What are exosomes?
As an autoimmune disease, T1D involves self-attacking immune responses, particularly towards the pancreatic β-cells. The islets of Langherhans, where the β-cells reside, often face invasion by host white blood cells and β-cell specific destruction4. How does this occur? One potential mechanism may be through exosomes.
Exosomes are vesicles (diameters 30-150nm) which can be released from many different cell types2. Research has shown that in diabetic-modeled rodents, there are increased exosomes from the islet of Langerhans, and that this elevated release also increases the T cell invasion into the islets5. The presence and contents of exosomes could be key in connecting the β-cells’ malfunction to the autoimmune response.
Contents of the Vesicles
Cell-type specificity is a driving pressure of T1D; unlike some other diseases, T1D mainly targets pancreatic β-cells. Exosomes contain a wide variety of molecules that could possibly direct these inflammatory responses. For one, exosomes could contain autoantigens against rare membrane proteins present in β-cells. GAD65 and IA-2 are two such proteins, whose autoantigens were released by exosomes in T1D rodent models.
T1D exosomes can also contain miRNAs, which are small, non-coding RNA molecules that can control gene expression. MiRNAs may control how β-cells differentiate and develop through T1D, and some have been shown to encourage β-cell apoptosis as well.
Researchers in Canada studied human islet-derived extracellular vesicles (EV). Isolating the human nondiabetic islets in culture, they found a heterogenous EV population8. In the EV produced by the normal islets, researchers observed diabetes autoantigens and beta-cell markers8.
New bioengineering strategies are emerging as prevention and treatment for T1D, with many focusing on systemic immunomodulation and antigen-specific immunotherapy.
- Use of monoclonal antibodies, either to delete or induce anergy non-specifically in immune effector cells7
- Treg therapy with induction and expansion of Tregs in and ex vivo7
- Engineered biomaterials as delivery vehicles to induce tolerogenic dendritic cells7
- Engineered materials and proteins to induce antigen-specific immune tolerance7
- Nano- and microparticle-based approaches to carry autoantigens in a tolerogenic way and to communicate antigen signals7
- Hydrogel scaffolds as engineered microenvironments to modulate immune cell response7, for long-term maintenance of islet and beta-cell function6
- Focus on using apoptosis as a mechanism to induce tolerance7
Phelps Laboratory at the University of Florida is one example of research being done on biomaterials engineering for T1D prevention and treatment. Their work focuses on advancing engineered therapies, with strategies such as synthetic hydrogel microenvironments, biomaterial matrices and engineered particles to carry immunomodulatory proteins and exosome-mimetic particles.
- Cianciaruso, C., Phelps, E., Pasquier, M., Hamelin, R., Demurtas, D., Ahmed, M., . . . Baekkeskov, S. (2017). Primary human and rat β-cells release the intracellular autoantigens GAD65, IA-2, and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes, 66, 460-473. doi:10.2337/db16-0671
- Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255-289. doi:10.1146/annurev-cellbio-101512-122326
- Guay, C., Kruit, J. K., Rome, S., Menoud, V., Mulder, N. L., Jurdzinski, A., . . . Regazzi, R. (2019). Lymphocyte-derived exosomal MicroRNAs promote pancreatic β cell death and may contribute to type 1 diabetes development doi:https://doi.org/10.1016/j.cmet.2018.09.011
- Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10(7):501-513. doi:10.1038/nri2787
- Rahman, M. J., Regn, D., Bashratyan, R., & Dai, Y. D. (2014). Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes, 63(3), 1008–1020. https://doi.org/10.2337/db13-0859
- Phelps Laboratory: Pancreatic Cellular and Biomaterials Engineering. (n.d.). Retrieved July 09, 2020, from https://www.bme.ufl.edu/labs/phelps/research/
- Baekkeskov, S., Hubbell, J. A., & Phelps, E. A. (2017). Bioengineering strategies for inducing tolerance in autoimmune diabetes. Advanced Drug Delivery Reviews, 114, 256-265. doi:10.1016/j.addr.2017.06.007
- Hasilo, C. P., Negi, S., Allaeys, I., Cloutier, N., Rutman, A. K., Gasparrini, M., . . . Paraskevas, S. (2017). Presence of diabetes autoantigens in extracellular vesicles derived from human islets. Scientific Reports, 7(1). doi:10.1038/s41598-017-04977-y