title: Impact of mammalian target of rapamycin inhibition on lymphoid homing and tolerogenic function of nanoparticle-labeled dendritic cells following allogeneic hematopoietic cell transplantation.
abstract: 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-gammaR-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.
authors.affiliation: Department of Diagnostic Radiology and Medical Physics, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Reichardt
authors.forename: Christoph
authors.initials: C
authors.lastname: Dürr
authors.forename: Dominik
authors.initials: D
authors.lastname: von Elverfeldt
authors.forename: Eva
authors.initials: E
authors.lastname: Jüttner
authors.forename: Ulrike V
authors.initials: UV
authors.lastname: Gerlach
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamada
authors.forename: Benjie
authors.initials: B
authors.lastname: Smith
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D003911:Dextrans; D052203:Ferrosoferric Oxide; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007501:Iron / Q000378:metabolism; D049449:Luminescence; D008221:Lymphoid Tissue / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles; D010087:Oxides / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases
chemical_list: D003911:Dextrans; D007166:Immunosuppressive Agents; D058185:Magnetite Nanoparticles; D010087:Oxides; D047428:Protein Kinase Inhibitors; D007501:Iron; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C065507:ferumoxides; D020123:Sirolimus; D052203:Ferrosoferric Oxide
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