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* Department of Diagnostic Radiology and Medical Physics, Freiburg University Medical Center,
Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center,
Department of Biology, and
Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; and
¶ Division of Cardiovascular Medicine, Department of Medicine, and
|| Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
Dendritic cells (DC) play a major role in the pathogenesis of graft-vs-host disease (GvHD). Directed modification of surface molecules on DC that provide instructive signals for T cells may create a tolerogenic DC phenotype that affects GvHD severity. To investigate the impact of the mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) on in vivo migratory capacities, tolerogenic function, and B7 superfamily surface expression on DC following allogeneic hematopoietic cell transplantation (aHCT), we generated a platform for magnetic resonance imaging and bioluminescence imaging based cell trafficking studies. Luciferase transgenic DC were labeled with superparamagnetic iron oxide nanoparticles bound to a murine IgG Ab that allowed for Fc-
R-mediated endocytosis. Locally injected luc+ DC could be tracked within their anatomical context by bioluminescence imaging and magnetic resonance imaging after aHCT, based on stable intracellular localization of superparamagnetic iron oxide-IgG complexes. RAPA preconditioned DC (DC-R) displayed reduced expression of MHC class II, B7-1 (CD80), and B7-2 (CD86) but not B7-H4 whose ligation of T cells has a profound inhibitory effect on their proliferation and cytokine secretion. DC-R of recipient genotype reduced GvHD severity that is compatible with their tolerogenic phenotype. CCR5, CCR7, and CD62L expression was not affected by mTOR inhibition, which allowed for DC-R in vivo trafficking to secondary lymphoid compartments where immunregulation is required. This study is the first to delineate the impact of RAPA on DC migration and tolerogenic function after aHCT. Modification of the DC phenotype by mTOR inhibition may have therapeutic potential in an attempt to reduce GvHD following aHCT.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (R01 CA0800065 to R.S.N.) and in part by the Deutsche Krebshilfe, Germany Grant 108034 (to R.Z.).
2 Address correspondence and reprint requests to Dr. Robert Zeiser, Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert Ludwigs University, Hugstetterstrasse 55, 79106 Freiburg, Germany. E-mail address: robert.zeiser{at}uniklinik-freiburg.de
3 Abbreviations used in this paper: aHCT, allogeneic hematopoietic cell transplantation; DC, dendritic cell; Treg, regulatory T cell; GvHD, graft-vs-host disease; RAPA, rapamycin; mTOR, mammalian target of RAPA; BLI, bioluminescence imaging; MRI, magnetic resonance imaging; SPIO, superparamagnetic iron oxide; PI, propidium iodide; wt, wild type; BMT, bone marrow transplantation; RT, room temperature; DAPI, 4',6-diamidino-2-phenylindole.
This article has been cited by other articles:
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  M. R. Janes and D. A. Fruman Immune Regulation by Rapamycin: Moving Beyond T Cells Sci. Signal., April 21, 2009; 2(67): pe25 - pe25. [Abstract] [Full Text] [PDF]
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