title: Mixed chimerism and growth factors augment β cell regeneration and reverse late-stage type 1 diabetes.
abstract: Type 1 diabetes (T1D) results from an autoimmune destruction of insulin-producing β cells. Currently, islet transplantation is the only curative therapy for late-stage T1D, but the beneficial effect is limited in its duration, even under chronic immunosuppression, because of the chronic graft rejection mediated by both auto- and alloimmunity. Clinical islet transplantation is also restricted by a severe shortage of donor islets. Induction of mixed chimerism reverses autoimmunity, eliminates insulitis, and reverses new-onset but not late-stage disease in the nonobese diabetic (NOD) mouse model of T1D. Administration of gastrin and epidermal growth factor (EGF) also reverses new-onset but not late-stage T1D in this animal model. Here, we showed that combination therapy of induced mixed chimerism under a radiation-free nontoxic anti-CD3/CD8 conditioning regimen and administration of gastrin/EGF augments both β cell neogenesis and replication, resulting in reversal of late-stage T1D in NOD mice. If successfully translated into humans, this combination therapy could replace islet transplantation as a long-term curative therapy for T1D.
authors.affiliation: Departments of Diabetes Research and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Racine
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Song
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Li
authors.forename: Indu
authors.initials: I
authors.lastname: Nair
authors.forename: Hongjun
authors.initials: H
authors.lastname: Liu
authors.forename: Alina
authors.initials: A
authors.lastname: Avakian-Mansoorian
authors.forename: Heather F
authors.initials: HF
authors.lastname: Johnston
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.forename: Christine
authors.initials: C
authors.lastname: Shen
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Brian
authors.initials: B
authors.lastname: Wilson
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D005260:Female; D005755:Gastrins / Q000008:administration & dosage; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D012038:Regeneration; D057170:Translational Research, Biomedical; D018183:Transplantation Chimera; D019172:Transplantation Conditioning
chemical_list: D005755:Gastrins; D004815:Epidermal Growth Factor