title: Potential limitations of IL-2 administration for the treatment of experimental acute graft-versus-host disease.
abstract: Low-dose IL-2 administration can control autoimmunity by specifically activating CD4(+) Foxp3(+) regulatory T cells (Tregs). Here, we studied IL-2-based immunotherapy in experimental graft-versus-host disease (GVHD). IL-2 administration to donor mice induced a dose-dependent expansion of Tregs in the graft but was insufficient to control GVHD. IL-2 administration to allogeneic-grafted recipient mice activated T-conventional cells (Tcons) and did not prevent GVHD. This loss of IL-2 selectivity toward Tregs was explained by an IL-2-induced increase in the IL-2 receptor α-chain expression on Tcons. Finally, in xeno-GVHD generated by human PBMCs transplanted into immunodeficient mice, low-dose IL-2 increased Treg frequencies but did neither control pro-inflammatory cytokine production by pathogenic Tcons, nor prevented GVHD. Furthermore, combination of low-dose IL-2 with rapamycin was ineffective in this model. Our results indicate that limitations on the use of IL-2 during acute GVHD are likely due to the massive activation of the allogeneic T cells unique to this setting.
authors.affiliation: INSERM U932, 26 rue d'Ulm, 75005 Paris, France; Institut Curie, Section Recherche, 26 rue d'Ulm, 75005 Paris, France; Université Pierre et Marie Curie Paris 06, UMR7211, Immunology-Immunopathology-Immunotherapy (I3), F-75013 Paris, France; CNRS, UMR7211, I3, F-75013 Paris, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Pérol
authors.affiliation: Université Paris-Est Créteil, Faculté de médecine, Créteil F-94010, France; INSERM U 955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil F-94010, France.
authors.forename: Gaëlle H
authors.initials: GH
authors.lastname: Martin
authors.affiliation: Université Paris-Est Créteil, Faculté de médecine, Créteil F-94010, France; INSERM U 955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil F-94010, France; AP-HP, Groupe Hospitalier Henri-Mondor Albert-Chenevier, CIC-BT-504, Créteil, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maury
authors.affiliation: Université Paris-Est Créteil, Faculté de médecine, Créteil F-94010, France; INSERM U 955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil F-94010, France; AP-HP, Groupe Hospitalier Henri-Mondor Albert-Chenevier, CIC-BT-504, Créteil, France. Electronic address: jose.cohen@inserm.fr.
authors.forename: José L
authors.initials: JL
authors.lastname: Cohen
authors.affiliation: INSERM U932, 26 rue d'Ulm, 75005 Paris, France; Institut Curie, Section Recherche, 26 rue d'Ulm, 75005 Paris, France; Université Pierre et Marie Curie Paris 06, UMR7211, Immunology-Immunopathology-Immunotherapy (I3), F-75013 Paris, France; CNRS, UMR7211, I3, F-75013 Paris, France; INSERM Center of Clinical Investigation (CIC-BT-507), 75005 Paris, France. Electronic address: eliane.piaggio@yahoo.com.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D064593:Heterografts; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020123:Sirolimus / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C508018:Il2ra protein, mouse; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D020123:Sirolimus
keywords: Bone marrow transplantation; Graft-vs-host disease; Immunotherapy; Interleukin-2; Regulatory T cell