduced allostimulatory capacity and IL-12 production w46x. In addition, when pulsed with exogenous antigen (keyhole limpet hemocyanin) these cells induced CD4q T cells towards a Th2-like response. The in vivo effect of FK506 on DC in humans was investigated with respect to epidermal DC following topical FK506 administration in atopic dermatitis w47,48x. Decreased expression of receptors for immunoglobulin E (IgE) on both LC and inflammatory dendritic epidermal cells was observed. Impaired function of human LC by FK506 has also been reported w49x. 4. Rapamycin (sirolimus) Rapamycin (RAPA; sirolimus) is a macrocyclic triene antibiotic produced by the actinomycete Streptomyces hygroscopicus w50x. The drug structurally resembles FK506 and binds to the same intracellular binding protein, FKBP12. RAPA-FKBP12 complexes act to
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inhibit the activity of the mammalian target of RAPA (mTOR) w51,52x. This results in inhibition of multiple biochemical pathways that are critical for cytokiney growth factor-induced cellular proliferation, ribosome synthesis, translation initiation and cell cycle progression into S phase w51,52x. T cells have been considered the principal targets of RAPA. Hackstein et al. w53x reported that, at clinicallyrelevant concentrations, RAPA inhibited endocytosis by mouse BM-derived DC, both in vitro and in vivo. This effect was not related to apoptotic cell death and the underlying mechanism remains uncertain. The authors also showed that RAPA suppressed the functional activation of BM-derived DC, both in vitro and in vivo w54x. Inhibition of DC maturation was IL-4-dependent and was antagonized by competition for FKBP12 binding. In addition, in vivo administration of RAPA suppressed DC generation and impaired costimulatory molecule upregulation, IL-12 production and T cell allostimulatory capacity. Impairment of T cell stimulatory ability of DC by RAPA has also been reported by other groups w22,55x. Chiang et al. w55x found that RAPA-treated BM-derived DC had markedly impaired ability to induce antigen-specific cytotoxic T cell activity and exhibited decreased IFN-g expression through inhibition of the Stat4 activation pathway, although RAPA did not alter costimulatory molecule expression on DC. Injection of RAPA-treated donor DC 7 days before transplant significantly prolonged heart allograft survival compared with untreated DC-injected controls. With respect to human cells, RAPA induces apoptosis of both Mo-DC and DC generated from CD34q precursors w56,57x. RAPA interferes with the GM-CSFyPI3Ky mTOR signaling pathway in DC and promotes apoptosis via increased p27KIP1 expression w58x. Monti et al. w57x reported that receptor-mediated endocytosis was impaired in RAPA-treated human DC. They further showed that allostimulatory ability, costimulatory molecule expression and IL-12 and IL-10 production were decreased by RAPA w57x. 5. Glucocorticoids (GC) GC are potent immunosuppressive and anti-inflammatory agents used to treat autoimmune diseases and to prevent graft rejection. Their immunosuppressive actions are focused mainly on T cells and monocytesymacrophages w59x. In addition, there have been more than 50 reports to date regarding the influence of GC on DC. Moser et al. w60x reported that GC reduced DC viability, downregulated the expression of costimulatory molecules on viable DC and strongly reduced the allostimulatory capacity of mouse spleen DC in vitro. They also showed that GC impaired the antigen-presenting function of DC in vivo. Dexamethasone (Dex) also downregulated costimulatory molecule expression and T
cell allostimulatory capacity of mouse BM-derived DC in vitro w22,61x and of a mouse epidermal DC line w62x. Matyszak et al. w61x reported that Dex-treated BMderived DC were unable to undergo full maturation and to prime Th1 cells efficiently. In addition, multiple restimulation of T cells with these DC gave rise to T reg cells (Tr1 cells; IFN-gy, IL-4y , IL-10q). The suppressive effect of Dex was not observed with DC pre-activated with LPS, indicating that the stage of DC maturation influenced the effect of GC. Inhibition of costimulatory molecule expression and the allostimulatory capacity on mouse LC has been reported w26,63x. Following topical administration of GC, the number of murine epidermal LC is reduced w63,64x. This effect has also been reported for rat, guinea pig and human LC and is associated with marked decrease in LC-induced T cell activation w65–67x. Decreased expression of MHC class II and loss of Birbeck granules in mouse LC was shown following systemic GC treatment w68x. Cumberbatch et al. w69x reported that systemically administered Dex inhibited mouse LC migration to draining lymph nodes following skin sensitization with contact allergen. In the rat, the effects of GC on thymic and lung DC have been reported w70–75x. Sacedon et al. w70x observed that thymic DC expressed GC receptors. Dextreated thymic DC showed impaired allostimulatory capacity and production of IL-1b and TNF-a, but not that of IL-6 or IL-10 was diminished in mixed leukocyte reaction (MLR) set up with Dex-treated thymic DC. These DC were resistant to GC-induced apoptosis w70x. The authors also showed that GC strongly influenced thymic DC maturation early in ontogeny w71x. Holt et al. w72–74x reported that exposure to inhaled GC rapidly and reversibly decreased the number of rat airway intraepithelial DC and their surface expression of MHC class II, whereas GC did not inhibit their antigenpresenting capacity. Brokaw et al. w75x showed that GCinduced apoptosis contributed to the rapid decrease of rat airway DC. In the rhesus macaque, topical GC treatment leads to a marked decrease in the number of skin CD1aq DC and to a shift in phenotype towards a more mature APC in the draining lymph nodes w76x. There have been numerous publications regarding effects of GC on human Mo-DC. Some of the data are conflicting. The reasons for these discrepancies between reports are largely unclear, but likely include the different maturation states of the DC used and different exposure times to different concentrations of GC. GC interfere strongly with the differentiation and function of human Mo-DC in vitro w31,77–79x. This inhibitory effect has also been reported for the development of dermal DC but not LC from CD34q hematopoietic progenitors w80x. Some reports have shown that GC induce DC apoptosis during their differentiation or maturation w77,80,81x. Expression of molecules involved in antigen presentation is impaired, while that of mole-
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cules involved in antigen uptake (mannose receptor; CD32) and adhesion molecules (CD11y18, CD54) is upregulated w78x. Whereas impairment of the T cell stimulating capacity of Mo-DC following treatment with GC during their w31,78,82,83x differentiation and maturation w35,77,83,84x has been reported, there are other accounts that GC do not affect the ability of Mo-DC to induce T cell proliferation w79,85,86x. Impairment of the allostimulatory capacities of lung DC by GC has been reported w87x. There are some discrepancies concerning the expression of costimulatory molecules or CD83 by DC exposed to GC. With regard to cytokine production, IL12p70, IL-6 and TNFa production by Mo-DC is decreased by GC w31,78,79,83–86,88,89x. In addition, some authors have shown increased IL-10 production by GC-treated DC w79,84x. There is also evidence that GC treatment impairs IFN-g secretion, but stimulates IL-10 and IL-5 production by CD4q Th cells w84– 86,88,89x. GC appear to transform CD40-triggered DC into APC with potential for suppression of adverse T cell response in vivo. Exposure of DC to GC during their differentiation from monocytes increases their endocytic activity w78,82x. However, failure of GC to affect antigen uptake by DC has also been described w85,88x. Vanderhyde et al. w89x reported that Mo-DC treated with methylprednisolone exhibited enhanced endocytic capacity. Recently, Schodell and Siegal w90x have shown that GC administration results in a decrease in IFN-a production by human peripheral blood mononuclear cells, accompanied by a reduction in circulating plasmacytoid DC numbers. Topical GC therapy reduces the number of human skin or mucosal CD1aq LC and their T cell stimulatory capacities w65,91–93x, whereas in vitro exposure of human LC to GC inhibits their antigenpresenting ability w94x. 6. Other drugs 6.1. Deoxyspergualin (DSG) and its novel analogue LF15-0195 (LF) DSG, a compound isolated from culture filtrates of Bacillus lacterosporus w95x, prolongs allograft survival in rodents. Although its mechanism of action is still poorly understood, DSG has been reported to inhibit NF-kB activation and antigen processing, T or B cell differentiation and antibody production w96–98x. Thomas et al. w99x have demonstrated in rhesus macaques that simultaneous targeting of both T cells (using anti-CD3 immunotoxin) and DC (using DSG) results in renal transplant tolerance. Mature DC (CD83q) were reduced markedly in lymph nodes of graft recipients and DSG inhibited rhesus DC maturation in vitro w99x. Inhibitory effects of the novel DSG
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analogue, 15-0195(LF) on mouse BM-derived DC maturation have also been reported w100x. Chiffoleau et al. w101x showed that LF treatment induced donor APCs to expand powerful T reg cells in a rat heart allograft model. Recently, Min et al. w100x reported that immature (tolerogenic) DC and T reg cells were increased using LF and anti-CD45RB antibody combination in a mouse cardiac transplantation tolerance model. In vitro study suggested that DC generated T reg cells ¨ T cells and that T reg cells (CD4qCD25q) from naıve generated tolerogenic DC, thus constituting a tolerogenic feedback loop. 6.2. Aspirin, vitamin D and N-acetyl-L-cysteine In addition, of these pharmacologic agents, a variety of other drugs have been shown to inhibit DC maturation and function. Among them are aspirin, vitamin D and N-acetyl-L-cysteine (NAC). Aspirin (salicylate) is the most commonly used analgesic and anti-inflammatory agent. At physiological concentrations, it inhibits the maturation of murine BMderived DC without impairing their generation from progenitor cells. Its inhibitory effect is cyclooxygenaseindependent and associated with suppressed activation of NF-kB p50. The T cell stimulatory activity of DC pre-exposed to aspirin is markedly diminished, both in vitro and in vivo, despite the ability of these cells to migrate to T cell areas of draining lymphoid tissue w102x. Suppression of maturation of human Mo-DC by aspirin has also been reported w103x. 1a, 25-(OH)2D3 (calcitrol), the biologically active metabolite of vitamin D3, is a secosteroid hormone that not only regulates bone and calciumyphosphate metabolism, but also exerts a number of biological activities, including modulation of immune responses. Penna and Adorini w104x showed that this agent could inhibit maturation and function of human Mo-DC in vitro and in vivo, leading to suppressed IL-12 and enhanced IL10 secretion upon CD40 ligation. 1a, 25-(OH)2D3 also promotes apoptosis of mature DC. These inhibitory effects 1a, 25-(OH)2D3 on DC have also been shown in murine BM-derived DC both in vitro and in vivo w105x and in murine LC in vitro w106x. NAC is classically used as a mucolytic agent, however, it has recently gained new interest in view of its immunologic effects. Verhasselt et al. w107x reported that NAC inhibited the activation of the NF-kB in human Mo-DC and inhibited their T cell allostimulatory capacity. The authors also demonstrated that NACtreated DC induced T reg cells in vitro w108x. 7. Conclusion Structurally diverse immunosuppressive drugs can exert strong inhibitory effects on DC maturation and
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function. In addition, exposure of DC to these agents results in suppressed or regulated T cell responses offering potential for manipulation of DC-T cell interactions to promote T cell unresponsiveness in a variety of clinical conditions, in particular transplantation and autoimmune disorders, but also allergic hypersensitivity. Acknowledgments The authors’ work is supported by National Institutes of Health grants DK49745, AI41011 and AIyDK51698. References w1x Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245 –252. w2x Bancherau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767 –811. w3x Morelli AE, Hackstein H, Thomson AW. Potential of tolerogenic dendritic cells for transplantation. Semin Immunol 2001;13:323 –335. w4x Coates PT, Thomson AW. Dendritic cells, tolerance induction and transplant outcome. Am J Tranplant 2002;2:299 –307. w5x Morel PA, Feili-Hariri M, Coates PT, Thomson AW. Dendritic cells, T cell tolerance and therapy of adverse immune reactions. Clin Exp Immunol 2003;133:1 –10. w6x Liu HN, Wong CK. In vitro immunosuppressive effects of methotrexate and azathioprine on Langerhans cells. Arch Dermatol Res 1997;289:94 –97. w7x Mizuno K, Tsujino M, Takada M, Hayashi M, Atsumi K. Studies on bredinin. I. Isolation, characterization and biological properties. J Antibiot (Tokyo) 1974;27:775 –782. w8x Mitchell BS, Dayton JS, Turka LA, Thompson CB. IMP dehydrogenase inhibitors as immunomodulators. Ann N Y Acad Sci 1993;685:217 –224. w9x Ichikawa Y, Ihara H, Takahara S, Takada K, Shrestha GR, Ishibashi M, et al. The immunosuppressive mode of action of mizoribine. Transplantation 1984;38:262 –267. w10x Thomson AW, Woo J, Yao GZ, Todo S, Starzl TE, Zeevi A. Effects of combined administration of FK506 and the purine biosynthesis inhibitors mizoribine and mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures. Transplant Immunol 1993;1:146 –150. w11x Fulton B, Markham A. Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs 1996;51:278 –298. w12x Sintchak MD, Fleming MA, Futer O, Raybuck SA, Chambers SP, Caron PR, et al. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell 1996;85:921 –930. w13x Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 1996;10:77 –84. w14x Mehling A, Grabbe S, Voskort M, Schwarz T, Luger TA, Beissert S. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J Immunol 2000;165:2374 – 2381. w15x Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1a, 25dihydroxyvitamin D3 and mycophenolate mofetil mediate transplantation tolerance. J Immunol 2001;167:1945 –1953.
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