title: Extracorporeal photopheresis attenuates murine graft-versus-host disease via bone marrow-derived interleukin-10 and preserves responses to dendritic cell vaccination.
abstract: Extracorporeal photopheresis (ECP) is emerging as a therapy for graft-versus-host-disease (GVHD), but the full mechanism of action and the impact on immunity have not been fully established. After murine minor histocompatibility antigen-mismatched bone marrow (BM) transplantation (allo-BMT), coinfusion of ECP-treated splenocytes with T cell-replete BM attenuated GVHD irrespective of the donor strain of the ECP-treated splenocytes, and was associated with increased numbers of regulatory T cells. Coculture of myeloid dendritic cells (DCs) with ECP-treated splenocytes resulted in increased interleukin (IL)-10 production after submaximal stimulation with lipopolysaccharide. Furthermore, male myeloid DCs exposed to ECP-treated splenocytes were less potent at inducing CD8(+) HY responses when used as a vaccine in vivo. The efficacy of ECP-treated splenocytes was enhanced when administered just before delayed donor lymphocyte infusion following T cell-depleted allo-BMT, allowing for the administration of sufficient numbers of T cells to respond to myeloid DC vaccination in the absence of a thymus. Finally, the therapeutic effect of ECP-treated splenocytes was lost in recipients of IL-10-deficient BM. We demonstrate that ECP-treated splenocytes attenuate GVHD irrespective of the source of ECP-treated cells via a mechanism that likely involves modulation of DCs and requires IL-10 produced by BM-derived cells. Importantly, the attenuation of GVHD by ECP-treated splenocytes permits donor lymphocyte infusion-dependent responses to DC vaccines after allo-BMT.
authors.affiliation: Immunology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. capitinic@mail.nih.gov
authors.forename: Christian M
authors.initials: CM
authors.lastname: Capitini
authors.forename: Jessica P E
authors.initials: JP
authors.lastname: Davis
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Larabee
authors.forename: Sarah
authors.initials: S
authors.lastname: Herby
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Nasholm
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000528:radiation effects* / Q000637:transplantation; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009000:Monocytes / Q000528:radiation effects* / Q000637:transplantation; D017893:Photopheresis / Q000379:methods*; D013154:Spleen / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014184:Transplantation, Homologous; D014466:Ultraviolet Rays; D014611:Vaccination / Q000379:methods*
chemical_list: D008070:Lipopolysaccharides; D016753:Interleukin-10; D008730:Methoxsalen