Curative potential of allogeneic hematopoietic stem cell transplant in type 1 diabetes

McCabe, Kristen E.; Pollock, Allison J.; Rehm, Jennifer L.; DeSantes, Kenneth

doi:10.1111/pedi.12430

Cited by 4 publications

(4 citation statements)

References 14 publications

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“…The period from onset of T1D to HSCT can affect the therapeutic efficacy for T1D with IPEX. In our late‐onset IPEX patient with R347H mutation, we speculated that HSCT rescued the pancreatic β‐cells because the insulin‐dependent diabetes occurred immediately before transplantation; this is well in agreement with the previous reports . Although the patient had acute onset of insulin‐dependent DM, insulin requirement was reduced to half following engraftment, and thereafter, the endogenous insulin secretion was significantly improved, ultimately resulting in withdrawal of insulin.…”

Section: Discussionsupporting

confidence: 90%

“…Recently, it was reported that immune‐based approach of “immunologic reset” with autologous HSCT can preserve β‐cell function and promote long‐term beneficial metabolic effects . In addition, a case of an adolescent with early phase T1D, in which exogenous insulin requirements were eliminated after HSCT for aplastic anemia, was reported . Thus, it was speculated that HSCT for IPEX patients can suppress autoimmunity in multiple organs including pancreas, and reverse the progression of immune‐mediated destruction of pancreatic β‐cells.…”

Section: Discussionmentioning

confidence: 99%

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Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

et al. 2019

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Immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T‐(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β‐cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16‐year‐old adolescent with late‐onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin‐dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC‐peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β‐cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D‐associated IPEX syndrome improves Treg deficiency and prevents elimination of β‐cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β‐cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

et al. 2019

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“…Our data suggest that the increased number of Tregs plays a role in the prevention of T1D. Although it has been reported that other stem cell technology, such as ESC- or induced pluripotent stem cell (iPSC)-derived pancreatic progenitors and allogeneic hematopoietic stem cell transplant have the potential for curing T1D [51, 52], the mechanisms by which our ESC-TECs ameliorate T1D appear to differ from these approaches.…”

Section: Discussionmentioning

confidence: 75%

Transplantation of MHC-mismatched mouse embryonic stem cell-derived thymic epithelial progenitors and MHC-matched bone marrow prevents autoimmune diabetes

Lin

et al. 2019

Stem Cell Res Ther

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Background Type 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. Methods To 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-2 g7 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. Results Transplantation 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. Conclusions Our results suggest that embryonic stem cell-derived TEPs may offer a new approach to control T1D. Electronic supplementary material The online version of this article (10.1186/s13287-019-1347-1) contains supplementary material, which is available to authorized users.

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“… 45 Nevertheless, there are reports of the curative potential of allogeneic HSCT in T1DM, in cases of allogeneic HSCT performed due to other indications, with cure of diabetes as an incidental outcome. 46 , 47 …”

Section: Discussionmentioning

confidence: 99%

Correction of T-Cell Repertoire and Autoimmune Diabetes in NOD Mice by Non-myeloablative T-Cell Depleted Allogeneic HSCT

Muskatel

Nathansohn-Levi

Reich-Zeliger

et al. 2023

Stem Cells Translational Medicine

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The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated the ability of this relatively safe transplant modality to eliminate autoimmune T-cell clones in the NOD mouse model which spontaneously develop T1DM. Our results demonstrate that using this approach, marked durable chimerism is attained, without any transplant-related mortality, and with a very high rate of diabetes prevention. TCR sequencing of transplanted mice showed profound changes in the T-cell repertoire and decrease in the prevalence of specific autoimmune T-cell clones directed against pancreatic antigens. This approach could be considered as strategy to treat people destined to develop T1DM but with residual beta cell function, or as a platform for prevention of beta cell destruction after transplantation of allogenic beta cells.

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Curative potential of allogeneic hematopoietic stem cell transplant in type 1 diabetes

Cited by 4 publications

References 14 publications

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

Transplantation of MHC-mismatched mouse embryonic stem cell-derived thymic epithelial progenitors and MHC-matched bone marrow prevents autoimmune diabetes

Correction of T-Cell Repertoire and Autoimmune Diabetes in NOD Mice by Non-myeloablative T-Cell Depleted Allogeneic HSCT

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