Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers.
Developing protocols aimed at inhibiting effector T cells would be key for the treatment of T cell-dependent autoimmune diseases including type 1 autoimmune diabetes (T1D) and multiple sclerosis (MS). While heme oxygenase-1 (HO-1) inducers are clinically approved drugs for non-immune-related diseases, they do have immunosuppressive properties when administered systemically in rodents. Here we show that HO-1 inducers inhibit antigen-specific effector T cells when injected intradermally together with the T cell cognate antigens in mice. This phenomenon was observed in both a CD8+T cell-mediated model of T1D and in a CD4+T cell-dependent MS model. Intradermal injection of HO-1 inducers induced the recruitment of HO-1+monocyte-derived dendritic cell (MoDCs) exclusively to the lymph nodes (LN) draining the site of intradermal injection. After encountering HO-1+MoDCs, effector T-cells exhibited a lower velocity and a reduced ability to migrate towards chemokine gradients resulting in impaired accumulation to the inflamed organ. Intradermal co-injection of a clinically approved HO-1 inducer and a specific antigen to non-human primates also induced HO-1+MoDCs to accumulate in dermal draining LN and to suppress delayed-type hypersensitivity. Therefore, in both mice and non-human primates, HO-1 inducers delivered locally inhibited effector T-cells in an antigen-specific manner, paving the way for repositioning these drugs for the treatment of immune-mediated diseases.
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France; INRA USC1383, IECM; LUNAM Université, Oniris, Nantes, EA4644, France; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Thomas
T
Simon
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France.
Julien
J
Pogu
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France.
Séverine
S
Rémy
Université Côte d'Azur, Inserm, CNRS, IPMC, 06560, Valbonne, France.
Frédéric
F
Brau
INRA USC1383, IECM; LUNAM Université, Oniris, Nantes, EA4644, France.
Sylvie
S
Pogu
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France.
Maud
M
Maquigneau
Université de Nantes, Inserm, UMR892, CNRS UMR6299, 44007, Nantes, France.
Jean-François
JF
Fonteneau
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France; OSE Immunotherapeutics, 44200 Nantes, France.
Nicolas
N
Poirier
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France.
Bernard
B
Vanhove
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France.
Gilles
G
Blancho
Institut Curie, Inserm, UMR932, 75005, Paris, France.
Eliane
E
Piaggio
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France.
Ignacio
I
Anegon
Université de Nantes, Inserm, UMR1064, Center for Research in Transplantation and Immunology, 44093, Nantes, France; Université Côte d'Azur, Inserm, CNRS, IPMC, 06560, Valbonne, France; INRA USC1383, IECM; LUNAM Université, Oniris, Nantes, EA4644, France. Electronic address: blancou@ipmc.cnrs.fr.
Philippe
P
Blancou
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D051379:Mice; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D048530:Papio anubis; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D001324:Autoantigens; D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D051547:Heme Oxygenase-1
Auto-immune encephalomyelitis; Autoimmunity; Delayed type hypersensitivity; Diabetes; Heme oxygenase-1; Migration; Monocyte-derived dendritic cells; T-lymphocyte; Tolerance