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      Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

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      Targeting Genetically Modified Macrophages to the Glomerulus

      review-article
      ,
      Cardiorenal Medicine
      S. Karger AG
      Inflammation, Glomerulonephritis, Adenovirus, Gene, Macrophages

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          Abstract

          Macrophages are key players in the development of the majority of renal diseases and are therefore ideal cellular vectors for site specifically targeting gene therapy to inflamed glomeruli. Macrophages can be genetically modified using viral vectors ex vivo then re-introduced into the body where they can home to the diseased site. This review summarises current experience in efficiently targeting modified macrophages to the inflamed glomerulus focussing on the factors controlling macrophage localisation, macrophage gene transfer methods, in vivo gene delivery and results of recent investigations using modified macrophage gene therapy for glomerular disease.

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          Most cited references4

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          Is Open Access

          Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis.

          Macrophages are intimately involved in the development of immune-mediated inflammation, including glomerulonephritis. We have transduced primary cultures of macrophages to express IL-10 and tested the ability of these cells to control rat nephrotoxic nephritis (NTN), a model of human glomerulonephritis. Ad-IL-10-transduced bone-marrow-derived macrophages (BMDM) produced large amounts of IL-10 in culture, and their TNF-alpha production was decreased in response to interferon-gamma and LPS. Transduced macrophages were injected into the renal artery of rats, 6 h after the induction of NTN, where they localized efficiently to inflamed rat glomeruli. Delivery of IL-10-expressing macrophages to nephritic rats produced a marked reduction in albuminuria compared with unmodified NTN or injection of Ad-null-transduced BMDM. IL-10 treatment decreased the number of glomerular ED1- and ED3-positive cells, MHC class II expression, and the number of fibrinoid lesions. Interestingly, anti-inflammatory changes in the Ad-IL-10-injected kidney were mirrored by changes in the contralateral kidney. These results highlight that Ad-IL-10-transduced macrophages infiltrate inflamed glomeruli and reduce the severity of glomerular inflammation, emphasizing the value of local delivery of genetically modified macrophages in the manipulation of inflammatory disease.
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            Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury in mouse Goodpasture syndrome

            T Yokoo (2001)
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              Prophylaxis of antibody-induced acute glomerulonephritis with genetically modified bone marrow-derived vehicle cells.

              Glomerulonephritis is an inflammatory disease of the renal glomerulus, which often progresses either slowly or rapidly, ending in renal death despite the availability of various antiinflammatory drugs. Gene therapy may be a promising method of suppressing the progression of glomerulonephritis through the blockage of key inflammatory molecule(s). However, the difficulty of local gene delivery into the glomerulus has made the clinical use of gene therapy difficult. As a solution to this issue, we applied a novel ex vivo technique that may allow site-specific gene delivery into the inflamed site and thus suppress local inflammation in the glomerulus, and examined the feasibility of this system as a prophylaxis of glomerulonephritis. The gene encoding the antiinflammatory cytokine interleukin 1 receptor antagonist (IL-1ra) was delivered into animal models of inflamed glomeruli evoked by anti-glomerular basement membrane antibody; this animal model is an analog of the human Goodpasture syndrome. Vehicle cells did indeed accumulate in the glomeruli on the induction of nephritis and were confirmed to secrete recombinant IL-1ra. Renal functions as well as morphology were preserved by this intervention for up to 14 days after IL-1ra introduction. These data demonstrate the possible application of gene therapy for acute glomerulonephritis. A gene encoding an antiinflammatory molecule, IL-1 receptor antagonist, was delivered into inflamed glomeruli, using a technique that may allow site-specific gene delivery into inflamed tissues. The progression of experimental acute glomerulonephritis was effectively suppressed by this intervention for at least 14 days after gene introduction. This success may strengthen the rationale for gene therapy in the treatment of inflammatory diseases such as glomerulonephritis.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2003
                August 2003
                17 November 2004
                : 94
                : 4
                : e113-e118
                Affiliations
                Department of Medicine and Therapeutics, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland
                Article
                72494 Nephron Exp Nephrol 2003;94:e113–e118
                10.1159/000072494
                12972709
                122c6d09-4d2a-4011-b3a5-c44dd1c6fbe8
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 1, References: 20, Pages: 1
                Categories
                Minireview

                Cardiovascular Medicine,Nephrology
                Inflammation,Glomerulonephritis,Adenovirus,Gene,Macrophages
                Cardiovascular Medicine, Nephrology
                Inflammation, Glomerulonephritis, Adenovirus, Gene, Macrophages

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