Estrogen Therapy Delays Autoimmune Diabetes and Promotes the Protective Efficiency of Natural Killer T-Cell Activation in Female Nonobese Diabetic Mice.
Therapeutic strategies focused on restoring immune tolerance remain the main avenue to prevent type 1 diabetes (T1D). Because estrogens potentiate FoxP3+ regulatory T cells (Treg) and invariant natural killer T (iNKT) cells, two regulatory lymphocyte populations that are functionally deficient in nonobese diabetic (NOD) mice, we investigated whether estradiol (E2) therapy influences the course of T1D in this model. To this end, female NOD mice were sc implanted with E2- or placebo-delivering pellets to explore the course of spontaneous and cyclophosphamide-induced diabetes. Treg-depleted and iNKT-cell-deficient (Jα18(-/-)) NOD mice were used to assess the respective involvement of these lymphocyte populations in E2 effects. Early E2 administration (from 4 wk of age) was found to preserve NOD mice from both spontaneous and cyclophosphamide-induced diabetes, and a complete protection was also observed throughout treatment when E2 treatment was initiated after the onset of insulitis (from 12 wk of age). This delayed E2 treatment remained fully effective in Treg-depleted mice but failed to entirely protect Jα18(-/-) mice. Accordingly, E2 administration was shown to restore the cytokine production of iNKT cells in response to in vivo challenge with the cognate ligand α-galactosylceramide. Finally, transient E2 administration potentiated the previously described protective action of α-galactosylceramide treatment in NOD females. This study provides original evidence that E2 therapy strongly protects NOD mice from T1D and reveals the estrogen/iNKT cell axis as a new effective target to counteract diabetes onset at the stage of insulitis. Estrogen-based therapy should thus be considered for T1D prevention.
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Pierre
P
Gourdy
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Elvire A
EA
Bourgeois
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Anaïs
A
Levescot
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Linh
L
Pham
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Elodie
E
Riant
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Marie-Louise
ML
Ahui
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Diane
D
Damotte
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Jean-Marc
JM
Gombert
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Francis
F
Bayard
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Claes
C
Ohlsson
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Jean-François
JF
Arnal
INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
André
A
Herbelin
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005699:Galactosylceramides / Q000819:agonists / Q000494:pharmacology / Q000627:therapeutic use; D007108:Immune Tolerance / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008212:Lymphocyte Depletion / Q000009:adverse effects; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D010052:Ovariectomy / Q000009:adverse effects; D011236:Prediabetic State / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D004343:Drug Implants; D004967:Estrogens; D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D004958:Estradiol