Approaches in Immunotherapy, Regenerative Medicine, and Bioengineering for Type 1 Diabetes

Abstract

Recent advances on using immune and stem cells as two-pronged approaches for type 1 diabetes mellitus (T1DM) treatment show promise for advancement into clinical practice. As T1DM is thought to arise from autoimmune attack destroying pancreatic β-cells, increasing treatments that use biologics and cells to manipulate the immune system are achieving better results in pre-clinical and clinical studies. Increasingly, focus has shifted from small molecule drugs that suppress the immune system nonspecifically to more complex biologics that show enhanced efficacy due to their selectivity for specific types of immune cells. Approaches that seek to inhibit only autoreactive effector T cells or enhance the suppressive regulatory T cell subset are showing remarkable promise. These modern immune interventions are also enabling the transplantation of pancreatic islets or β-like cells derived from stem cells. While complete immune tolerance and body acceptance of grafted islets and cells is still challenging, bioengineering approaches that shield the implanted cells are also advancing. Integrating immunotherapy, stem cell-mediated β-cell or islet production and bioengineering to interface with the patient is expected to lead to a durable cure or pave the way for a clinical solution for T1DM.

Keywords: autoimmunity; immunosuppression; regulatory T cell; transplantation immunology; type 1 diabetes.

Figures

Figure 1

Overview of mechanisms of etiology of type 1 diabetes by miss-guided autoreactive adaptive immune response following infection, major stress, or trauma to the pancreas. (A) Following bacterial or viral infections or trauma in the pancreas, dendritic cells (DCs) are activated. While DCs normally only present on their MHCI and MHCII antigens from pathogens, in rare circumstances DCs also activate T lymphocytes that have some affinity for autoantigens, a phenomenon referred to as “molecular mimicry.” Acute destruction of endocrine pancreatic cells, especially β-cells, can then give rise to type 1 diabetes mellitus (T1DM). (B) Representative diagram showing infiltration of pancreatic islets by immune cells and partial islet destruction. (C) The main postulated triggers of T1DM include autoantigens, certain mutations in genes activating regulatory T-cells or Th17 cells, and viral and bacterial infections. (D) Overview of current and experimental approaches using immune and stem cells to treat T1DM.

Figure 2

Comparison of small molecule drugs and complex biologics. (A) Small molecule drugs for immunosuppressive therapy include the well-known corticosteroids, nucleotide synthesis inhibitors, NFAT pathway inhibitors, and mTOR pathway inhibitors. Although some immune cells may express more intracellular targets than other types of immune cells, typically the selectivity of small molecule drugs for target vs off-target cells is not high enough and, therefore, leads to side effects. (B) Biologics include antibodies (which can be blocking, stimulatory, or inhibitory), cytokines, and cytokine receptors or decoys that either amplify or attenuate cytokine signaling. These biologics are usually administered as pure agents, or are further integrated on carrier platforms (such as nanoparticles, liposomes, polymers). If biologics are linked to each other or to carriers/platforms, then additional considerations apply to optimization of linkers (free, fused, tagged, covalent).

Figure 3

Adaptive immune response and its polarization for different classes of infection or stress. (A) Antigen-presenting cells include dendritic cells (DCs), macrophages, and B cells, but only DCs are thought to initiate activation of naïve T lymphocytes, with macrophages and B cells sustaining activation of already primed T cells. These immune cells interact by both membrane-spanning protein receptors displayed on the cell surface (dark and light segments), as well as soluble growth factors and cytokines. The main activating signals have been traditionally referred to as signal 1 (antigen specificity), signal 2 (co-stimulation), signal 3 (growth factor), and signal 4 (differentiation, polarization to distinct cell types). Note that not all of these interactions occur simultaneously, and that while this depiction occurs in secondary organs (lymph nodes, spleen), similar interactions also occur in peripheral tissues, especially near sites of infection or pathology where APC-lymphocyte clusters may assemble to ectopic lymphoid clusters. (B) Overview of T helper cell differentiation. Antigen specificity (signal 1), co-stimulation (signal 2), and growth factor (signal 3) are postulated to activate CD4 T cells (indicated right below the naïve CD4 T cells), with signal 4 (polarizing cytokines) skewing them to particular Th subsets (whose identity is maintained by the master transcription factors shown).

Figure 4

Biologics targeting core immune pathways. Current (FDA-approved) biologic medications are shown as stimulatory (red font), inhibitory (blue font), or experimental (black font). These biologics are listed below each of the main four pathways, plus the critical TNF receptor and checkpoint pathways. The lower left panel lists examples of composite biologics composed of two or more biologics and carriers.

Figure 5

Islet encapsulation and their integration in medical devices for implantation in patient. (A) Empty alginate capsules (left panel), and alginate capsules containing islets (right panel). (B) Examples of devices to contain naked or encapsulated islets and features that enhance their integration with the body.