|
1
|
Kotwica-Mojzych K, Jodłowska-Jędrych B, Mojzych M. CD200:CD200R Interactions and Their Importance in Immunoregulation. Int J Mol Sci 2021; 22:ijms22041602. [PMID: 33562512 PMCID: PMC7915401 DOI: 10.3390/ijms22041602] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 01/07/2023] Open
Abstract
The molecule CD200, described many years ago as a naturally occurring immunomodulatory agent, capable of regulating inflammation and transplant rejection, has attracted additional interest over the past years with the realization that it may also serve as an important marker for progressive malignancy. A large body of evidence also supports the hypothesis that this molecule can contribute to immunoregulation of, among other diseases, infection, autoimmune disease and allergy. New data have also come to light to characterize the receptors for CD200 (CD200R) and their potential mechanism(s) of action at the biochemical level, as well as the description of a novel natural antagonist of CD200, lacking the NH2-terminal region of the full-length molecule. Significant controversies exist concerning the relative importance of CD200 as a ligand for all reported CD200Rs. Nevertheless, some progress has been made in the identification of the structural constraints determining the interaction between CD200 and CD200R, and this information has in turn proved of use in developing novel small molecule agonists/antagonists of the interaction. The review below highlights many of these newer findings, and attempts to place them in the broad context of our understanding of the role of CD200-CD200R interactions in a variety of human diseases.
Collapse
Affiliation(s)
- Katarzyna Kotwica-Mojzych
- Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland;
- Correspondence:
| | - Barbara Jodłowska-Jędrych
- Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland;
| | - Mariusz Mojzych
- Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland;
| |
Collapse
|
|
2
|
Navarro-Barriuso J, Mansilla MJ, Martínez-Cáceres EM. Searching for the Transcriptomic Signature of Immune Tolerance Induction-Biomarkers of Safety and Functionality for Tolerogenic Dendritic Cells and Regulatory Macrophages. Front Immunol 2018; 9:2062. [PMID: 30298066 PMCID: PMC6160751 DOI: 10.3389/fimmu.2018.02062] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 08/21/2018] [Indexed: 12/12/2022] Open
Abstract
The last years have witnessed a breakthrough in the development of cell-based tolerance-inducing cell therapies for the treatment of autoimmune diseases and solid-organ transplantation. Indeed, the use of tolerogenic dendritic cells (tolDC) and regulatory macrophages (Mreg) is currently being tested in Phase I and Phase II clinical trials worldwide, with the aim of finding an effective therapy able to abrogate the inflammatory processes causing these pathologies without compromising the protective immunity of the patients. However, there exists a wide variety of different protocols to generate human tolDC and Mreg and, consequently, the characteristics of each product are heterogeneous. For this reason, the identification of biomarkers able to define their functionality (tolerogenicity) is of great relevance, on the one hand, to guarantee the safety of tolDC and Mreg before administration and, on the other hand, to compare the results between different cell products and laboratories. In this article, we perform an exhaustive review of protocols generating human tolDC and Mreg in the literature, aiming to elucidate if there are any common transcriptomic signature or potential biomarkers of tolerogenicity among the different approaches. However, and although several effectors seem to be induced in common in some of the most reported protocols to generate both tolDC or Mreg, the transcriptomic profile of these cellular products strongly varies depending on the approach used to generate them.
Collapse
Affiliation(s)
- Juan Navarro-Barriuso
- Division of Immunology, Germans Trias i Pujol University Hospital and Research Institute, Barcelona, Spain.,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - María José Mansilla
- Division of Immunology, Germans Trias i Pujol University Hospital and Research Institute, Barcelona, Spain.,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eva M Martínez-Cáceres
- Division of Immunology, Germans Trias i Pujol University Hospital and Research Institute, Barcelona, Spain.,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| |
Collapse
|
|
3
|
Diehl R, Ferrara F, Müller C, Dreyer AY, McLeod DD, Fricke S, Boltze J. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol 2016; 14:146-179. [PMID: 27721455 PMCID: PMC5301156 DOI: 10.1038/cmi.2016.39] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 05/30/2016] [Accepted: 05/30/2016] [Indexed: 02/06/2023] Open
Abstract
Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.
Collapse
Affiliation(s)
- Rita Diehl
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Fabienne Ferrara
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany.,Institute of Vegetative Physiology, Charite University Medicine and Center for Cardiovascular Research, Berlin 10115, Germany
| | - Claudia Müller
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Antje Y Dreyer
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | | | - Stephan Fricke
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Johannes Boltze
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany.,Fraunhofer Research Institution for Marine Biotechnology and Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck 23562, Germany
| |
Collapse
|
|
4
|
Baroja-Mazo A, Revilla-Nuin B, Parrilla P, Martínez-Alarcón L, Ramírez P, Pons JA. Tolerance in liver transplantation: Biomarkers and clinical relevance. World J Gastroenterol 2016; 22:7676-91. [PMID: 27678350 PMCID: PMC5016367 DOI: 10.3748/wjg.v22.i34.7676] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/04/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as "operational tolerance". However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.
Collapse
|
|
5
|
Xia MJ, Shan J, Li YP, Zhou YN, Guo YJ, Sun GX, Wu WQ, Feng L. Adoptive transfusion of tolerant dendritic cells prolong the survival of renal allografts: a systematic review. J Evid Based Med 2013; 6:250-64. [PMID: 24325419 DOI: 10.1111/jebm.12070] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 09/10/2013] [Indexed: 02/05/2023]
Abstract
OBJECTIVE The aim of this study was to systematically review the effects of transfusing Tol-DCs induced by different methods on renal transplantation and survival time. METHOD PubMed and EMbase were searched for relevant articles from inception to July 20(th), 2013. Renal allograft survival time was regarded as the endpoint outcome. The effects of Tol-DCs on renal transplantation were evaluated semi-quantitatively. RESULTS Sixteen articles were included. There were three sources of Tol-DCs, including bone marrow, spleen, and thoracic duct lymph node. Rats were administrated cells intravenously and 83% of mice through the portal vein. Four subtypes of bone marrow Tol-DCs enhanced renal allograft time: immature DCs enhanced allograft survival 4.9-fold in rats and 2.0-fold in mice, gene modified DCs enhanced allograft survival 4.4-fold in rats and 2.2-fold in mice, and drug and cytokine induced enhanced allograft survival 2.9-fold and 2.7-fold, respectively, in rats. Tol-DCs from the spleen and thoracic duct lymph nodes prolonged allograft survival 2.7-fold and 1.8-fold, respectively, in rats. 1-2 × 10(6) doses of Tol-DCs extended the survival time of rats following renal transplantation. The key mechanisms by which Tol-DCs enhance allograft and overall survival included: (i) inducing T-cell hyporeactivity; (ii) reducing the effects of cytotoxic lymphocytes; and (iii) inducing Th2 differentiation. CONCLUSION Bone marrow Tol-DCs can extend allograft survival and induce immune tolerance in fully MHC-mismatched renal transplantation in rats and mice. The effects of imDCs and gene modified Tol-DCs in mice are less marked. In conclusion, a single-injection of 1-2 × 10(6) doses of bone marrow Tol-DCs (i.v.), in combination with an immune-suppressor, a co-stimulator, and accessory cells can significantly extend renal allograft survival.
Collapse
Affiliation(s)
- Meng Juan Xia
- Key Laboratory of Transplant Engineering and Immunology of the National Health and family Planning Committee of China, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Tse GH, Hughes J, Marson LP. Systematic review of mouse kidney transplantation. Transpl Int 2013; 26:1149-60. [PMID: 23786597 DOI: 10.1111/tri.12129] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 04/29/2013] [Accepted: 05/13/2013] [Indexed: 01/06/2023]
Abstract
A mouse model of kidney transplantation was first described in 1973 by Skoskiewicz et al. Although the mouse model is technically difficult, it is attractive for several reasons: the mouse genome has been characterized and in many aspects is similar to man and there is a greater diversity of experimental reagents and techniques available for mouse studies than other experimental models. We reviewed the literature on all studies of mouse kidney transplantation to report the donor and recipient strain combinations that have been investigated and the resultant survival and histological outcomes. Some models of kidney transplantation have used the transplanted kidney as a life-supporting organ, however, in many studies the recipient mouse's native kidney has been left in situ. Several different combinations of inbred mouse strains have been reported, with varying degrees of injury, survival or tolerance because of haplotype differences. This model has been exceptionally useful as an investigational tool to understand multiple aspects of transplantation including acute rejection, cellular and humoral rejection mechanisms and their treatment. Furthermore, this model has been used to investigate disease mechanisms beyond transplant rejection including intrinsic renal disease and infection-associated pathology.
Collapse
Affiliation(s)
- George Hondag Tse
- MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | | | | |
Collapse
|
|
7
|
Giannoukakis N, Trucco M. Dendritic cell therapy for Type 1 diabetes suppression. Immunotherapy 2013; 4:1063-74. [PMID: 23148758 DOI: 10.2217/imt.12.76] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
While dendritic cell-based therapy is a clinical reality for human malignancies, until now, some conceptual concerns have served to delay its consideration to treat human autoimmune diseases, even in light of almost two decades' worth of overwhelmingly supportive preclinical animal studies. This article provides an overview of the development of dendritic cell-based therapy for Type 1 diabetes mellitus, given that this is the best-studied autoimmune disorder and that there is a good understanding of the underlying immunology. This article also highlights data from the authors' pioneering Phase I clinical trial with tolerogenic dendritic cells, which hopes to motivate the clinical translation of other dendritic cell-based approaches, to one or more carefully selected Type 1 diabetic patient populations.
Collapse
Affiliation(s)
- Nick Giannoukakis
- Department of Pathology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Rangos Research Center, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | | |
Collapse
|
|
8
|
Gárate D, Rojas-Colonelli N, Peña C, Salazar L, Abello P, Pesce B, Aravena O, García-González P, Ribeiro CH, Molina MC, Catalán D, Aguillón JC. Blocking of p38 and transforming growth factor β receptor pathways impairs the ability of tolerogenic dendritic cells to suppress murine arthritis. ACTA ACUST UNITED AC 2013; 65:120-9. [PMID: 22972370 DOI: 10.1002/art.37702] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 09/04/2012] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Dendritic cells (DCs) modulated with lipopolysaccharide (LPS) are able to reduce inflammation when therapeutically administered into mice with collagen-induced arthritis (CIA). The aim of this study was to uncover the mechanisms that define the tolerogenic effect of short-term LPS-modulated DCs on CIA. METHODS Bone marrow-derived DCs were stimulated for 4 hours with LPS and characterized for their expression of maturation markers and their cytokine secretion profiles. Stimulated cells were treated with SB203580 or SB431542 to inhibit the p38 or transforming growth factor β (TGFβ) receptor pathway, respectively, or were left unmodified and, on day 35 after CIA induction, were used to inoculate mice. Disease severity was evaluated clinically. CD4+ T cell populations were counted in the spleen and lymph nodes from inoculated or untreated mice with CIA. CD4+ splenic T cells were transferred from mice with CIA treated with LPS-stimulated DCs or from untreated mice with CIA into other mice with CIA on day 35 of arthritis. RESULTS Treatment with LPS-stimulated DCs increased the numbers of interleukin-10 (IL-10)-secreting and TGFβ-secreting CD4+ T cells, but decreased the numbers of Th17 cells. Adoptive transfer of CD4+ T cells from treated mice with CIA reproduced the inhibition of active CIA accomplished with LPS-stimulated DCs. The therapeutic effect of LPS-stimulated DCs and their influence on T cell populations were abolished when the p38 and the TGFβ receptor pathways were inhibited. CONCLUSION DCs modulated short-term (4 hours) with LPS are able to confer a sustained cure in mice with established arthritis by re-educating the CD4+ T cell populations. This effect is dependent on the p38 and the TGFβ receptor signaling pathways, which suggests the participation of IL-10 and TGFβ in the recovery of tolerance.
Collapse
Affiliation(s)
- David Gárate
- University of Chile and Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Liu L, Li L, Min J, Wang J, Wu H, Zeng Y, Chen S, Chu Z. Butyrate interferes with the differentiation and function of human monocyte-derived dendritic cells. Cell Immunol 2012; 277:66-73. [PMID: 22698927 DOI: 10.1016/j.cellimm.2012.05.011] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 03/18/2012] [Accepted: 05/18/2012] [Indexed: 02/06/2023]
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that are uniquely capable of either inducing immune responses or maintaining a state of self-tolerance, depending on their stage of maturation. In the present study, we describe a way to interfere with DCs maturation. The compound butyrate can affect the differentiation of DCs generated from human monocytes and can inhibit T cell proliferation. We demonstrate that butyrate substantially down-regulates the expression of CD80, CD83, and MHC class II molecules; increases endocytic capability; reduces allostimulatory abilities; promote interleukin-10 (IL-10) production; and inhibits interleukin-12 (IL-12) and interferon-γ (IFN-γ) production. These results demonstrate a specific immune suppression property of butyrate and supports further investigation for butyrate as a new immunotherapeutic agent.
Collapse
Affiliation(s)
- Lu Liu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Current state of type 1 diabetes immunotherapy: incremental advances, huge leaps, or more of the same? Clin Dev Immunol 2011; 2011:432016. [PMID: 21785616 PMCID: PMC3139873 DOI: 10.1155/2011/432016] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Accepted: 04/28/2011] [Indexed: 01/09/2023]
Abstract
Thus far, none of the preclinically successful and promising immunomodulatory agents for type 1 diabetes mellitus (T1DM) has conferred stable, long-term insulin independence to diabetic patients. The majority of these immunomodulators are humanised antibodies that target immune cells or cytokines. These as well as fusion proteins and inhibitor proteins all share varying adverse event occurrence and severity. Other approaches have included intact putative autoantigens or autoantigen peptides. Considerable logistical outlays have been deployed to develop and to translate humanised antibodies targeting immune cells, cytokines, and cytokine receptors to the clinic. Very recent phase III trials with the leading agent, a humanised anti-CD3 antibody, call into question whether further development of these biologics represents a step forward or more of the same. Combination therapies of one or more of these humanised antibodies are also being considered, and they face identical, if not more serious, impediments and safety issues. This paper will highlight the preclinical successes and the excitement generated by phase II trials while offering alternative possibilities and new translational avenues that can be explored given the very recent disappointment in leading agents in more advanced clinical trials.
Collapse
|
|
11
|
Zimmer A, Luce S, Gaignier F, Nony E, Naveau M, Biola-Vidamment A, Pallardy M, Van Overtvelt L, Mascarell L, Moingeon P. Identification of a new phenotype of tolerogenic human dendritic cells induced by fungal proteases from Aspergillus oryzae. THE JOURNAL OF IMMUNOLOGY 2011; 186:3966-76. [PMID: 21368225 DOI: 10.4049/jimmunol.1003184] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We characterized a new pathway to induce tolerogenic dendritic cells (DCs) following treatment of human monocyte-derived DCs with proteases from the fungus Aspergillus oryzae (ASP). ASP-treated DCs (ASP-DCs) exhibit a CD80(-)CD83(-)CD86(-)Ig-like transcript (ILT)2(-)ILT3(-)ILT4(+) phenotype, do not secrete cytokines or chemokines, and express tolerogenic markers such as glucocorticoid-induced leucine zipper, NO synthetase-2, retinaldehyde dehydrogenase-1 or retinaldehyde dehydrogenase-2. When cocultured with naive CD4(+) T cells, ASP-DCs induce an anergic state that can be reversed by IL-2. Generated T cells mediate a suppressive activity in third-party experiments that is not mediated by soluble factors. A comparison between dexamethasone-treated DCs used as a reference for regulatory T cell-inducing DCs and ASP-DCs reveals two distinct phenotypes. In contrast to dexamethasone, ASP treatment induces glucocorticoid-induced leucine zipper independently of glucocorticoid receptor engagement and leads to NF-κB p65 degradation. Abrogation of protease activities in ASP using specific inhibitors reveals that aspartic acid-containing proteases are key inducers of regulatory genes, whereas serine, cysteine, and metalloproteases contribute to NF-κB p65 degradation. Collectively, those features correspond to a previously unreported anergizing phenotype for human DCs. Such regulatory mechanisms may allow fungi to downregulate host immune responses and provide clues for new approaches to treat proinflammatory disorders.
Collapse
|
|
12
|
Phillips B, Giannoukakis N, Trucco M. Dendritic cell-based therapy in Type 1 diabetes mellitus. Expert Rev Clin Immunol 2010; 5:325-39. [PMID: 20477010 DOI: 10.1586/eci.09.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Dendritic cell (DC) immunotherapy is a clinical reality. Despite two decades of considerable data demonstrating the feasibility of using DCs to prolong transplant allograft survival and to prevent autoimmunity, only now are these cells entering clinical trials in humans. Type 1 diabetes is the first autoimmune disorder to be targeted for treatment in humans using autologous-engineered DCs. This review will highlight the role of DCs in autoimmunity and the manner in which they have been engineered to treat these disorders in rodent models, either via the induction of immune hyporesponsiveness, which may be cell- and/or antigen-specific, or indirectly by upregulation of other immune cell networks.
Collapse
Affiliation(s)
- Brett Phillips
- University of Pittsburgh School of Medicine, Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA.
| | | | | |
Collapse
|
|
13
|
Induction of Donor-Specific T-Cell Hyporesponsiveness Using Dexamethasone-Treated Dendritic Cells in Two Fully Mismatched Rat Kidney Transplantation Models. Transplantation 2008; 86:1275-82. [DOI: 10.1097/tp.0b013e31818a6682] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
14
|
Anderson AE, Swan DJ, Sayers BL, Harry RA, Patterson AM, von Delwig A, Robinson JH, Isaacs JD, Hilkens CMU. LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells. J Leukoc Biol 2008; 85:243-50. [PMID: 18971286 PMCID: PMC2700018 DOI: 10.1189/jlb.0608374] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Autoimmune pathologies are caused by a breakdown in self-tolerance. Tolerogenic dendritic cells (tolDC) are a promising immunotherapeutic tool for restoring self-tolerance in an antigen-specific manner. Studies about tolDC have focused largely on generating stable maturation-resistant DC, but few have fully addressed questions about the antigen-presenting and migratory capacities of these cells, prerequisites for successful immunotherapy. Here, we investigated whether human tolDC, generated with dexamethasone and the active form of vitamin D3, maintained their tolerogenic function upon activation with LPS (LPS-tolDC), while acquiring the ability to present exogenous autoantigen and to migrate in response to the CCR7 ligand CCL19. LPS activation led to important changes in the tolDC phenotype and function. LPS-tolDC, but not tolDC, expressed the chemokine receptor CCR7 and migrated in response to CCL19. Furthermore, LPS-tolDC were superior to tolDC in their ability to present type II collagen, a candidate autoantigen in rheumatoid arthritis. tolDC and LPS-tolDC had low stimulatory capacity for allogeneic, naïve T cells and skewed T cell polarization toward an anti-inflammatory phenotype, although LPS-tolDC induced significantly higher levels of IL-10 production by T cells. Our finding that LPS activation is essential for inducing migratory and antigen-presenting activity in tolDC is important for optimizing their therapeutic potential.
Collapse
Affiliation(s)
- Amy E Anderson
- Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Sandovici M, Deelman LE, de Zeeuw D, van Goor H, Henning RH. Immune modulation and graft protection by gene therapy in kidney transplantation. Eur J Pharmacol 2008; 585:261-9. [DOI: 10.1016/j.ejphar.2008.02.087] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Revised: 01/25/2008] [Accepted: 02/06/2008] [Indexed: 01/20/2023]
|
|
16
|
Xiang J, Gu X, Zhou Y, Gong X, Qian S, Chen Z. Administration of dendritic cells modified by RNA interference prolongs cardiac allograft survival. Microsurgery 2007; 27:320-3. [PMID: 17477425 DOI: 10.1002/micr.20364] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Systemic administration of immature donor-dendritic cells (DC) that are deficient in co-stimulatory molecules delays the onset of allograft rejection. However, it is not easy to control culture condition and guarantee that the administered DC are in the immature stages, which obviously affects their therapeutic effect. In this study, we attempted to inhibit expression of CD86 on DC using an RNA interference technology. The function of CD86(low) DC was determined by the influence on their capacity to stimulate T cell proliferation and by the effect of DC systemic administration on survival of cardiac allografts. CD86(low) DC stimulated low T cell proliferative responses in vitro and administration of CD86(low) DC prolonged survival of heart allografts in vivo. These results suggest that RNA interference is a useful approach to modify DC function, which has potentials for clinical application.
Collapse
Affiliation(s)
- Jianbin Xiang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | | | | | | | | | | |
Collapse
|
|
17
|
Trucco M, Giannoukakis N. Immunoregulatory dendritic cells to prevent and reverse new-onset Type 1 diabetes mellitus. Expert Opin Biol Ther 2007; 7:951-63. [PMID: 17665986 DOI: 10.1517/14712598.7.7.951] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Herein, the authors provide an overview of where dendritic cells lie in the immunopathology of autoimmune Type 1 diabetes mellitus and how dendritic cell-based therapy may be usefully translated to treat and reverse the disease. The immunopathology of Type 1 diabetes mellitus offers a number of windows at which immunotherapy can be applied to delay, stop and even reverse the autoimmune processes, especially in light of the recent antibody-based accomplishment of improvement in residual beta-cell mass function. As in almost all cell-specific inflammatory processes, dendritic cells are central regulators of diabetes onset and progression. This realisation, along with accumulating data confirming a role for dendritic cells in maintaining and inducing tolerance in multiple therapeutic settings, has prompted a line of investigation to identify the most effective embodiments of dendritic cells for diabetes immunotherapy.
Collapse
Affiliation(s)
- Massimo Trucco
- Children's Hospital of Pittsburgh, Diabetes Institute, Pittsburgh, PA 15213, USA
| | | |
Collapse
|
|
18
|
Tschöke S, Oberholzer A. [Gene therapy for treatment of acute inflammatory immune response]. DER ORTHOPADE 2007; 36:259-64. [PMID: 17333067 PMCID: PMC7096085 DOI: 10.1007/s00132-007-1060-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Acute inflammation and the innate immune response to severe tissue trauma continue to pose a critical pathophysiological challenge in the intensive care regimen. Advances in the development of improved gene therapeutics and their application in diverse animal models of acute inflammation have shown promising results in reducing both morbidity and mortality. The introduction of inflammatory antagonists, by either viral or non-viral vectors, has thereby proven to play a significant role in determining the overall outcome. Recent findings of utilizing the functional characteristics of immunocompetent cells (e.g. dendritic cells) in combination with the gene therapy-induced overexpression of anti-inflammatory target proteins have significantly expanded this gene therapeutic spectrum. The results from diverse experiments in our own murine model of sepsis, in connection with findings from various other analogous international studies, have demonstrated great potential to revolutionize the clinical treatment concept and prevention of acute inflammatory diseases.
Collapse
Affiliation(s)
- S.K. Tschöke
- Zentrum für Spezielle Chirurgie des Bewegungsapparates, Klinik für Unfall- und Wiederherstellungschirurgie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | - A. Oberholzer
- Zentrum für Gelenk- und Sportchirurgie, Klinik Pyramide am See, Bellerivestraße 34, CH-8034 Zürich, Schweiz
| |
Collapse
|
|
19
|
Jiga LP, Ehser S, Kleist C, Opelz G, Terness P. Inhibition of Heart Allograft Rejection With Mitomycin C???Treated Donor Dendritic Cells. Transplantation 2007; 83:347-50. [PMID: 17297411 DOI: 10.1097/01.tp.0000248854.30016.11] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
We showed previously that dendritic cells (DCs) treated with mitomycin C (MMC) tolerize allogeneic T cells in vitro and this might be mediated by downregulation of CD80, CD86, and ICAM-1. Here we analyze the suppression of the T-cell response induced by MMC-DCs in vivo. Rats injected with allogeneic DCs developed a strong lymph node reaction, whereas MMC-DCs induced no reaction. The same effect was obtained when CD80, CD86, and ICAM-1 expressed by DCs were blocked with antibodies. One injection of donor MMC-DCs strongly prolonged heart allograft survival in a donor-specific manner. Suppression of rejection was also achieved when donor DCs were pretreated with a combination of anti-CD80, anti-CD86, and anti-ICAM-1 antibodies, showing that downregulation of these molecules confers the DCs inhibitory properties. We conclude that allogeneic MMC-DCs specifically inhibit the T-cell response in vivo and that downregulation of CD80, CD86, and ICAM-1 is a potential mechanism of this effect.
Collapse
Affiliation(s)
- Lucian P Jiga
- Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany.
| | | | | | | | | |
Collapse
|
|
20
|
Gu X, Xiang J, Yao Y, Chen Z. Effects of RNA interference on CD80 and CD86 expression in bone marrow-derived murine dendritic cells. Scand J Immunol 2007; 64:588-94. [PMID: 17083614 DOI: 10.1111/j.1365-3083.2006.01845.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
To investigate whether RNA interference (RNAi) induced by small interfering RNA (siRNA) could suppress CD80 and CD86 expression in bone marrow-derived murine dendritic cells (DC). The bone marrow-derived DC of mice were separated and cultured in vitro, chemically synthesized siRNA were then transferred into the cells by LipofectAMINE 2000, and the siRNA transfection efficacy was assessed by both fluorescence microscope and flow cytometry. The mRNA expression and protein synthesis were analysed by real-time RT-PCR and flow cytometry. The cell viability of transfected DC was determined by annexin V and propidium iodine staining. Transfection of bone marrow-derived murine DC with a non-silencing FITC-labelled control siRNA demonstrated a high (71.86%) transfection efficiency without affecting cellular viability. CD80-1 siRNA was the most effective siRNA to block CD80 expression in three candidates. Similarly, CD86-3 siRNA was extraordinarily effective in repressing the expression of CD86. Cotransfection of siRNA specific to CD80 and CD86 can enhance gene silencing that is not affected by DC activation-inducing signals. CD80 and CD86 siRNA suppressed the expression of CD80 and CD86 to 31.05 +/- 2.41% and 25.43 +/- 0.85%, respectively, of the level in untreated cells (P < 0.05). siRNA is capable of triggering RNAi in bone marrow-derived DC; it can specifically and effectively knock down CD80 and CD86 gene expression. This approach is a useful tool by which costimulatory molecules of DC can be studied as well as a potential therapeutic option for allograft rejection.
Collapse
Affiliation(s)
- X Gu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | | | | | | |
Collapse
|
|
21
|
Abstract
Dendritic cells (DCs) play a crucial role during the initiation of immune responses against non-self antigens. Following organ transplantation, activated donor- and recipient-derived DCs participate actively in graft rejection by sensitising recipient T cells via the direct or indirect pathways of allorecognition, respectively. There is increasing evidence that immature/semi-mature DCs induce antigen-specific unresponsiveness or tolerance to self antigens, both in central lymphoid tissue and in the periphery, through a variety of mechanisms (deletion, anergy and regulation). In the past few years, DC-based therapy of experimental allograft rejection has focused on ex vivo biological, pharmacological and genetic engineering of DCs to mimic/enhance their natural tolerogenicity. Successful outcomes in rodent models have built the case that DC-based therapy may provide a novel approach to transplant tolerance. Ongoing research into the role that DCs play in the induction of tolerance should allow for its clinical application in the near future.
Collapse
Affiliation(s)
- Mahyar Nouri-Shirazi
- Texas A&M University System Health Science Center, Baylor College of Dentistry, Department of Biomedical Sciences, Immunology Laboratory, 3302 Gaston Avenue, Dallas, TX 75246, USA.
| | | |
Collapse
|
|
22
|
Vanclée A, Schouten HC, Bos GMJ. Murine dendritic cells that are resistant to maturation are unable to induce tolerance to allogeneic stem cells. Transpl Immunol 2006; 16:8-13. [PMID: 16701170 DOI: 10.1016/j.trim.2006.03.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2006] [Accepted: 03/09/2006] [Indexed: 11/23/2022]
Abstract
Induction of donor-specific hyporesponsiveness would minimize the need for intensive immunosuppression in the clinical setting of graft rejection and dendritic cells (DCs) might be useful tools for this purpose. Besides their ability to induce immunogenic T-cell responses, these antigen presenting cells can lead to T-cell anergy, when antigen presentation occurs in the absence of costimulation as is the case in immature DCs (iDCs). In continuance of publications reporting on the use of iDCs to induce tolerance to various organs, we set out to determine whether tolerance could be induced in a model of allogeneic stem cell transplantation. Immature DCs were obtained by culture with very low concentrations of GM-CSF and by treating DCs with Dexamethasone (Dex). We show that these DCs express low levels of MHCII and costimulatory molecules and that this immature phenotype is retained after application of maturation stimuli. We also prove that these alternatively activated DCs are unable to induce T-cell proliferation in vitro. When used in vivo however, these tolerogenic DCs do not provide tolerance to fully mismatched or haploidentical stem cells.
Collapse
Affiliation(s)
- Ariane Vanclée
- Department of Internal Medicine, Division of Hematology and Oncology, University Hospital Maastricht, The Netherlands
| | | | | |
Collapse
|
|
23
|
Hackstein H. Modulation of Dendritic Cells for Tolerance Induction*. Transfus Med Hemother 2006. [DOI: 10.1159/000091105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
|
|
24
|
Yu K, Chen Z, Wang S, Gorczynski R. Decreased Alloreactivity Using Donor Cells from Mice Expressing a CD200 Transgene Under Control of a Tetracycline-Inducible Promoter. Transplantation 2005; 80:394-401. [PMID: 16082336 DOI: 10.1097/01.tp.0000168152.72560.82] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND CD200 delivers an immunsuppressive signal that augments allograft survival following interaction with its receptor, CD200R1. We hypothesized that mice overexpressing CD200 as a trangene would also show a diminished alloresponsiveness and decreased allograft rejection. METHODS A transgenic mouse on a C57BL/6 background, expressing a murine CD200 cDNA genetically linked to a green fluorescent protein tag (GFP) under control of a tetracycline response element (TRE), was mated with a commercial transgenic mouse carrying the reverse tetracycline regulated transactivator gene under control of a human CMV promoter. F1 mice were examined for induction of alloimmunity in vivo/in vitro, and for their ability to reject skin allografts in vivo. RESULTS The F1 hybrid expressed CD200 after exposure to doxycyline (DOX), as assessed both by enhanced GFP expression in multiple organs and CD200-GFP expression. Splenocytes from F1 mice stimulated with LPS or allogeneic cells in vitro in the presence/absence of DOX showed reduced production of TNFalpha, and of allospecific CTL. Splenocytes from F1 mice used as stimulator cells in allogeneic MLCs in the presence of DOX were inefficient at induction of cytokines or CTL in vitro from normal allogeneic responder cells. Skin grafts from transgenic mice were inefficient at induction of CTL in vivo. Transgenic mice receiving DOX showed prolonged acceptance of skin allografts, which was abolished by infusion of anti-CD200 mAb. CONCLUSIONS Our data confirmed that overexpression of CD200 in transgenic mice, or in skin grafts from these mice, decreases alloimmunity. This has potential clinical utility in transplantation and other diseases.
Collapse
Affiliation(s)
- Kai Yu
- The Toronto Hospital, University Health Network, Departments of Surgery and Immunology, University of Toronto, Toronto, Canada
| | | | | | | |
Collapse
|
|
25
|
Oberholzer C, Tschoeke SK, Bahjat K, LaFace D, Hutchins B, Clare-Salzler MJ, Moldawer LL, Oberholzer A. In vivo transduction of thymic dendritic cells with adenovirus and its potential use in acute inflammatory diseases. Scand J Immunol 2005; 61:309-15. [PMID: 15853912 DOI: 10.1111/j.1365-3083.2005.01574.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Dendritic cells (DC) represent a potential target for gene therapy. In their ability to process antigens and present them to T cells, DC have been allocated a unique role as initiators of the immune response in both the innate and acquired immunity. Recent in vitro studies have showed the feasibility of DC transduction with adenoviral recombinants. In cancer therapy, targeting of DC with adenovirus has been proved to be effective in inhibiting tumour growth, as well as in reducing the number of tumour metastases. The aim of our study is to evaluate the feasibility of in vivo transduction of DC in a murine lymphocyte-rich compartment (thymus) as a potential treatment for acute inflammatory diseases. Nearly 50% of the total thymic DC were transduced with a first-generation adenoviral construct following intrathymic injection, and post-transductional inflammation was neglectable. Transduction of thymic cells with adenoviral recombinants was able to induce the expression of an intracellular protein (beta-galactosidase, green fluorescent protein), as well as the secretion of human interleukin-10, within the local compartment. Furthermore, this induction of the latter significantly decreased thymic apoptosis in the applied model of acute bacterial peritonitis (cecal ligation and puncture).
Collapse
Affiliation(s)
- C Oberholzer
- Department of Trauma and Reconstructive Surgery, CHARITE- University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
| | | | | | | | | | | | | | | |
Collapse
|
|
26
|
van der Wouden EA, Sandovici M, Henning RH, de Zeeuw D, Deelman LE. Approaches and methods in gene therapy for kidney disease. J Pharmacol Toxicol Methods 2004; 50:13-24. [PMID: 15233963 DOI: 10.1016/j.vascn.2004.03.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2003] [Accepted: 03/08/2004] [Indexed: 11/22/2022]
Abstract
Renal gene therapy may offer new strategies to treat diseases of native and transplanted kidneys. Several experimental techniques have been developed and employed using nonviral, viral, and cellular vectors. The most efficient vector for in vivo transfection appears to be adenovirus. Glomeruli, blood vessels, interstitial cells, and pyelum can be transfected with high efficiency. In addition, electroporation and microbubbles with ultrasound, both being enhanced naked plasmid techniques, offer good opportunities. Trapping of mesangial cells into the glomeruli as well as natural targeting of monocytes or macrophages to inflamed kidneys are elegant methods for site-specific delivery of genes. For gene therapy in kidney transplantation, hemagglutinating virus of Japan liposomes are efficient vectors for tubular transfection, whereas enhanced naked plasmid techniques are suitable for glomerular transfection. However, adenovirus offers the best opportunities in a renal transplantation setup because varying parameters of graft perfusion allows targeting of different cell types. In renal grafts, lymphocytes can be used for selective targeting to sites of inflammation. In conclusion, for both in vivo and ex vivo renal transfection, enhanced naked plasmids and adenovirus offer the best perspectives for effective clinical application. Moreover, the development of safer, nonimmunogenic vectors and the large-scale production could make clinical renal gene therapy a realistic possibility for the near future.
Collapse
Affiliation(s)
- Els A van der Wouden
- Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
| | | | | | | | | |
Collapse
|
|
27
|
Morelli AE, Thomson AW. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunol Rev 2003; 196:125-46. [PMID: 14617202 DOI: 10.1046/j.1600-065x.2003.00079.x] [Citation(s) in RCA: 229] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Dendritic cells (DCs) are uniquely well-equipped antigen-presenting cells (APCs) regarded classically as sentinels of the immune response, which induce and regulate T-cell reactivity. They play critical roles in central tolerance and in the maintenance of peripheral tolerance in the normal steady state. Following cell or organ transplantation, DCs present antigen to T cells via the direct or indirect pathways of allorecognition. These functions of DCs set in train the rejection response, but they also serve as potential targets for suppression of alloimmune reactivity and promotion of tolerance induction. Much evidence from various model systems now indicates that DCs can induce specific T-cell tolerance. Although underlying mechanisms have not been fully elucidated, the capacity to induce T-regulatory cells may be an important property of tolerogenic or regulatory DCs. Efforts to generate "designer" DCs with tolerogenic properties in the laboratory using specific cytokines, immunologic or pharmacologic reagents, or genetic engineering approaches have already met with some success. Alternatively, targeting of DCs in vivo (e.g. by infusion of apoptotic allogeneic cells) to take advantage of their inherent tolerogenicity has also demonstrated exciting potential. The remarkable heterogeneity and plasticity of these important APCs present additional challenges to optimizing DC-based therapies that may lead to improved tolerance-enhancing strategies in the clinic.
Collapse
Affiliation(s)
- Adrian E Morelli
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
| | | |
Collapse
|
|
28
|
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. [PMID: 12823271 PMCID: PMC1808741 DOI: 10.1046/j.1365-2249.2003.02161.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2002] [Indexed: 01/07/2023] Open
Abstract
Dendritic cells (DC) are uniquely able to either induce immune responses or to maintain the state of self tolerance. Recent evidence has shown that the ability of DC to induce tolerance in the steady state is critical to the prevention of the autoimmune response. Likewise, DC have been shown to induce several type of regulatory T cells including Th2, Tr1, Ts and NKT cells, depending on the maturation state of the DC and the local microenvironment. DC have been shown to have therapeutic value in models of allograft rejection and autoimmunity, although no success has been reported in allergy. Several strategies, including the use of specific DC subsets, genetic modification of DC and the use of DC at various maturation stages for the treatment of allograft rejection and autoimmune disease are discussed. The challenge for the future use of DC therapy in human disease is to identify the appropriate DC for the proposed therapy; a task made more daunting by the extreme plasticity of DC that has recently been demonstrated. However, the progress achieved to date suggests that these are not insurmountable obstacles and that DC may become a useful therapeutic tool in transplantation and autoimmune disease.
Collapse
Affiliation(s)
- P A Morel
- Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | | | | | | |
Collapse
|
|
29
|
Woltman AM, van Kooten C. Functional modulation of dendritic cells to suppress adaptive immune responses. J Leukoc Biol 2003; 73:428-41. [PMID: 12660217 DOI: 10.1189/jlb.0902431] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In recent years, dendritic cells (DCs) have entered the center court of immune regulation. Dependent on their ontogeny, state of differentiation, and maturation and thereby a variable expression of membrane-bound and soluble molecules, DCs can induce immunostimulatory as well as immunoregulatory responses. This dual function has made them potential targets in vaccine development in cancer and infections as well as for the prevention and treatment of allograft rejection and autoimmune diseases. The present review is focused on the effect of immune-modulatory factors, such as cytokines and immunosuppressive drugs, and on the survival, differentiation, migration, and maturation of DC human subsets. A better understanding of DC immunobiology may lead to the development of specific therapies to prevent or dampen immune responses.
Collapse
Affiliation(s)
- Andrea M Woltman
- Department of Nephrology, Leiden University Medical Center, The Netherlands.
| | | |
Collapse
|
|
30
|
Kaneko K, Wang Z, Kim SH, Morelli AE, Robbins PD, Thomson AW. Dendritic cells genetically engineered to express IL-4 exhibit enhanced IL-12p70 production in response to CD40 ligation and accelerate organ allograft rejection. Gene Ther 2003; 10:143-52. [PMID: 12571643 DOI: 10.1038/sj.gt.3301872] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
C57BL/10 (B10; H2(b)) bone marrow-derived myeloid dendritic cells (DC) propagated in GM-CSF + IL-4 were transduced with r adenoviral (Ad) vectors encoding either control neomycin-resistance gene (Ad-Neo) or murine IL-4 (Ad-IL-4) on day 5 of culture following CD11c immunomagnetic bead purification. Both Ad-Neo- and Ad-IL-4-transduced DC displayed upregulated surface MHC class II and costimulatory molecules (CD40, CD80, CD86). Ad-IL-4 DC secreted higher levels of bioactive IL-12p70 after CD40 ligation or LPS stimulation than either Ad-Neo or unmodified DC. Only Ad-IL-4 DC produced IL-12p70 in primary MLR, in which they induced augmented proliferative responses of naïve allogeneic C3H/HeJ (C3H; H2(k)) T-cells. Compared with Ad-Neo DC, Ad-IL-4 DC were also more effective in priming naïve allogeneic recipients to exhibit specifically enhanced anti-donor T-cell proliferative and CTL responses. T-cells primed in vivo 7 days previously with Ad-IL-4 DC displayed enhanced secretion of Th2 (IL-4, IL-10) but also higher Th1 cytokine (IFNgamma) production following ex vivo challenge with donor alloAg. Moreover, pretreatment of vascularized heart graft recipients with i.v. Ad-IL-4 DC, 1 week before transplant, significantly accelerated rejection and antagonized the therapeutic effect of anti-CD40L (CD154) mAb. These data contrast markedly with recently reported inhibitory effects of autologous Ad-IL-4 DC on autoimmune inflammatory disease.
Collapse
Affiliation(s)
- K Kaneko
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | | | | | | | | | | |
Collapse
|
|
31
|
Takayama T, Kaneko K, Morelli AE, Li W, Tahara H, Thomson AW. Retroviral delivery of transforming growth factor-beta1 to myeloid dendritic cells: inhibition of T-cell priming ability and influence on allograft survival. Transplantation 2002; 74:112-9. [PMID: 12134108 DOI: 10.1097/00007890-200207150-00019] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Transforming growth factor (TGF)-beta inhibits the maturation and function of antigen-presenting cells. Our purpose was to evaluate the impact of retroviral delivery of human TGF-beta1 to murine myeloid dendritic cell (DC) progenitors on (i) their in vitro properties, (ii) their in vivo function, and (iii) their influence on organ allograft survival. METHODS C57BL10 (B10; H2b) bone marrow cells were lineage depleted and stimulated with granulocyte-macrophage colony-stimulating factor for 6 days. Replicating DC progenitors were transduced on days 2, 3, and 4 of culture by ecotropic retrovirus encoding human TGF-beta1 using centrifugal enhancement. Secretion of TGF-beta1 and other cytokines was quantified by enzyme immunoassay. Allogeneic C3H/HeJ (C3H; H2k) T-cell proliferative responses and generation of cytotoxic T lymphocytes in mixed leukocyte reaction were determined by [3H]thymidine incorporation and 51Cr release assays, respectively. DC migration was analyzed by immunohistochemistry, and their impact on survival of intra-abdominal heart transplants was determined. RESULTS Maximal TGF-beta1 transduction efficiency was 60%. The TGF-beta-transduced DC showed pronounced impairment (>80%) of T-cell allostimulatory activity in vitro. After their IV injection, B10 TGF-beta-transduced DC (IAb+) were detected in T-cell areas of spleens of allogeneic C3H recipients. Splenic T-cell responses to donor alloantigens of mice that received TGF-beta-transduced DC were severely impaired. This was accompanied by marked inhibition of interleukin-2 and interferon-gamma production in response to restimulation with donor alloantigen. Survival of B10 cardiac allografts in C3H mice given B10 TGF-beta-transduced DC (2x106 IV, 7 days before transplantation), was extended modestly but significantly. CONCLUSION Retroviral transduction of myeloid DC progenitors to overexpress TGF-beta is associated with marked impairment of their T-cell allostimulatory activity but with only modest prolongation of organ allograft survival.
Collapse
Affiliation(s)
- Takuya Takayama
- Thomas E. Starzl Transplantation Institute, and Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA
| | | | | | | | | | | |
Collapse
|
|
32
|
Affiliation(s)
- P Toby H Coates
- Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, PA 15213, USA
| | | |
Collapse
|
|
33
|
Bickerstaff AA, Wang JJ, Pelletier RP, Orosz CG. Murine renal allografts: spontaneous acceptance is associated with regulated T cell-mediated immunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 167:4821-7. [PMID: 11673485 DOI: 10.4049/jimmunol.167.9.4821] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
It was shown >20 yr ago that mice will spontaneously accept renal allografts in the absence of immunosuppression, but the mechanism responsible for this is not understood. We transplanted DBA/2 (H-2(d)) kidneys into nephrectomized C57BL/6 (H-2(b)) mice, and the allografts were spontaneously accepted for >60 days without immunosuppression. In contrast, nonimmunosuppressed cardiac and skin allografts in the same strain combination are rejected within approximately 10 days. The accepted renal allografts have a prominent leukocytic infiltrate, suggesting an ongoing, local immune response. At 60 days post-transplant, the recipients of accepted renal allografts display DBA/2-reactive alloantibodies. They also display DBA/2-reactive delayed-type hypersensitivity responses that are actively counter-regulated by DBA/2-induced TGF-beta production, but not by IL-10 production. These data suggest that a donor-reactive, cell-mediated immune mechanism involving TGF-beta is associated with the spontaneous acceptance of renal allografts in mice.
Collapse
Affiliation(s)
- A A Bickerstaff
- Department of Surgery, Ohio State University College of Medicine, Columbus, OH 43210, USA.
| | | | | | | |
Collapse
|
|
34
|
Abstract
Dendritic cells (DC) are professional antigen (Ag)-presenting cells considered traditionally as the passenger leukocytes that, after migration from transplanted tissues, stimulate allospecific naive T cell responses and trigger acute rejection. However, there is recent evidence that, besides their role in central T lymphocyte deletion in the thymus, DC perform a crucial function to induce/maintain peripheral T cell tolerance. This paper outlines conceptual models that try to explain how DC may induce/maintain tolerance. It also considers how such ideas have been implemented recently in an effort to generate tolerogenic DC to induce donor Ag-specific tolerance/ immunosuppression and prolonged allograft survival. These approaches include genetic engineering of donor- or recipient-derived DC to express molecules capable of promoting tolerance to alloAg.
Collapse
Affiliation(s)
- A E Morelli
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
| | | | | |
Collapse
|
|
35
|
Hackstein H, Morelli AE, Thomson AW. Designer dendritic cells for tolerance induction: guided not misguided missiles. Trends Immunol 2001; 22:437-42. [PMID: 11473833 DOI: 10.1016/s1471-4906(01)01959-7] [Citation(s) in RCA: 100] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play crucial roles as initiators and modulators of adaptive immune responses. Although DC-based vaccines have been utilized successfully to generate cytolytic T-cell activity against tumor antigens (Ags), evidence has accumulated that DCs also have potent capabilities to tolerize T cells in an Ag-specific manner. DCs cultured in the laboratory can suppress auto- or alloimmunity. Current and prospective strategies to promote this inherent tolerogenic potential of DCs might prove to be important for the therapy of transplant rejection and autoimmune diseases.
Collapse
Affiliation(s)
- H Hackstein
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, W1544 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | | | | |
Collapse
|