Research ArticleType 1 Diabetes

Mixed Chimerism and Growth Factors Augment β Cell Regeneration and Reverse Late-Stage Type 1 Diabetes

Science Translational Medicine  09 May 2012:
Vol. 4, Issue 133, pp. 133ra59
DOI: 10.1126/scitranslmed.3003835

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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.

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