Abstract
Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 diabetes (T1D), the quest for therapeutic options capable of delaying/reverting the diseases is still ongoing. Among all strategies currently tested in T1D, the use of hematopoietic stem cell (HSC)-based approaches and of teplizumab, showed the most encouraging results. Few clinical trials have already demonstrated the beneficial effects of HSCs in T1D, while the durability of the effect is yet to be established. Investigators are also trying to understand whether the use of selected and better-characterized HSCs subsets may provide more benefits with less risks. Interestingly, ex vivo manipulated HSCs showed promising results in murine models and the recent introduction of the humanized mouse models accelerated the translational potentials of such studies and their final road to clinic. Indeed, immunomodulatory as well as trafficking abilities can be enhanced in genetically modulated HSCs and genetically engineered HSCs may be viewed as a novel “biologic” therapy, to be further tested and explored in T1D and in other autoimmune/immune-related disorders.
Highlights
Hematopoietic stem cells (HSCs) have been extensively used as an effective therapeutic approach in hematological malignancies and have demonstrated to be safe in human subjects [1]
The results obtained in clinical trials with the use of autologous hematopoietic stem cells transplantation (AHSCT) in type 1 diabetes (T1D) suggest a potential novel approach to treat autoimmune diseases, despite all the aforementioned limitations
HSCs, endowed with immunomodulatory properties, may offer a potent immunoregulatory effect without inducing T lymphocytes depletion, which is commonly observed with teplizumab
Summary
Hematopoietic stem cells (HSCs) have been extensively used as an effective therapeutic approach in hematological malignancies and have demonstrated to be safe in human subjects [1]. The introduction of new protective MHC class II through lentiviral delivery in HSCs of NOD mice was able to prevent the onset of T1D, mainly through the deletion of autoreactive T cells which did not engage in the MHC class II-mediated response [19, 20] While this approach was again limited by the need of immune ablation for the HSCs infusion, which is feasible in NOD mice but at high risk in humans, it paved the way for exploring genetic engineering of HSCs to better exploit their multiple properties in autoimmunity. The introduction of the NOD-Rag1null IL2rgnull Ins2Akita (NRGAkita) mouse, a humanized mouse model available in diabetes research which develops spontaneous hyperglycemia, fostered studies in the field [27, 28] This model, in which human immune cells can be infused without being rejected, may be extremely useful in testing the potency of newly genetically engineered human HSCs in the diabetes prevention. A cost-effectiveness analysis conducted in patients with T1D undergoing AHSCT as compared to patients with T1D remaining on insulin therapy demonstrated that AHSCT provides some benefits over time depending on the Hematopoietic Stem Cells in Autoimmune Diabetes B
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