Abstract
BackgroundType 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-secreting islet β cells by autoreactive T cells. Non-obese diabetic (NOD) mice are the widely used animal model for human T1D. Autoimmunity in NOD mice is associated with particular major histocompatibility complex (MHC) loci and impaired islet autoantigen expression and/or presentation in the thymus, which results in defects in both central and peripheral tolerance. It has been reported that induction of mixed chimerism with MHC-mismatched, but not MHC-matched donor bone marrow (BM) transplants prevents the development T1D in NOD mice. We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to generate thymic epithelial progenitors (TEPs) that further develop into thymic epithelial cells (TECs) in vivo to support T cell development.MethodsTo determine whether transplantation of MHC-mismatched mESC-TEPs could prevent the development of insulitis and T1D, NOD mice were conditioned and injected with MHC-mismatched B6 mESC-TEPs and MHC-matched BM from H-2g7 B6 mice. The mice were monitored for T1D development. The pancreas, spleen, BM, and thymus were then harvested from the mice for evaluation of T1D, insulitis, chimerism levels, and T cells.ResultsTransplantation of MHC-mismatched mESC-TEPs and MHC-matched donor BM prevented insulitis and T1D development in NOD mice. This was associated with higher expression of proinsulin 2, a key islet autoantigen in the mESC-TECs, and an increased number of regulatory T cells.ConclusionsOur results suggest that embryonic stem cell-derived TEPs may offer a new approach to control T1D.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-secreting islet β cells by autoreactive T cells
We show here that transplantation of major histocompatibility complex (MHC)-mismatched C57BL/6 (B6) mouse embryonic stem cells (mESCs)-thymic epithelial progenitors (TEPs) and MHC-matched nonautoimmune donor bone marrow (BM) prevents insulitis and T1D development in Non-obese diabetic (NOD) mice that were pre-conditioned with anti-CD3/CD8 antibodies (Abs)
Induction of mixed chimerism with MHC-mismatched but not matched BM transplants prevents insulitis and T1D development in NOD mice It has been reported that BM cells in combination with donor CD8+ T cells induced stable permanent mixed chimerism without graft-versus-host disease (GVHD) [17]
Summary
Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-secreting islet β cells by autoreactive T cells. It has been reported that induction of mixed chimerism with MHC-mismatched, but not MHC-matched donor bone marrow (BM) transplants prevents the development T1D in NOD mice. Transgenic expression of diabetes-protective MHC alleles in the thymus has been reported to prevent T1D development in NOD mice [13, 14]. This approach cannot readily be translated to humans. Induction of either mixed or complete chimerism with MHCmismatched nonautoimmune donor BM transplants prevented the development of T1D in NOD mice [15,16,17,18,19,20,21]. In clinical settings, allogeneic BM transplantation (BMT) has the risk of inducing graft-versus-host disease (GVHD) [22]
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