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.

Growth factors and medium hyperglycemia induce Sox9+ductal cell differentiation into β cells in mice with reversal of diabetes

“…As illustrated in Fig. S1A, diabetic mice with medium and high hyperglycemia were given a daily injection of low-dose GE (gastrin, 3 μg per kg of body weight; EGF, 1 μg per kg of body weight), as described (4,26) or control PBS for 8 wk, starting at 4 wk after induction of diabetes. The treated mice were monitored for blood glucose for another 8 wk before ending the experiments.…”

“…Because treatment with GE was reported to induce β-cell neogenesis from adult pancreatic ductal cells in vitro (25), and because we observed neogenesis in mixed chimeric late-stage diabetic NOD mice after long-term (8 wk) administration of GE (4), in the present studies, we tested whether long-term administration of GE was able to induce Sox9 + pancreatic ductal cell differentiation into insulinproducing β cells in diabetic C57BL/6 mice, using a Cre-based lineage-tracing construct driven by Sox9 regulatory sequences. The same strain of mice was used as in the studies of Kopp et al (17), but a founder with higher recombination efficiency was used in the present studies.…”

“…Because of the lack of donors for islet transplantation and because islet grafts only last for ∼3 y (3), augmentation of endogenous β-cell regeneration would be the more favorable approach. We previously reported that combination therapy of induction of mixed chimerism and administration of gastrin and epidermal growth factor (GE) not only reversed autoimmunity, but also augmented β-cell neogenesis and replication and subsequently cured late-stage T1D in autoimmune nonobese diabetic (NOD) mice (4). However, the origin of neogenesis remains unknown.…”

MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice

“…However, induction of MHC-mismatched mixed chimerism is able to reverse autoimmunity in mouse models (10,11). In particular, we have reported that induction of mixed chimerism under a radiation-free anti-CD3/CD8 conditioning regimen reversed autoimmune type 1 diabetes (T1D) and systemic lupus (12)(13)(14)(15)(16)(17)(18)(19). Induction of MHC-mismatched mixed chimerism can restore central tolerance by deleting autoreactive thymocytes with cross-reactivity (18), and tolerize residual T cells in the periphery and delete preexisting and immature autoreactive B cells (15,17).…”

Induction of Mixed Chimerism Depletes Pre-existing and De Novo–Developed Autoreactive B Cells in Autoimmune NOD Mice

“…We have demonstrated that induction of mixed chimerism via hematopoietic cell transplantation (HCT) is an effective therapy to reverse autoimmune T1D in NOD mice, using a radiation-free nontoxic anti-CD3/CD8 conditioning regimen (19)(20)(21)(22)(23)(24)(25)(26). Induction of chimerism…”