Advances in Regulatory Cell Therapy for Type 1 Diabetes: Emerging Strategies and Future Directions

Abstract

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing β-cells in the pancreas. Despite advances in insulin therapy and β-cell replacement, a definitive cure addressing the underlying cause of the disease, that is the loss of immune tolerance to β-cells remains elusive. Emerging strategies to reshape the immune response to pancreatic autoantigens include the adoptive transfer of ex vivo cultured regulatory cells, either mesenchymal stem cells (MSCs), regulatory T cells (Tregs), or dendritic cells (DCs), collectively known as regulatory cell therapy. This review aims to provide an overview of the regulatory cell-based approaches for T1D currently under development. Although several clinical trials have demonstrated the safety of in vivo administration of regulatory cells to T1D patients, only mild signs of efficacy have been reported. The most promising results were observed in patients with shorter disease duration and higher residual β-cell mass, suggesting that early interventions may result in clinical benefit. Significant challenges remain, including the long-term efficacy and stability of the infused products. In the future, approaches combining regulatory cell-based therapies with immunomodulatory agents or strategies to restore the damaged insulin-producing cells may hold the key to achieving a functional cure for T1D.

Keywords: adoptive cell therapy; autoimmunity; dendritic cells; regulatory T cells; tolerance.

FIGURE 1

Schematic representation of proposed adoptive cell therapy strategies to restore tolerance in T1D. Strategies currently under investigation in clinical trials (upper panels) or in preclinical development (lower panels) based on the use of stem cells (left panel), Tregs (middle panel), or DCs (right panel). HSCs: Hematopoietic stem cells; MNCs: mononuclear cells; UCB‐SCs: umbilical cord blood‐derived stem cells; MSCs: mesenchymal stem cells; Tregs: regulatory T cells; CAR: chimeric antigen receptor; ASO: antisense oligonucleotides; HSP60: heat shock protein 60; VitD3: vitamin D3: Dexa: dexamethasone.