Linked Life Data

20624462

Source:http://linkedlifedata.com/resource/pubmed/id/20624462

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pubmed-article:20624462pubmed:abstractTextMixed hematopoietic chimerism provides a powerful means of achieving transplantation tolerance. We investigated the efficacy of combined blockade of the CD40/CD154 and CD28/B7 costimulation pathways to induce sustained mixed chimerism in cynomolgus monkeys following major histocompatibility complex-mismatched bone marrow (BM) transplants. A nonmyeloablative conditioning regimen of busulfan, intravenous and intraosseous ifosfamide, and anti-thymocyte globulin was used. BM transplantation was followed by a one-week course of CTLA4-Ig/anti-CD154 monoclonal antibodies. Three recipients achieved a wide range of transient chimerism (10.8-79.8%). A rapid proliferation of host effector memory (CD28(low)CD95(high)) CD8(+) T cells was observed in conditioned animals whether or not they received allogeneic BM, and this expansion occurred concurrently with the loss of chimerism in BM recipients. CD8(+) T cells from the recipients had increased reactivity to donor stimulators vs. third-party stimulators. Additional immunosuppression with tacrolimus or deoxyspergualin after transplantation delayed post-transplant proliferation of effector memory CD8(+) T cells but did not promote chimerism. A one-month course of costimulatory blockade also did not prevent marrow rejection. These studies demonstrate that combined CD40/CD154 and CD28/B7 costimulatory blockade supports transient mixed chimerism induction following nonmyeloablative conditioning in primates, but is insufficient to overcome host immune resistance likely mediated by effector memory CD8(+) T cells.lld:pubmed
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pubmed-article:20624462pubmed:authorpubmed-author:KishimotoHide...lld:pubmed
pubmed-article:20624462pubmed:authorpubmed-author:SuzukiToshihi...lld:pubmed
pubmed-article:20624462pubmed:authorpubmed-author:IshidaHidekiHlld:pubmed
pubmed-article:20624462pubmed:authorpubmed-author:TanabeKazunar...lld:pubmed
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pubmed-article:20624462pubmed:authorpubmed-author:SetoguchiKiyo...lld:pubmed
pubmed-article:20624462pubmed:authorpubmed-author:OhnukiKazunob...lld:pubmed
pubmed-article:20624462pubmed:authorpubmed-author:TateYoshikiYlld:pubmed
pubmed-article:20624462pubmed:authorpubmed-author:FujiokaShiger...lld:pubmed
pubmed-article:20624462pubmed:copyrightInfoCrown Copyright © 2010. Published by Elsevier B.V. All rights reserved.lld:pubmed
pubmed-article:20624462pubmed:issnTypeElectroniclld:pubmed
pubmed-article:20624462pubmed:volume23lld:pubmed
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pubmed-article:20624462pubmed:pagination194-203lld:pubmed
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pubmed-article:20624462pubmed:year2010lld:pubmed
pubmed-article:20624462pubmed:articleTitlePotential role of host effector memory CD8+ T cells in marrow rejection after mixed chimerism induction in cynomolgus monkeys.lld:pubmed
pubmed-article:20624462pubmed:affiliationDepartment of Urology, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. setoguchi-jua@umin.ac.jplld:pubmed
pubmed-article:20624462pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:20624462pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed