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      Prolongation of Corneal Allograft Survival by Topical Application of Everolimus in Experimental Keratoplasty

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          Abstract

          Background: Everolimus is a novel proliferation signal inhibitor that has potent immunosuppressive activity. As previously shown, systemic administration of the drug could effectively enhance the mean survival time (MST) of corneal allografts. Commonly, the topical application of immunomodulatory agents is preferred over systemic use, in order to reduce the side effects. Purpose: To investigate the efficacy of topically applied everolimus to prevent corneal graft rejection in an experimental model. Methods: A total of 45 female Lewis rats received 3.5-mm grafts of MHCI/II incompatible Dark Agouti donors. Recipients were randomly assigned to receive either: (1) 0.05% everolimus microemulsion, (2) 0.025% everolimus microemulsion or (3) a vehicle as the control. Treatment was started on the day of surgery and applied 5 times daily. Grafts were graded every day and a rejection score was generated based on cornea clarity and oedema. Results: Local administration of 0.05 or 0.025% everolimus was effective in prolonging the mean survival time of corneal grafts (MST = 21 ± 6.57 days and 16.4 ± 2.3 days, respectively) as compared to vehicle control group (MST = 13.3 ± 1.7 days; p < 0.001 and p < 0.001). Real-time PCR demonstrated that topical administration of everolimus increased the mRNA levels of CD25, IL-10 and IFN-γ, but this was significant only for IL-10 (p = 0.015). Conclusions: These data indicate that topically applied everolimus is effective in prolonging corneal allograft survival in an experimental keratoplasty model.

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          Most cited references 26

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          Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by bone marrow-derived dendritic cells.

          Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that use 2 major pathways for antigen uptake: constitutive macropinocytosis and mannose receptor-mediated endocytosis. Efficient endocytosis is critical for DCs to fulfill their sentinel function in immunity. We investigated the influence of the immunosuppressive macrolide rapamycin on macropinocytosis of fluorescein isothiocyanate (FITC)-albumin and mannose receptor-mediated endocytosis of FITC-dextran by murine bone marrow-derived DCs by flow cytometry. The data show that (1) at a low, physiologically relevant concentration (1 ng/mL), rapamycin impairs macropinocytosis and mannose receptor-mediated endocytosis; (2) the effects are independent of DC maturation and can be demonstrated specifically in immature CD11c(+) major histocompatibility complex (MHC) class II(lo) DCs by 3-color flow cytometry; (3) inhibition of endocytosis is not related to apoptotic cell death; and (4) molar excess of the structurally related molecule FK506 inhibits the actions of rapamycin. The inhibitory effects of rapamycin on DC endocytosis were confirmed in vivo. To our knowledge, this is the first report that a clinically relevant immunosuppressant inhibits DC endocytosis.
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            The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation.

            Vascular smooth muscle cells (VSMC) in mature, normal blood vessels exhibit a differentiated, quiescent, contractile morphology, but injury induces a phenotypic modulation toward a proliferative, dedifferentiated, migratory phenotype with upregulated extracellular matrix protein synthesis (synthetic phenotype), which contributes to intimal hyperplasia. The mTOR (the mammalian target of rapamycin) pathway inhibitor rapamycin inhibits intimal hyperplasia in animal models and in human clinical trials. We report that rapamycin treatment induces differentiation in cultured synthetic phenotype VSMC from multiple species. VSMC treated with rapamycin assumed a contractile morphology, quantitatively reflected by a 67% decrease in cell area. Total protein and collagen synthesis were also inhibited by rapamycin. Rapamycin induced expression of the VSMC differentiation marker contractile proteins smooth muscle (SM) alpha-actin, calponin, and SM myosin heavy chain (SM-MHC), as observed by immunoblotting and immunohistochemistry. Notably, we detected a striking rapamycin induction of calponin and SM-MHC mRNA, suggesting a role for mTOR in transcriptional control of VSMC gene expression. Rapamycin also induced expression of the cyclin-dependent kinase inhibitors p21(cip) and p27(kip), consistent with cell cycle withdrawal. Rapamycin inhibits mTOR, a signaling protein that regulates protein synthesis effectors, including p70 S6K1. Overexpression of p70 S6K1 inhibited rapamycin-induced contractile protein and p21(cip) expression, suggesting that this kinase opposes VSMC differentiation. In conclusion, we report that regulation of VSMC differentiation is a novel function of the rapamycin-sensitive mTOR signaling pathway.
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              Regulatory CD25+ T cells in human kidney transplant recipients.

              Recent evidence suggests that a population of professional regulatory cells, which limit immune responsiveness, exist in rodents and healthy human subjects. However, their role in disease states remains unclear. A proportion of renal transplant recipients do not demonstrate in vitro reactivity toward their mismatched donor-derived HLA-DR antigens; it was therefore hypothesized that this may be due to such regulatory cells. A cohort of 23 renal transplant recipients was studied at a single institution. In patients with no history of acute rejection, 6 (40%) of 15 demonstrated regulation toward the mismatched HLA-DR allopeptides by CD25(+) cells. By contrast, only one (12.5%) in eight of those with a history of acute rejection demonstrated regulation. Interestingly, if the patient assays were stratified according to initial in vitro immune responsiveness toward the mismatched allopeptides, 8 (47.1%) of 17 of patient assays with low allopeptide responsiveness (alloreactive T cell frequencies less than 60/million) demonstrated regulation of indirect pathway alloresponses by CD25(+) cells, whereas 0 of 8 with higher responses (frequencies greater than 60/million) demonstrated no such regulation (P < 0.05 by chi(2) test). The regulatory cells are present in the circulation as early as 3 mo after transplantation and persist for a number of years, despite conventional immunosuppression. Furthermore, induction treatment with anti-IL-2R mAb did not prevent the development of these regulatory CD25(+) cells. Data from two patients suggest that these cells may also play a role in preventing epitope shifting, implicated in the ongoing immune activation contributing to chronic rejection, and that loss of regulation in a given patient may precede an episode of rejection.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2008
                October 2008
                07 August 2008
                : 40
                : 6
                : 309-314
                Affiliations
                aDepartment of Ophthalmology and bInstitute of Medical Immunology, Charité – Universitätsmedizin Berlin, and cInstitute of Pharmacy, Free University Berlin, Berlin, Germany; dDepartment of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                Article
                150444 Ophthalmic Res 2008;40:309–314
                10.1159/000150444
                18688173
                © 2008 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.

                Page count
                Figures: 3, References: 37, Pages: 6
                Categories
                Original Paper

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