title: Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone.
abstract: Type I diabetes mellitus is caused by autoimmune destruction of pancreatic beta cells, and effective treatment of the disease might require rescuing beta cell function in a context of reinstalled immune tolerance. Sertoli cells (SCs) are found in the testes, where their main task is to provide local immunological protection and nourishment to developing germ cells. SCs engraft, self-protect, and coprotect allogeneic and xenogeneic grafts from immune destruction in different experimental settings. SCs have also been successfully implanted into the central nervous system to create a regulatory environment to the surrounding tissue which is trophic and counter-inflammatory. We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic [NOD]) mice, with no need for additional beta cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-beta-dependent emergence of autoantigen-specific regulatory T cells and recovery of beta cell function in the diabetic recipients.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Luca
authors.forename: Mario
authors.initials: M
authors.lastname: Calvitti
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancuso
authors.forename: Claudio
authors.initials: C
authors.lastname: Nastruzzi
authors.forename: Maria C
authors.initials: MC
authors.lastname: Fioretti
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Ennio
authors.initials: E
authors.lastname: Becchetti
authors.forename: Anne
authors.initials: A
authors.lastname: Burgevin
authors.forename: Roland
authors.initials: R
authors.lastname: Kratzer
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Riccardo
authors.initials: R
authors.lastname: Calafiore
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control / Q000628:therapy*; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology* / Q000201:enzymology; D034421:Sus scrofa; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous; D000098815:T-bet Transcription Factor
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007328:Insulin; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta