AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice
Mallol, Cristina (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Casaña Lorente, Estefania (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Jimenez, Veronica (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Casellas, Alba (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Haurigot Mendonça, Virginia (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Jambrina Pallarés, Claudia (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Sacristan, Victor (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Morró Larrubia, Meritxell (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Agudo, Judith (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Vilà, Laia (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Bosch i Tubert, Fàtima (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)

Data:	2017
Resum:	Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties. Transgenic NOD mice overexpressing IGF1 specifically in β-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28-30 weeks. In transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of β-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved β-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice. Local expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a therapeutic strategy for autoimmune diabetes in humans.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Autoimmune diabetes ; NOD ; IGF1 ; Pancreas ; AAV
Publicat a:	Molecular metabolism, Vol. 6 (may 2017) , p. 664-680, ISSN 2212-8778

DOI: 10.1016/j.molmet.2017.05.007
PMID: 28702323

17 p, 5.4 MB

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