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Effects of Adoptive Transfer of Tolerogenic Dendritic Cells on Allograft Survival in Organ Transplantation Models: An Overview of Systematic Reviews. J Immunol Res 2016; 2016:5730674. [PMID: 27547767 PMCID: PMC4980535 DOI: 10.1155/2016/5730674] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 05/06/2016] [Accepted: 05/12/2016] [Indexed: 02/05/2023] Open
Abstract
Objective. To dissect the efficacy of Tol-DC therapy with or without IS in multiple animal models of transplantation. Methods and Results. PubMed, Medline, Embase, and the Cochrane Library were searched for reviews published up to April 2015. Six systematic reviews and a total of 61 articles were finally included. Data were grouped by organ transplantation models and applied to meta-analysis. Our meta-analysis shows that Tol-DC therapy successfully prolonged allograft survival to varying extents in all except the islet transplantation models and with IS drugs further prolonged the survival of heart, skin, and islet allografts in mice, but not of heart allografts in rats. Compared with IS drugs alone, Tol-DC therapy with IS extended islet allograft survival in rats but failed to influence the survival of skin, small intestine, and heart allografts in rats or of heart and skin allografts in mice. Conclusion. Tol-DC therapy significantly prolonged multiple allograft survival and further prolonged survival with IS. However, standardized protocols for modification of Tol-DC should be established before its application in clinic.
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Ritter T, Pleyer U. Novel gene therapeutic strategies for the induction of tolerance in cornea transplantation. Expert Rev Clin Immunol 2014; 5:749-64. [DOI: 10.1586/eci.09.59] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Dendritic cell-based approaches for therapeutic immune regulation in solid-organ transplantation. J Transplant 2013; 2013:761429. [PMID: 24307940 PMCID: PMC3824554 DOI: 10.1155/2013/761429] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 09/16/2013] [Indexed: 12/18/2022] Open
Abstract
To avoid immune rejection, allograft recipients require drug-based immunosuppression, which has significant toxicity. An emerging approach is adoptive transfer of immunoregulatory cells. While mature dendritic cells (DCs) present donor antigen to the immune system, triggering rejection, regulatory DCs interact with regulatory T cells to promote immune tolerance. Intravenous injection of immature DCs of either donor or host origin at the time of transplantation have prolonged allograft survival in solid-organ transplant models. DCs can be treated with pharmacological agents before injection, which may attenuate their maturation in vivo. Recent data suggest that injected immunosuppressive DCs may inhibit allograft rejection, not by themselves, but through conventional DCs of the host. Genetically engineered DCs have also been tested. Two clinical trials in type-1 diabetes and rheumatoid arthritis have been carried out, and other trials, including one trial in kidney transplantation, are in progress or are imminent.
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Wu W, Shan J, Li Y, Luo L, Sun G, Zhou Y, Yang T, Xia M, Guo Y, Feng L. Adoptive transfusion of tolerance dendritic cells prolongs the survival of cardiac allograft: a systematic review of 44 basic studies in mice. J Evid Based Med 2012; 5:139-53. [PMID: 23672221 DOI: 10.1111/j.1756-5391.2012.01191.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE Tolerogenic DCs (Tol-DCs), a group of cells with imDC phenotype, can stably induce T cells low-reactivity and immune tolerance. We systematically reviewed the adoptive transfusion of Tol-DCs induced by different ways to prolong cardiac allograft survival and its possible mechanism. METHOD MEDLINE (1966 to March 2011), EMbase (1980 to March 2011), and ISI (inception to March 2011) were searched for identification of relevant studies. We used allogeneic heart graft survival time as endpoint outcome to analyze the effect of adoptive transfusion of Tol-DC on cardiac allograft. By integrating studies' information, we summarized the mechanisms of Tol-DC in prolonging cardiac grafts. RESULTS Four methods were used to induce Tol-DC in all of the 44 included studies including gene-modified, drug-intervened, cytokine-induced, and other-derived (liver-derived & spleen-derived) DCs. The results showed that all types of Tol-DC can effectively prolong graft survival, and the average extension of graft survival time for each group was as follows: 22.02 ± 21.9 days (3.2 folds to control group) in the gene modified group, 25.94 ± 16.9 days (4.3 folds) in the drug-intervened groups, 9.00 ± 8.13 days (1.9 folds) in the cytokine-induced group, and 10.69 ± 9.94 days (2.1 folds) in the other-derived group. The main mechanisms of Tol-DCs to prolong graft survival were as follows: (1) induceT-cell hyporeactivity (detected by MLR); (2) reduce the effect of cytotoxic lymphocyte (CTL); (3) promote Th2 differentiation; (4) induce Treg; (5) induce chimerism. CONCLUSION For fully MHC mismatched allogeneic heart transplant recipients of inbred mouse, adoptive transfusion of Tol-DC, which can be gene-modified, drug-intervened, cytokine-induced, spleen-derived or liver-derived, can clearly prolong the survival of cardiac allograft or induce immune tolerance. Gene-modified and drug-induced Tol-DC can prolong graft survival most obviously. Having better reliability and stability than drug-induction, gene-modification is the best way to induce Tol-DCs at present. One-time intravenous infusion of 2 × 10(6) Tol-DC is a simple and feasible way to induce long-term graft survival. Multiple infusions will prolong it but increase the risk and cost. Adoptive transfusion of Tol-DC in conjunction with immunosuppressive agents may also prolong the graft survival time.
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Affiliation(s)
- Wenqiao Wu
- Key Laboratory of Transplant Engineering and Immunology of Health Ministry of China, Regenerative medical research center, West China Hospital, Sichuan University, Chengdu, China
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Haider HK, Mustafa A, Feng Y, Ashraf M. Genetic Modification of Stem Cells for Improved Therapy of the Infarcted Myocardium. Mol Pharm 2011; 8:1446-57. [DOI: 10.1021/mp2001318] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Husnain Kh. Haider
- Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio 45267
| | - Anique Mustafa
- Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio 45267
| | - Yuliang Feng
- Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio 45267
| | - Muhammad Ashraf
- Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio 45267
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Wang H, Zhang L, Kung SKP. Emerging applications of lentiviral vectors in dendritic cell-based immunotherapy. Immunotherapy 2010; 2:685-95. [DOI: 10.2217/imt.10.44] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Dendritic cells are professional antigen-presenting cells that initiate, regulate and shape the induction of specific immune responses. The ability to use dendritic cells in the induction of antigen-specific tolerance, antigen-specific immunity or specific differentiation of T-helper subsets holds great promise in dendritic cell-based immunotherapy of various diseases such as cancer, viral infections, allergy, as well as autoimmunity. Replication-incompetent HIV-1-based lentiviral vector is now emerging as a promising delivery system to genetically modify dendritic cells through antigen recognition, costimulatory molecules and/or polarization signals for the manipulation of antigen-specific immunity in vivo. This article discusses some of the recent advances in the uses of lentiviral vectors in dendritic cell-based immunotherapy.
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Affiliation(s)
- Huiming Wang
- University of Manitoba, Department of Immunology, Room 417 Apotex Center, 750 McDermot Avenue, Winnipeg, Manitoba, R3E 0T5, Canada
| | - Liang Zhang
- University of Manitoba, Department of Immunology, Room 417 Apotex Center, 750 McDermot Avenue, Winnipeg, Manitoba, R3E 0T5, Canada
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7
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Programmed death-1 signaling is essential for the skin allograft protection by alternatively activated dendritic cell infusion in mice. Transplantation 2010; 88:864-73. [PMID: 19935456 DOI: 10.1097/tp.0b013e3181b6ea74] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Alternatively activated dendritic cell (aaDC) can prolong allograft survival in the mouse model. However, the molecular mechanism(s) by which these DCs function to regulate alloreactive T-cell responses remains to be clearly defined. METHODS Bone marrow-derived DCs were incubated in the presence of interleukin (IL)-10 (immature DC), stimulated with lipopolysaccharide only (mature DC), or pretreated with IL-10 and then activated with lipopolysaccharide (aaDC). These cells were compared for their phenotypes and regulatory capacities both in vitro and in vivo. In addition, programmed death-1 (PD-1)/PD-L pathway was blocked to test its contribution to the regulatory function of aaDC. RESULTS The expression of surface major histocompatibility complex class II, CD80, and CD86 on aaDC was lower than that on mDC, whereas aaDC had a higher expression of PD-L1 and PD-L2 compared with immature DC or untreated DC. In vitro co-culture of aaDC with allogeneic T cells led to a significant decrease in the T-cell response as well as a reduction of interferon-gamma secretion and an enhanced IL-10 production while CD4 CD25 Foxp3 T cells were expanded. Interestingly, these regulatory effects of aaDC were partially abolished when PD-1/PD-L pathway was blocked using anti-PD-1 blocking antibody. Infusion of BALB/c donor-derived aaDC into naive C57BL/6 recipients resulted in a significantly prolonged skin allograft survival, which was, at least in part, PD-1/PD-L pathway dependent. CONCLUSION Our data indicate that the PD-1/PD-L pathway plays an important role in aaDC-mediated prolongation of skin allograft survival.
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8
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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: 107] [Impact Index Per Article: 6.3] [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.
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Affiliation(s)
- Amy E Anderson
- Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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9
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Yang DF, Qiu WH, Zhu HF, Lei P, Wen X, Dai H, Zhou W, Shen GX. CTLA4-Ig-modified dendritic cells inhibit lymphocyte-mediated alloimmune responses and prolong the islet graft survival in mice. Transpl Immunol 2008; 19:197-201. [PMID: 18667318 DOI: 10.1016/j.trim.2008.05.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2008] [Revised: 04/30/2008] [Accepted: 05/02/2008] [Indexed: 11/15/2022]
Abstract
The induction of antigen specific tolerance is critical for prevention and treatment of allograft rejection. In this study, we transfected CTLA4-Ig gene into dendritic cells (DCs), and investigated their effect on inhibition of lymphocyte activity in vitro and induction of immune tolerance on pancreatic islet allograft in mice. An IDDM C57BL/6 murine model induced by streptozotocin is as model mouse. The model mice were transplanted of the islet cells isolated from the BALB/c mice to their kidney capsules, and injected of CTLA4-Ig modified DCs (mDCs). The results showed that mDCs could significantly inhibit T lymphocyte proliferation and induce its apoptosis; whereas, unmodified DCs (umDCs) promoted the murine lymphocyte proliferation. Compared with injection of umDCs and IgG1 modified DCs, the injection of mDCs prolonged IDDM mice's allograft survival, and normalized their plasma glucose (PG) levels within 3 days and maintained over 2 weeks. The level of IFN-gamma was lower and the level of IL-4 was higher in mDCs treated recipient mice than that in control mice, it indicated that mDCs led to Th1/Th2 deviation. After 7 days of islet transplantation, HE stain of the renal specimens showed that the islets and kidneys were intact in structure, and islet cells numbers are increased in mDCs treated mice. Our studies suggest that DCs expressing CTLA4-Ig fusion protein can induce the immune tolerance to islet graft and prolong the allograft survival through the inhibition of T cell proliferation in allogeneic mice.
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Affiliation(s)
- Dao-Feng Yang
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
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Abstract
In recent years, considerable attention has been given to immune tolerance and its potential clinical applications for the treatment of cancers and autoimmune diseases, and the prevention of allo-graft rejection and graft-versus-host diseases. Advances in our understanding of the underlying mechanisms of establishment and maintenance of immune tolerance in various experimental settings and animal models, and in our ability to manipulate the development of various immune tolerogenic cells in vitro and in vivo, have generated significant momentum for the field of cell-based tolerogenic therapy. This review briefly summarizes the major tolerogenic cell populations and their mechanisms of action, while focusing mainly on potential exploitation of their tolerogenic mechanisms for clinical applications.
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Affiliation(s)
- Ping-Ying Pan
- Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA
| | - Junko Ozao
- Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA
| | - Zuping Zhou
- Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA
| | - Shu-Hsia Chen
- Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA
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Xiao BG, Zhu WH, Lu CZ. The presence of GM-CSF and IL-4 interferes with effect of TGF-beta1 on antigen presenting cells in patients with multiple sclerosis and in rats with experimental autoimmune encephalomyelitis. Cell Immunol 2007; 249:30-6. [PMID: 18061154 DOI: 10.1016/j.cellimm.2007.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2007] [Revised: 10/22/2007] [Accepted: 10/23/2007] [Indexed: 11/29/2022]
Abstract
The possibility to generate and expand tolerogenic dendritic cells (DC) with TGF-beta1 in vitro opens new therapeutic perspectives for the treatment of autoimmune diseases. In the present study, GM-CSF+IL-4 induced the differentiation of DC from adherent peripheral blood mononuclear cells, which had a higher expression of HLA-DR, CD86 and CD1a and the capacity to stimulate T cells. TGF-beta1 alone slightly promoted the generation of antigen presenting cells (APC) with higher expression of CD14, but did not differentiate them into E-cadherin+Langerhans cell (LC)-like DC. TGF-beta1-driven APC exhibited the morphology, phenotypes and functions of tolerogenic immature DC, and had lower capacity to stimulate T cells. In vivo experiment demonstrates that TGF-beta1-treated APC exhibited the therapeutic potential in Lewis rats with experimental autoimmune encephalomyelitis (EAE), followed by increase of IL-10 production in lymph nodes and decrease of inflammatory cells in spinal cords. Most importantly, GM-CSF/IL-4 used in DC preparation abolished the effect of TGF-beta1 to induce tolerogenic APC in vitro and in vivo. The results reveal that the usage of GM-CSF for the generation of tolerogenic DC should not be copied from DC preparation for anti-tumor therapy.
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Affiliation(s)
- Bao-Guo Xiao
- Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China.
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12
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Lan YY, Wang Z, Raimondi G, Wu W, Colvin BL, de Creus A, Thomson AW. "Alternatively activated" dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig. THE JOURNAL OF IMMUNOLOGY 2006; 177:5868-77. [PMID: 17056511 DOI: 10.4049/jimmunol.177.9.5868] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2(d)) mouse bone marrow progenitors in IL-10 and TGF-beta, then stimulated the cells with LPS. These "alternatively activated" (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (B7-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4+Foxp3+ cells were expanded. The AADC-expanded allogeneic CD4+CD25+ T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged subsequent heart graft survival. This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC. Transfer of CD4+ T cells from recipients of long-surviving grafts (>100 days) that were infiltrated with CD4+Foxp3+ cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ transplantation.
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Affiliation(s)
- Yuk Yuen Lan
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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13
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Cheng O, Thuillier R, Sampson E, Schultz G, Ruiz P, Zhang X, Yuen PST, Mannon RB. Connective tissue growth factor is a biomarker and mediator of kidney allograft fibrosis. Am J Transplant 2006; 6:2292-306. [PMID: 16889607 DOI: 10.1111/j.1600-6143.2006.01493.x] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Chronic allograft nephropathy (CAN) is a leading cause of kidney graft failure following transplantation. Its causes are complex and include both immunological and nonimmunological factors. Here we have studied the development of CAN in a mouse model of kidney transplantation comparing isografts and allografts. Unlike the normal histology and normal serum creatinine of the uninephrectomized, nonrejecting isografted mice (0.219 +/- 0.024 mg/dL), allografted mice demonstrated severe renal dysfunction (mean serum creatinine 0.519 +/- 0.061 mg/dL; p < 0.005) with progressive inflammation and fibrosis of the kidney. These animals also showed an increased expression of connective tissue growth factor (CTGF), both systemically and within the graft. CTGF was highly expressed in tubuloepithelial cells of allografts, along with alpha-smooth muscle actin, a marker of myofibroblasts, and transcriptionally associated with other markers of fibrosis. In vitro studies of tubular epithelium indicate that CTGF is capable of inducing EMT, independent of TGF-beta. Finally, in human transplant recipients, serum and urine CTGF levels are significantly elevated compared to naïve individuals. Urinary levels correlated with the histological presence of CAN. These studies suggest a critical role of CTGF in graft fibrogenesis, for both mouse and man. Thus, CTGF has potential as a biomarker of CAN, and also a therapeutic target in managing graft fibrosis.
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MESH Headings
- Animals
- Biomarkers/metabolism
- Biopsy
- Blotting, Western
- Cells, Cultured
- Connective Tissue Growth Factor
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Fibrosis/complications
- Fibrosis/metabolism
- Fibrosis/pathology
- Gene Expression
- Graft Rejection/complications
- Graft Rejection/metabolism
- Graft Rejection/pathology
- Humans
- Immediate-Early Proteins/genetics
- Immediate-Early Proteins/immunology
- Immediate-Early Proteins/metabolism
- Insulin-Like Growth Factor Binding Proteins/metabolism
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/immunology
- Intercellular Signaling Peptides and Proteins/metabolism
- Kidney Failure, Chronic/etiology
- Kidney Failure, Chronic/metabolism
- Kidney Failure, Chronic/pathology
- Kidney Transplantation/pathology
- Kidney Tubules/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Polymerase Chain Reaction
- RNA, Messenger/genetics
- Transplantation, Homologous
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Affiliation(s)
- O Cheng
- Transplantation Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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14
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Abstract
Bioregulators are naturally occurring organic compounds that regulate a multitude of biologic processes. Under natural circumstances, bioregulators are synthesized in minute quantities in a variety of living organisms and are essential for physiologic homeostasis. In the wrong hands, these compounds have the capability to be used as nontraditional threat agents that are covered by the prohibitions of the Chemical Weapons Convention and the Biological and Toxin Weapons Convention. Unlike traditional biowarfare/bioterrorism agents that have a latency period of hours to days,the onset of action of bioregulators may occur within minutes after host exposure. Concerns regarding the potential misuse of bioregulators for nefarious purposes relate to the ability of these nontraditional agents to induce profound physiologic effects.
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Affiliation(s)
- Elliott Kagan
- Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
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15
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Abstract
The dramatic improvements in short-term graft survival and acute rejection rates could only have been dreamed of 20 years ago. Late graft loss following kidney transplantation is now the critical issue of this decade. Frequently, graft loss is associated with the development of tubular atrophy and interstitial fibrosis within the kidney (i.e. chronic allograft nephropathy; CAN). Major treatment strategies in this disorder are non-specific and the focus of intervention has been on limiting injurious events. Following graft injury is a fibrogenesis phase featuring both proliferative and infiltrative responses mediated by chemokines, cytokines and growth factors. In particular, TGFbeta has been strongly implicated in the pathogenesis of chronic injury and epithelial-mesenchymal transformation (EMT) may be part of this process. The cascade of events results in matrix accumulation, due to either increased production and/or reduced degradation of matrix. Recent investigations into the pathogenesis of tissue fibrosis have suggested a number of new strategies to ameliorate matrix synthesis. While the majority of therapies have focused on TGFbeta, this may not be an ideal maneuver in transplant settings and alternative targets identified in other fibrotic diseases will be discussed. Attacking graft fibrosis should be a new focus in organ transplantation.
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Affiliation(s)
- R B Mannon
- Transplantation Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
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16
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Clarke JH, Cha JY, Walsh MD, Harken AH, McCarter MD. Dendritic cells as therapeutic adjuncts in surgical disease. Surgery 2005; 138:844-50. [PMID: 16291384 DOI: 10.1016/j.surg.2005.02.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2004] [Accepted: 02/13/2005] [Indexed: 12/22/2022]
Affiliation(s)
- Jason H Clarke
- Department of Surgery, University of Colorado Health Sciences Center, Denver, CO 80262, USA
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Cheng J, Xia SS, Xie S, Tang LG, Shi XF. Transforming Growth Factor β1–Modified Donor Cell Transfusion Induced Allo-Heart Tolerance. Transplant Proc 2005; 37:2360-4. [PMID: 15964416 DOI: 10.1016/j.transproceed.2005.03.106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2004] [Indexed: 11/22/2022]
Abstract
The therapeutic value of the transforming growth factor beta 1 (TGF-beta1) in transplantation has been reported; however, cell-mediated gene therapy using TGF-beta1 is not a widespread application in organ transplantation. This study was performed to evaluate whether TGF-beta1-modified donor spleen cell-specific transfusion could induce tolerogenicity and prolong allograft survival in rat heterotopic heart transplantation. Stable TGF-beta1-transduced spleen cells were established. Wistar rat splenic T-cell responses to donor spleen cells that received TGF-beta1-transduced were severely impaired. Survival of Sprague-Dawley cardiac allografts in Wistar rats given TGF-beta1-modified donor spleen cells (5 x 10(6), 7 days before transplantation), was extended modestly but significantly. Liposome transduction of donor spleen cells to overexpress TGF-beta1 is associated with marked impairment of their T-cell allostimulatory activity but only modest prolongation of allo-heart survival.
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Affiliation(s)
- J Cheng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, People's Republic of China.
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18
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Li M, Qian H, Ichim TE, Ge WW, Popov IA, Rycerz K, Neu J, White D, Zhong R, Min WP. Induction of RNA interference in dendritic cells. Immunol Res 2005; 30:215-30. [PMID: 15477662 DOI: 10.1385/ir:30:2:215] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Dendritic cells (DC) reside at the center of the immunological universe, possessing the ability both to stimulate and inhibit various types of responses. Tolerogenic/regulatory DC with therapeutic properties can be generated through various means of manipulations in vitro and in vivo. Here we describe several attractive strategies for manipulation of DC using the novel technique of RNA interference (RNAi). Additionally, we overview some of our data regarding yet undescribed characteristics of RNAi in DC such as specific transfection strategies, persistence of gene silencing, and multi-gene silencing. The advantages of using RNAi for DC genetic manipulation gives rise to the promise of generating tailor-made DC that can be used effectively to treat a variety of immunologically mediated diseases.
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Affiliation(s)
- Mu Li
- Department of Surgery, Microbiology and Immunology, The University of Western Ontario, Canada
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19
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Taner T, Hackstein H, Wang Z, Morelli AE, Thomson AW. Rapamycin-treated, alloantigen-pulsed host dendritic cells induce ag-specific T cell regulation and prolong graft survival. Am J Transplant 2005; 5:228-36. [PMID: 15643982 DOI: 10.1046/j.1600-6143.2004.00673.x] [Citation(s) in RCA: 209] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Tolerogenic properties of dendritic cells (DC), particularly those in the immature state, and their therapeutic potential are increasingly being recognized. Among several distinct approaches to generate stably immature DC, pharmacologic manipulation stands out as a promising and clinically applicable option. We have shown recently that the immunophilin ligand rapamycin (Rapa) can inhibit DC maturation and their effector functions. Here, we examined the impact of Rapa exposure on subsequent alloantigen (Ag) presentation by myeloid DC via the indirect pathway. Rapa-treated, allogeneic lysate-pulsed host DC (Rapa-DC) were inferior stimulators of syngeneic T cells, compared to lysate-pulsed control DC. Rapa exposure did not block alloAg uptake by DC nor impair their in vivo homing to splenic T cell areas after adoptive transfer. T cells primed by Rapa-treated, alloAg-pulsed DC showed decreased capacity to produce IL-2 and IFNgamma, and were hyporesponsive to subsequent challenge via both the direct and indirect pathways, in an Ag-specific manner. When infused 1 week before transplantation, these Rapa-DC significantly prolonged alloAg-specific heart graft survival. This effect was reversed by systemic IL-2 administration but enhanced by either repeated infusion of the cells or a short post-transplant course of FK506. These therapeutic effects, achieved by targeting both major pathways of allorecognition, provide the basis for a clinically applicable strategy to suppress graft rejection.
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Affiliation(s)
- Timuçin Taner
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA, USA
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20
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Yang L, Liang J, Yao G, Chen P, Hou Y. 17β-estradiol regulates the numbers, endocytosis, stimulative capacity and IL-10 secretion of mouse spleen dendritic cells. Toxicol Lett 2005; 155:239-46. [PMID: 15603918 DOI: 10.1016/j.toxlet.2004.09.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2004] [Revised: 09/17/2004] [Accepted: 09/23/2004] [Indexed: 11/17/2022]
Abstract
The 17beta-estradiol (17beta-E2) is a steroid sex hormone that has a profound influence on the immune cells in inducing the apoptosis of both T and B lymphocytes. In this study, mouse spleen dendritic cells (SDCs) were treated with 17beta-E2 and the numbers, endocytosis, stimulative capacity and cytokine production of SDCs were analysed. The results showed that 17beta-E2 reduced the proliferation and stimulative capacity of SDCs and increased the endocytosis of SDCs in a dose-dependent pattern. 17beta-E2 up-regulated IL-10 mRNA level in SDCs in a dose-dependent manner except for the 24 h time point. These data suggest that 17beta-E2 may regulate the physiological and pathological immune response by reducing the number and stimulation of SDCs, increasing their endocytosis and IL-10 mRNA expression at the same time.
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Affiliation(s)
- Linsong Yang
- Immunology and Reproductive Biology Lab, Medical School, Nanjing University, 22 Hankou Road, Nanjing 210093, PR China
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21
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Newland A, Kireta S, Russ G, Krishnan R. Ovine dendritic cells transduced with an adenoviral CTLA4eEGFP fusion protein construct induce hyporesponsiveness to allostimulation. Immunology 2004; 113:310-7. [PMID: 15500617 PMCID: PMC1782587 DOI: 10.1111/j.1365-2567.2004.01966.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
CTLA4 (CD152) is a transmembrane molecule expressed on activated T cells and functions as a negative regulator of T cell activation upon binding to the costimulatory molecules CD80/86. In this study, CTLA4eEGFP constructs were engineered by cloning the extracellular domains of ovine and human CTLA4 (CTLA4e) 'in frame' with the enhanced green fluorescent protein (EGFP). Recombinant adenoviral vectors were generated by incorporation of the CTLA4eEGFP sequence into the adenoviral genome using homologous recombination in Esherichia coli. The functional activity of the adenoviral vectors was shown by the secretion of the CTLA4eEGFP upon infection of ovine fibroblasts and the binding of the fusion protein to the target ovine and human dendritic cells expressing CD80/86 receptors by flow cytometry. The EGFP tag facilitated molecular size determinations and quantification of the secreted ovine CTLA4 fusion protein by immunoprecipitation and enzyme-linked immunosorbent assay (ELISA), respectively, using anti-GFP mAbs. Ovine dendritic cells obtained from pseudoafferent lymphatic cannulation of sheep were characterized based on high major histocompatibility complex (MHC) class II expression and cross-reactivity with monoclonal antibodies to the human dendritic cell markers, CD83 and CMRF-56. In addition, ovine dendritic cells (DC) were transfected with the adenoviral CTLA4eEGFP and when used as stimulators in a mixed lymphocyte reaction showed a reduced capacity to induce allogeneic lymphocyte proliferation. This study verifies that the ovine CTLA4eEGFP fusion protein functions similarly to its human homologue and that DC modified with adenoviral CTLA4-EGFP may provide an effective therapeutic approach in targeting alloreactive T cells to prolong allograft acceptance in a preclinical ovine model of renal transplantation.
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Affiliation(s)
- Ashley Newland
- Transplantation Immunology Laboratory, Basil Hetzel Institute, The Queen Elizabeth HospitalWoodville
- Department of Medicine, University of AdelaideSouth Australia, Australia
| | - Svjetlana Kireta
- Transplantation Immunology Laboratory, Basil Hetzel Institute, The Queen Elizabeth HospitalWoodville
| | - Graeme Russ
- Transplantation Immunology Laboratory, Basil Hetzel Institute, The Queen Elizabeth HospitalWoodville
- Department of Medicine, University of AdelaideSouth Australia, Australia
| | - Ravi Krishnan
- Transplantation Immunology Laboratory, Basil Hetzel Institute, The Queen Elizabeth HospitalWoodville
- Department of Medicine, University of AdelaideSouth Australia, Australia
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22
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Kempster S, Collins ME, Edington N. Time of transforming growth factor beta 1 inoculation alters the incubation of BSE in mice. Neuroreport 2004; 15:2233-6. [PMID: 15371740 DOI: 10.1097/00001756-200410050-00018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Groups of 20 C57BL/6J mice (10 males and 10 females) were given BSE strain 301C i.p. and subsequently given 2 microg recombinant human TGFbeta1 s.c. at single or multiple times. There was a significant positive correlation between the day of TGFbeta1 administration and incubation time; the later TGFbeta1 was administered after BSE inoculation the longer the incubation time became. The administration of TGFbeta1 at any time point did not significantly alter the distribution or severity of pathology. The effects of TGFbeta1 on BSE pathogenesis appears to be dependent upon its time of administration; early administration shortens the incubation time and late administration lengthens the incubation time.
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Affiliation(s)
- S Kempster
- Royal Veterinary College, Department of Pathology and Infectious diseases, Royal College Street, London, NW1 0TU, UK.
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23
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Xu MQ, Suo YP, Gong JP, Zhang MM, Yan LN. Prolongation of liver allograft survival by dendritic cells modified with NF-κB decoy oligodeoxynucleotides. World J Gastroenterol 2004; 10:2361-8. [PMID: 15285020 PMCID: PMC4576289 DOI: 10.3748/wjg.v10.i16.2361] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To induce the tolerance of rat liver allograft by dendritic cells (DCs) modified with NF-κB decoy oligodeoxynucleotides (ODNs).
METHODS: Bone marrow (BM)-derived DCs from SD rats were propagated in the presence of GM-CSF or GM-CSF + IL-4 to obtain immature DCs or mature DCs. GM-CSF+IL-4-propagated DCs were treated with double-strand NF-κB decoy ODNs containing two NF-κB binding sites or scrambled ODNs to ascertain whether NF-κB decoy ODNs might prevent DC maturation. GM-CSF-propagated DCs, GM-CSF + NF-κB decoy ODNs or scrambled ODNs-propagated DCs were treated with LPS for 18 h to determine whether NF-κB decoy ODNs could prevent LPS-induced IL-12 production in DCs. NF-κB binding activities, costimulatory molecule (CD40, CD80, CD86) surface expression, IL-12 protein expression and allostimulatory capacity of DCs were measured with electrophoretic mobility shift assay (EMSA), flow cytometry, Western blotting, and mixed lymphocyte reaction (MLR), respectively. GM-CSF-propagated DCs, GM-CSF + IL-4 -propagated DCs, and GM-CSF + NF-κB decoy ODNs or scrambled ODNs-propagated DCs were injected intravenously into recipient LEW rats 7 d prior to liver transplantation and immediately after liver transplantation. Histological grading of liver graft rejection was determined 7 d after liver transplantation. Expression of IL-2, IL-4 and IFN-γ mRNA in liver graft and in recipient spleen was analyzed by semiquantitative RT-PCR. Apoptosis of liver allograft-infiltrating cells was measured with TUNEL staining.
RESULTS: GM-CSF-propagated DCs, GM-CSF+NF-κB decoy ODNs-propagated DCs and GM-CSF+ scrambled ODNs-propagated DCs exhibited features of immature DCs, with similar low level of costimulatory molecule(CD40, CD80, CD86) surface expression, absence of NF-κB activation, and few allocostimulatory activities. GM-CSF + IL-4-propagated DCs displayed features of mature DCs, with high levels of costimulatory molecule (CD40, CD80, CD86) surface expression, marked NF-κB activation, and significant allocostimulatory activity. NF-κB decoy ODNs completely abrogated IL-4-induced DC maturation and allocostimulatory activity as well as LPS-induced NF-κB activation and IL-12 protein expression in DCs. GM-CSF + NF-κB decoy ODNs-propagated DCs promoted apoptosis of liver allograft-infiltrating cells within portal areas, and significantly decreased the expression of IL-2 and IFN-γ mRNA but markedly elevated IL-4 mRNA expression both in liver allograft and in recipient spleen, and consequently suppressed liver allograft rejection, and promoted liver allograft survival.
CONCLUSION: NF-κB decoy ODNs-modified DCs can prolong liver allograft survival by promoting apoptosis of graft-infiltrating cells within portal areas as well as down-regulating IL-2 and IFN-γ mRNA and up-regulating IL-4 mRNA expression both in liver graft and in recipient spleen.
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Affiliation(s)
- Ming-Qing Xu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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24
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Sun W, Wang Q, Zhang L, Liu Y, Zhang M, Wang C, Wang J, Cao X. Blockade of CD40 pathway enhances the induction of immune tolerance by immature dendritic cells genetically modified to express cytotoxic T lymphocyte antigen 4 immunoglobulin. Transplantation 2004; 76:1351-9. [PMID: 14627915 DOI: 10.1097/01.tp.0000083557.25887.ee] [Citation(s) in RCA: 26] [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
BACKGROUND Immature dendritic cells (DCs) have the tolerogenic potential to induce alloantigen-specific immune tolerance. Cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) gene-modified immature DCs have been shown to maintain their tolerogenicity and prolong allograft survival to some extent. We investigated whether blockade of CD40 pathway by anti-CD40 ligand (L) monoclonal antibody (mAb) could enhance the immune tolerance induction by immature DCs genetically modified to express CTLA4Ig (DC-CTLA4Ig). METHODS The tolerogenic properties of DC-CTLA4Ig were analyzed. In the vascularized heterotopic heart transplantation murine model, 2 x 10(6) DC-CTLA4Ig were infused intravenously into recipients, with or without a concomitant administration of anti-CD40L mAb 7 days before transplantation. Host responses to donor alloantigen were quantified by mixed leukocyte reaction and CTL assays. Donor major histocompatibility complex class II (Iab) expression in recipient lymph nodes was detected posttransplantation by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS The allostimulatory activity of DC-CTLA4Ig was reduced. DC-CTLA4Ig also induced alloantigen-specific T-cell hyporesponsiveness and polarized T helper 2 cytokine production. Pretreatment of the recipients with DC-CTLA4Ig modestly prolonged allograft survival, without long-term allograft acceptance. Combined administration of DC-CTLA4Ig and anti-CD40L mAb significantly prolonged cardiac allograft survival, with long-term (>100 days) survival of 50% of the allografts in the pretreated recipients. More potent donor-specific inhibition of immune response against alloantigens and increased microchimerism were observed in these recipients. CONCLUSIONS Blockade of CD40 pathway with anti-CD40L mAb potentiates the tolerogenic potential of DC-CTLA4Ig and enhances the induction of antigen-specific immune tolerance more effectively.
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Affiliation(s)
- Wenji Sun
- Institute of Immunology, Zhejiang University, Hangzhou, China
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25
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Zhu M, Wei MF, Liu F, Shi HF, Wang G. Interleukin-10 modified dendritic cells induce allo-hyporesponsiveness and prolong small intestine allograft survival. World J Gastroenterol 2003; 9:2509-12. [PMID: 14606086 PMCID: PMC4656530 DOI: 10.3748/wjg.v9.i11.2509] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether IL-10-transduced dendritic cells (DCs) could induce tolerogenicity and prolong allograft survival in rat intestinal transplantation.
METHODS: Spleen-derived DCs were prepared and genetically modified by hIL-10 gene. The level of IL-10 expression was quantitated by ELISA. DC function was assessed by MTT in mixed leukocyte reaction. Allogeneic T-cell apoptosis was examined by flow cytometric analysis. Seven days before heterotopic intestinal transplantation, 2 × 106 donor-derived IL-10-DC were injected intravenously, then transplantation was performed between SD donor and Wistar recipient.
RESULTS: Compared with untransduced DC, IL-10-DC could suppress allogeneic mixed leukocyte reaction (MLR). The inhibitory effect was the most striking with the stimulator/effector (S/E) ratio of 1:10. The inhibition rate was 33.25%, 41.19% (P < 0.01) and 22.92% with the S/E ratio of 1:1, 1:10 and 1:50 respectively. At 48 h and 72 h by flow cytometry counting, apoptotic T cells responded to IL-10-DC in MLR were 13.8% and 30.1%, while untransduced group did not undergo significant apoptosis (P < 0.05). IL-10-DC pretreated recipients had a moderate survival prolongation with a mean allograft survival of 19.8 d (P < 0.01), compared with 7.3 ± 2.4 d in control group and 8.3 ± 2.9 d in untransduced DC group. Rejection occurred in the control group within three days. The difference between untreated DC group and control group was not significant.
CONCLUSION: IL-10-DC can induce allogenic T-cell hyporesponsiveness in vitro and apoptosis may be involved in it. IL-10-DC pretreatment can prolong intestinal allograft survival in the recipient.
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Affiliation(s)
- Min Zhu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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26
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Beagley KW, Gockel CM. Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY 2003; 38:13-22. [PMID: 12900050 DOI: 10.1016/s0928-8244(03)00202-5] [Citation(s) in RCA: 297] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Women mount more vigorous antibody- and cell-mediated immune responses following either infection or vaccination than men. The incidence of most autoimmune diseases is also higher in women than in men; however, during pregnancy many autoimmune diseases go into remission, only to flare again in the early post-partum period. Successful pregnancy requires that the female immune system tolerate the presence of a semi-allogeneic graft for 9 months. Oral contraceptive use can increase susceptibility to certain genital tract infections and sexually transmitted diseases in women. Moreover, treatment of mice and rats with female sex hormones is required to establish animal models of genital tract Chlamydia, Neisseria and Mycoplasma infection. This review describes what is currently known about the effects of the female sex hormones oestradiol and progesterone on innate and adaptive immune responses in order to provide a framework for understanding these sex differences. Data from both human and animal studies will be reviewed.
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Affiliation(s)
- Kenneth W Beagley
- School of Biomedical Sciences, The University of Newcastle, Royal Newcastle Hospital, Newcastle, NSW 2300, Australia.
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27
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Ding CL, Yao K, Zhang TT, Zhou F, Xu L, Xu JY. Generation of cytotoxic T cell against HBcAg using retrovirally transduced dendritic cells. World J Gastroenterol 2003; 9:1512-5. [PMID: 12854153 PMCID: PMC4615494 DOI: 10.3748/wjg.v9.i7.1512] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Cytotoxic T lymphocytes (CTLs) play an important role in resolving HBV infection. In the present study, we attempted to evaluate the efficiency of bone marrow-derived dendritic cells (DCs) transduced with recombinant retroviral vector bearing hepatitis B virus (HBV) core gene and the capability of generating CTLs against HBcAg by genetically modified DCs in vivo.
METHODS: A retroviral vector containing HBV core gene was constructed. Replicating DC progenitor of C57BL/6 mice was transduced by retroviral vector and continually cultured in the presence of recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and interleukin-4(IL-4) for 6 d. LPS was added and cultured for additional two days. The efficiency of gene transfer was determined by PCR, Western blot and FACS. Transduced DCs immunized C57BL/6 mice subcutaneously 2 times at an one-week interval. Intracellular IFN-γ and IL-4 of immunized mice lymphocytes were analyzed. Generation of CTLs in lymphocytes stimulated with mitomycin C-treated EL4-C cell which stably expresses HBcAg was determined by LDH release assays.
RESULTS: Recombinant retroviral expression vector (pLCSN) was positively detected by PCR as well as enzyme digestion with EcoRI and BamH I. Retroviruses were generated by pLCSN transfection packing cell and the virus titer was 3 × 105 CFU/ml. Indirect immunofluorescence and FACS showed that HBV core gene was expressed in murine fibroblasts. Transduced bone marrow cells had capability of differentiating into DCs in vitro in the presence of rmGM-CSF and rmIL-4. The result of PCR showed that HBV core gene was integrated into the genome of transduced DCs. Western blot analysis showed that HBV core gene was expressed in DCs. The transduction rate was 28% determined by FACS. Retroviral transduction had no influence on DCs expressions of CD80 and MHC class II. HBcAg specific CTLs and Th1 type immune responses could be generated in the mice by using transduced DCs as antigen presenting cells (APCs).
CONCLUSION: Retroviral transduction of myeloid DCs progenitors expresses efficiently HBcAg, and genetically modified DCs evoke a higher CTLs response than HBcAg in vivo.
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Affiliation(s)
- Chuan-Lin Ding
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
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28
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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.
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Affiliation(s)
- P A Morel
- Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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29
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Hoves S, Krause SW, Halbritter D, Zhang HG, Mountz JD, Schölmerich J, Fleck M. Mature but not immature Fas ligand (CD95L)-transduced human monocyte-derived dendritic cells are protected from Fas-mediated apoptosis and can be used as killer APC. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 170:5406-13. [PMID: 12759415 DOI: 10.4049/jimmunol.170.11.5406] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Several in vitro and animal studies have been performed to modulate the interaction of APCs and T cells by Fas (CD95/Apo-1) signaling to delete activated T cells in an Ag-specific manner. However, due to the difficulties in vector generation and low transduction frequencies, similar studies with primary human APC are still lacking. To evaluate whether Fas ligand (FasL/CD95L) expressing killer APC could be generated from primary human APC, monocyte-derived dendritic cells (DC) were transduced using the inducible Cre/Loxp adenovirus vector system. Combined transduction of DC by AdLoxpFasL and AxCANCre, but not single transduction with these vectors, resulted in dose- and time-dependent expression of FasL in >70% of mature DC (mDC), whereas <20% of immature DC (iDC) expressed FasL. In addition, transduction by AdLoxpFasL and AxCANCre induced apoptosis in >80% of iDC, whereas FasL-expressing mDC were protected from FasL/Fas (CD95/Apo-1)-mediated apoptosis despite coexpression of Fas. FasL-expressing mDC eliminated Fas(+) Jurkat T cells as well as activated primary T cells by apoptosis, whereas nonactivated primary T cells were not deleted. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC and cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC, cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. The present results demonstrate that FasL-expressing killer APC can be generated from human monocyte-derived mDC using adenoviral gene transfer. Our results support the strategy to use killer APCs as immunomodulatory cells for the treatment of autoimmune disease and allograft rejection.
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Affiliation(s)
- Sabine Hoves
- Department of Internal Medicine I, Regensburg, Germany
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30
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Hwang JS, Chung HK, Bae EK, Lee AY, Ji HJ, Park DW, Jung HJ, Cho CW, Choi HJ, Lee DS, Lee KR, Youn HJ. The polysaccharide fraction AIP1 from Artemisia iwayomogi suppresses apoptotic death of the mouse spleen cells in culture. Arch Pharm Res 2003; 26:294-300. [PMID: 12735687 DOI: 10.1007/bf02976958] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
A polysaccharide fraction, AIP1, purified from Artemisia iwayomogi was shown to have immunomodulating and anti-tumor activities in mice. In order to determine how the AIP1 fraction exhibits the immunomodulating activity, the effect of the fraction on the apoptosis of mouse spleen cells was investigated. Treatment of the mouse spleen cells with the AIP1 fraction resulted in the suppression of apoptotic death and an extension of cell survival in culture, indicating that the fraction might modulate the death of spleen cells. Treatment of the mice with the AIP1 fraction in vivo also resulted in less apoptosis of the spleen cells, which indicates the physiological relevance of the anti-apoptosis effect of the fraction in vitro. A mouse gene array was used to determine the profile of the gene expression change showing a pattern of up- and down-regulated genes by the AIP1 treatment. This study provides preliminary information regarding the immunomodulatory mechanism of the AIP1 fraction.
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Affiliation(s)
- Jung Suk Hwang
- Department of Microbiology, School of Biotechnology & Biomedical Science, Inje University, Gimhae, Gyungnam 621-749, Korea
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Abstract
One major complication facing organ transplant recipients is the requirement for life-long systemic immunosuppression to prevent rejection, which is associated with an increased incidence of malignancy and susceptibility to opportunistic infections. Gene therapy has the potential to eliminate problems associated with immunosuppression by allowing the production of immunomodulatory proteins in the donor grafts resulting in local rather than systemic immunosuppression. Alternatively, gene therapy approaches could eliminate the requirement for general immunosuppression by allowing the induction of donor-specific tolerance. Gene therapy interventions may also be able to prevent graft damage owing to nonimmune-mediated graft loss or injury and prevent chronic rejection. This review will focus on recent progress in preventing transplant rejection by gene therapy.
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Affiliation(s)
- J Bagley
- Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
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32
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Ahn H, Kim JY, Lee HJ, Kim YK, Ryu JH. Inhibitors of inducible nitric oxide synthase expression from Artemisia iwayomogi. Arch Pharm Res 2003; 26:301-5. [PMID: 12735688 DOI: 10.1007/bf02976959] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Nitric oxide (NO) is an important bioactive agent that mediates a wide variety of physiological and pathophysiological events. NO overproduction by inducible nitric oxide synthase (iNOS) results in severe hypotension and inflammation. This investigation is part of a study to discover new iNOS inhibitors from medicinal plants using a macrophage cell culture system. Two sesquiterpenes (1 and 2) were isolated from Artemisia iwayomogi (Compositae) and were found to inhibit NO synthesis (IC50 3.64 microg/mL and 2.81 microg/mL, respectively) in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Their structures were identified as 3-O-methyl-isosecotanapartholide (1) and iso-secotanapartholide (2). Compounds 1 and 2 inhibited the LPS-induced expression of the iNOS enzyme in the RAW 264.7 cells. The inhibition of NO production via the down regulation of iNOS expression may substantially modulate the inflammatory responses.
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Affiliation(s)
- Hanna Ahn
- College of Pharmacy, Sookmyung Womens University, Seoul 140-742, Korea
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Franceschini N, Cheng O, Zhang X, Ruiz P, Mannon RB. Inhibition of prolyl-4-hydroxylase ameliorates chronic rejection of mouse kidney allografts. Am J Transplant 2003; 3:396-402. [PMID: 12694061 DOI: 10.1034/j.1600-6143.2003.00081.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Interstitial fibrosis, glomerulosclerosis and arteriosclerosis are the major components of chronic allograft nephropathy (CAN), the leading cause of late graft failure after transplantation. To investigate the mechanism of collagen deposition in CAN, we studied the effects of prolyl-hydroxylase inhibitor (PHI), an enzyme essential for collagen formation, using a mouse model of kidney transplantation. Kidneys from H-2b mice were transplanted into MHC-incompatible H-2d recipients (allografts) and at 3 weeks post-transplant, received either PHI or vehicle treatment daily for 3 weeks. At 6 weeks post-transplant, GFR was significantly improved in the allografts receiving PHI (3.3 +/- 0.5 mL/min/kg) compared with those receiving vehicle (1.8 +/- 0.5 mL/min/kg, p < 0.05), while renal function was relatively unimpaired in the nonrejecting isografts (6.45 +/- 0.53 mL/min/kg). Allografts had histologic changes of CAN but the severity was significantly reduced with PHI treatment compared with vehicle, with reductions in interstitial inflammation and fibrosis. Furthermore, TGFâ and connective tissue growth factor mRNA expression was enhanced in both allograft groups compared with the isografts. In conclusion, PHI-treated allografts had improved renal function and reduced the severity of renal injury as a result of CAN. Inhibition of matrix synthesis may be a useful adjunct in ameliorating the development of CAN in humans.
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Affiliation(s)
- Nora Franceschini
- Department of Medicine, Division of Nephrology, Duke and Durham VA Medical Centers, Durham, North Carolina, USA
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