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Flt3L Combined with Rapamycin Promotes Cardiac Allograft Tolerance by Inducing Regulatory Dendritic Cells and Allograft Autophagy in Mice  [PDF]
Ali Xiong, Lihua Duan, Jie Chen, Zhigang Fan, Fang Zheng, Zheng Tan, Feili Gong, Min Fang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046230
Abstract: The induction of immune tolerance is still a formidable challenge in organ transplantation. Dendritic cells (DCs) play an important role in orchestrating immune responses by either mediating protective immune responses or inducing antigen specific tolerance. Previous studies demonstrated that the fms-like tyrosine kinase 3 receptor (Flt3) and its ligand (Flt3L) play an essential role in the regulation of DC commitment and development. Here, we report a synergic effect between Flt3L and low-dose rapamycin (Rapa) in the protection of allograft rejction. It was found that Flt3L combined with Rapa significantly prolonged murine cardiac allograft survival time as compared with that of untreated recipients or recipients treated with Rapa or Flt3L alone. Mechanistic studies revealed that Flt3L combined with low-dose of Rapa induced the generation of tolerogenic DCs along with the production of CD25+ Foxp3+ regulatory T cells and IL-10 secretion. We also observed enhanced autophagy in the cardiac allograft, which could be another asset contributing to the enhanced allograft survival. All together, these data suggest that Flt3L combined with low-dose of Rapa could be an effective therapeutic approach to induce tolerance in clinical setting of transplantation.
Peripheral Regulatory Cells Immunophenotyping in Kidney Transplant Recipients with Different Clinical Profiles: A Cross-Sectional Study  [PDF]
Janette Furuzawa-Carballeda,Guadalupe Lima,Perla Simancas,Dolores Ramos-Bello,Margaret Simancas,Ian C. Bostock,Mario Vilatobá,Bernardo Gabilondo,Julio Granados,Luis Morales-Buenrostro,Josefina Alberú,Luis Llorente
Journal of Transplantation , 2012, DOI: 10.1155/2012/256960
Abstract: Regulatory Foxp3-expressing T cells (Tregs), IL-10-producing B cells (Bregs), and IDO-expressing dendritic cells (DCregs) downregulate inflammatory processes and induces peripheral tolerance. These subpopulations also might participate in maintaining allograft immunological quiescence in kidney transplant recipients (KTRs) with an excellent long-term graft function under immunosuppression (ELTGF). The aim of the study was to characterize and to enumerate peripheral Tregs, Bregs, and DCregs in KTR with an ELTGF for more than 5 years after transplant. Fourteen KTR with an ELTGF, 9 KTR with chronic graft dysfunction (CGD), and 12 healthy donors (HDs) were included in the study. CD19
Inhibition of Arterial Allograft Intimal Hyperplasia Using Recipient Dendritic Cells Pretreated with B7 Antisense Peptide
Yu-Feng Yao,Yi-Ming Zhou,Jian-Bin Xiang,Xiao-Dong Gu,Duan Cai
Clinical and Developmental Immunology , 2012, DOI: 10.1155/2012/892687
Abstract: Background. Low expression or absence of dendritic cell (DC) surface B7 molecules can induce immune tolerance or hyporesponse. Whether DCs could induce indirect allogeneic-specific cross-tolerance or hyporesponse to recipient T cells remains unclear. Methods. Generated from C3H/He mice bone marrow cells pulsed with donor antigen from C57BL/6 mice, recipient DCs were incubated with B7 antisense peptide (B7AP). Immune regulatory activities were examined in vitro by a series of mixed lymphocyte reactions. Murine allogeneic carotid artery orthotopic transplantation was performed from C57BL/6 to C3H/He. Recipients were given B7AP-treated DCs 7 days before transplantation. Allograft pathological analysis was done 2 months after transplantation. Results. B7AP-pretreated DCs markedly inhibited T-cell proliferation compared with untreated group. Pretreated T cells exhibited markedly reduced response to alloantigen versus third-party antigen. Pathological analysis of arterial allografts demonstrated significant reduction of intimal hyperplasia in B7-AP pretreated group versus control. Conclusion. Blockade of B7 molecules by B7AP could induce indirect allogeneic-specific hyporesponse and inhibit arterial allograft intimal hyperplasia, which may be involved in future strategies for human allograft chronic rejection.
Plasmacytoid Dendritic Cells Are Inefficient in Activation of Human Regulatory T Cells  [PDF]
Mario Hubo, Helmut Jonuleit
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044056
Abstract: Background Dendritic cells (DC) play a key role in initiation and regulation of immune responses. Plasmacytoid DC (pDC), a small subset of DC, characterized as type-I interferon producing cells, are critically involved in anti-viral immune responses, but also mediate tolerance by induction of regulatory T cells (Treg). In this study, we compared the capacity of human pDC and conventional DC (cDC) to modulate T cell activity in presence of Foxp3+ Treg. Principal Findings In coculture of T effector cells (Teff) and Treg, activated cDC overcome Treg anergy, abrogate their suppressive function and induce Teff proliferation. In contrast, pDC do not break Treg anergy but induce Teff proliferation even in coculture with Treg. Lack of Treg-mediated suppression is independent of proinflammatory cytokines like IFN-α, IL-1, IL-6 and TNF-α. Phenotyping of pDC-stimulated Treg reveals a reduced expression of Treg activation markers GARP and CTLA-4. Additional stimulation by anti-CD3 antibodies enhances surface expression of GARP and CTLA-4 on Treg and consequently reconstitutes their suppressive function, while increased costimulation with anti-CD28 antibodies is ineffective. Conclusions/Significance Our data show that activated pDC induce Teff proliferation, but are insufficient for functional Treg activation and, therefore, allow expansion of Teff also in presence of Treg.
Role of dendritic cells in the induction of regulatory T cells
Rahul Kushwah, Jim Hu
Cell & Bioscience , 2011, DOI: 10.1186/2045-3701-1-20
Abstract: Dendritic cells (DCs) are professional antigen presenting cells and are essential mediators of immunity and tolerance. DCs are the key players in maintaining immune tolerance, for their ablation has been shown to result in autoimmunity, highlighting the active role that DCs play under steady state conditions in maintaining immune tolerance[1]. In order to prevent autoimmune reactions, self reactive lymphocytes need to be deleted or their function needs to be suppressed. The generation of normal lymphocyte repertoire which is largely self-tolerant depends on positive and negative selection, which occurs in the thymus and the process, is referred to as central tolerance. However, some self-reactive lymphocytes that escape thymic deletion enter peripheral tissues and the suppression of their function is needed to prevent autoimmune reactions, which is referred to as peripheral tolerance. Central tolerance in the thymus is largely mediated by cortical epithelial cells, medullary epithelial cells and thymic DCs and involves deletion of self reactive thymocytes along with induction of naturally occurring regulatory T cells (Tregs), which play a key role in maintaining self tolerance and suppressing a variety of pathological immune responses[2]. In contrast to central tolerance, peripheral tolerance is mediated by DCs through generation of Tregs and clonal deletion of self reactive T cells. Tregs generated in the periphery are thought to be important in controlling immune response to non-self antigens. Peripheral Tregs include IL-10 secreting Tr1 Tregs, inducible foxp3+ Tregs, Th3 cells and double negative Tregs. DC induced generation of these Treg subsets is largely mediated by IL-27, TGF-β, IL-10, retinoic acid, indoleamine-2,3-dioxygenase and vitamin D. The generation of these Tregs is either mediated by tissue resident specific DC subsets with a specialized Treg inducing function or by the action of mediators present in local tissue microenvironment, which act on DCs a
Peripheral Regulatory Cells Immunophenotyping in Kidney Transplant Recipients with Different Clinical Profiles: A Cross-Sectional Study  [PDF]
Janette Furuzawa-Carballeda,Guadalupe Lima,Perla Simancas,Dolores Ramos-Bello,Margaret Simancas,Ian C. Bostock,Mario Vilatobá,Bernardo Gabilondo,Julio Granados,Luis Morales-Buenrostro,Josefina Alberú,Luis Llorente
Journal of Transplantation , 2012, DOI: 10.1155/2012/256960
Abstract: Regulatory Foxp3-expressing T cells (Tregs), IL-10-producing B cells (Bregs), and IDO-expressing dendritic cells (DCregs) downregulate inflammatory processes and induces peripheral tolerance. These subpopulations also might participate in maintaining allograft immunological quiescence in kidney transplant recipients (KTRs) with an excellent long-term graft function under immunosuppression (ELTGF). The aim of the study was to characterize and to enumerate peripheral Tregs, Bregs, and DCregs in KTR with an ELTGF for more than 5 years after transplant. Fourteen KTR with an ELTGF, 9 KTR with chronic graft dysfunction (CGD), and 12 healthy donors (HDs) were included in the study. CD19+-expressing peripheral B lymphocytes were purified by positive selection. IL-10-producing B cells, CD4+/CD25hi, and CD8+/CD28? Tregs, as well as CCR6+/CD123+/IDO+ DCs, were quantitated by flow cytometry. IL-10-producing Bregs (immature/transitional, but not CD19+/CD38hi/CD24hi/CD27+B10 cells), CCR6+/CD123+/IDO+ DCs, and Tregs from ELTGF patients had similar or higher percentages versus HD ( ). By contrast, number of Tregs, DCregs, and Bregs except for CD27+B10 cells from CGD patients had lower levels versus HD and ELTGF patients ( ). The findings of this exploratory study might suggest that in ELTGF patients, peripheral tolerance mechanisms could be directly involved in the maintenance of a quiescent immunologic state and graft function stability. 1. Introduction Progress in elucidating cellular, molecular, and biochemical processes that regulate immune response provides increasingly plausible explanations for the normal status of tolerance to self-antigens that guards most humans from Ehrlich’s imagined horror autotoxicus [1]. Emerging data on regulatory antigen-presenting cells (APCs) provide fertile ground for resolving some perplexing immunological paradoxes. One specific mechanism that appears to play a key role is the catabolism of tryptophan, by the enzyme indoleamine 2,3-dioxygenase (IDO) [2, 3]. IDO is upmodulated during antigen presentation by the engagement of CTLA-4/B7.1/B7.2 (CD80/CD86) molecules on lymphocytes and human dendritic cells (DCs), in response to infection and tissue inflammation (TNF-α, PGE2, IFN-α/β/γ secretion) [2–4]. IDO generates kynurenines, 3-hydroxyanthranilic, and quinolic acids, molecules with the ability to induce T-cell apoptosis and to exert cytotoxic action on T, B, and NK cells, but not on DCs themselves [5, 6]. IDO has a selective sensitivity of Th1 over Th2 cells to tryptophan metabolites, suggesting a potential role for Th2
A novel cell subset: Interferon-producing killer dendritic cells
JiongKun Wang,FeiYue Xing
Science China Life Sciences , 2008, DOI: 10.1007/s11427-008-0084-y
Abstract: Recent reports introduce a novel cell subset of DCs with antigenic phenotypes shared by both NK cells and B cells, but without surface markers of pDCs and T cells, appearing to be a chimera of NK cells and DCs, namely interferon-producing killer dendritic cells (IKDCs). IKDCs not only secret type I and type II interferons to recognize and kill tumor cells effectively, but also express MHC-II molecules to present antigens. Thus, IKDCs are considered as important immunosurveilance cells for tumors, providing a link between innate and adaptive immunity.
In Situ-Targeting of Dendritic Cells with Donor-Derived Apoptotic Cells Restrains Indirect Allorecognition and Ameliorates Allograft Vasculopathy  [PDF]
Zhiliang Wang, William J. Shufesky, Angela Montecalvo, Sherrie J. Divito, Adriana T. Larregina, Adrian E. Morelli
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004940
Abstract: Chronic allograft vasculopathy (CAV) is an atheromatous-like lesion that affects vessels of transplanted organs. It is a component of chronic rejection that conventional immuno-suppression fails to prevent, and is a major cause of graft loss. Indirect allo-recognition through T cells and allo-Abs are critical during CAV pathogenesis. We tested whether the indirect allo-response and its impact on CAV is down-regulated by in situ-delivery of donor Ags to recipient's dendritic cells (DCs) in lymphoid organs in a pro-tolerogenic fashion, through administration of donor splenocytes undergoing early apoptosis. Following systemic injection, donor apoptotic cells were internalized by splenic CD11chi CD8α+ and CD8? DCs, but not by CD11cint plasmacytoid DCs. Those DCs that phagocytosed apoptotic cells in vivo remained quiescent, resisted ex vivo-maturation, and presented allo-Ag for up to 3 days. Administration of donor apoptotic splenocytes, unlike cells alive, (i) promoted deletion, FoxP3 expression and IL-10 secretion, and decreased IFN-γ-release in indirect pathway CD4 T cells; and (ii) reduced cross-priming of anti-donor CD8 T cells in vivo. Targeting recipient's DCs with donor apoptotic cells reduced significantly CAV in a fully-mismatched aortic allograft model. The effect was donor specific, dependent on the physical characteristics of the apoptotic cells, and was associated to down-regulation of the indirect type-1 T cell allo-response and secretion of allo-Abs, when compared to recipients treated with donor cells alive or necrotic. Down-regulation of indirect allo-recognition through in situ-delivery of donor-Ag to recipient's quiescent DCs constitutes a promising strategy to prevent/ameliorate indirect allorecognition and CAV.
Tolerance Induction by Exosomes from Immature Dendritic Cells and Rapamycin in a Mouse Cardiac Allograft Model  [PDF]
Xiao Li, Jun-Jie Li, Jing-Yue Yang, De-Sheng Wang, Wei Zhao, Wen-Jie Song, Wei-Min Li, Jian-Feng Wang, Wei Han, Zhuo-Chao Zhang, Yong Yu, Da-Yong Cao, Ke-Feng Dou
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044045
Abstract: Background Dendritic cells (DCs) release bioactive exosomes that play an important role in immune regulation. Because they express low levels of class I major histocompatibility complex (MHC) and co-stimulatory molecules, exosomes derived from donor immature DCs (imDex) prolong allograft survival by inhibiting T-cell activation. However, this effect is limited and does not induce immunological tolerance when imDex are administered alone. Thus, we tested the effect of combined treatment with donor imDex and low-dose rapamycin on inducing tolerance in a mouse cardiac transplantation model. Methods ImDex were obtained from the culture supernatant of immature DCs derived from donor mouse (C57BL/6) bone marrow and were injected with suboptimal doses of rapamycin into recipient mouse (BALB/c) before and after transplantation. The capacity of this treatment to induce immune tolerance was analyzed in vitro and in vivo using the mouse cardiac transplantation model. Results Donor imDex expressed moderate levels of MHC class II and low levels of MHC class I and co-stimulatory molecules, but neither imDex nor subtherapeutic rapamycin dose alone induced cardiac allograft tolerance. Combined treatment with imDex and rapamycin, however, led to donor specific cardiac allograft tolerance. This effect was accompanied by decreased anti-donor antigen cellular response and an increased percentage of spleen CD4+CD25+ T cells in recipients. Furthermore, this donor specific tolerance could be further transferred to na?ve allograft recipients through injection of splenocytes, but not serum, from tolerant recipients. Conclusion Combined with immunosuppressive treatment, donor imDex can prolong cardiac allograft survival and induce donor specific allograft tolerance.
Generation of Immune Inhibitory Dendritic Cells and CD4+T Regulatory Cells Inducing by TGF
Saeid Abediankenari,Maryam Ghasemi
Iranian Journal Of Allergy, Asthma and Immunology , 2009,
Abstract: Variety of positive as well as negative regulatory signals are provided by antigen presenting cell in particular by dendritic cells. In this research, we studied the capacity of dendritic cells to expand antigen-specific T regulatory cells.We also investigated the role of TGF-beta in induction inhibitory functions of dendritic cells in mixed leukocyte reactions.Dendritic cells were generated from blood CD14+ monocytes with granulocyte-Monocyte colony stimulating factor and interleukin-4 with or without TGF-beta (TGF-β-GM-DC or GM-DC). CD4+ T cell were isolated to assess lymphocyte proliferation by lymphocyte transformation test assay and the ratio of CD4+FOXp3+ CD25+ T cells were determined by fluorescene-activated cell sorter. T cell proliferation responses in GM-DC showed a significance antigen-specific proliferative response comparing with TGFβ-GM -DC. T Cell proliferation was inhibited in co-culture system containing DC-treated TGF-β. It can be suggested that the expsansion of T regulatory by TGF-β-GM-DC provides a means for antigen specific control of unwanted immune reactions.
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