title: Antigen-presenting cell-derived complement modulates graft-versus-host disease.
abstract: Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell-derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell-mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor-null (Daf1(-/-)) host BM and Daf1(-/-) donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell-mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Wing-Hong
authors.initials: WH
authors.lastname: Kwan
authors.forename: Daigo
authors.initials: D
authors.lastname: Hashimoto
authors.forename: Estela
authors.initials: E
authors.lastname: Paz-Artal
authors.forename: Katya
authors.initials: K
authors.lastname: Ostrow
authors.forename: Melanie
authors.initials: M
authors.lastname: Greter
authors.forename: Hugo
authors.initials: H
authors.lastname: Raedler
authors.forename: M Edward
authors.initials: ME
authors.lastname: Medof
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000208:Acute Disease; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D015926:Complement C3a / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D011951:Receptors, Complement; D015926:Complement C3a; D015936:Complement C5a