Gina Do

Introduction: Type 1 diabetes mellitus (T1D) is an autoimmune disease where the host’s immune system attacks pancreatic β-cells, causing insufficient insulin production and, therefore, hyperglycemia¹. Symptomatic progression of T1D often occurs during childhood and adolescence, with new diagnoses estimated at almost 90,000 children annually worldwide¹. There is no absolute cure but treatment currently addresses insulin deficiency through the use of exogenous insulin. However, many clinical trials have been exploring the option of β-cell preservation to prevent insulin deficiency altogether². In particular, experimental models have established the potential use of regulatory T-cells (Tregs) in autoimmune diseases such as T1D². A major function of Tregs is to suppress autoreactive T-cells, which could interrupt the pathogenesis of T1D by inhibition of T-cells attacking the insulin-producing pancreatic β-cells^2,3. Methods: Experiments included non-antigen specific Treg treatment and antigen specific Treg treatment. Two non-antigen specific treatment was administered to humans and used ex vivo-expanded autologous polyclonal Tregs^4,5. One study was done on adults and the other was done on children. C-peptide levels were measured to determine the presence of functional β-cells^4,5. Two antigen specific treatment was administered to non-obese diabetic (NOD) mice and used β-cell/islet specific therapy to induce Tregs^6,7. Suppressive ability and effectiveness was determined by Bcl-2 levels or diabetogenic CD8+ 8.3 T cell levels as well as incidence of T1D. All studies were statistically compared to controls^6,7. Results: The non-antigen specific treatments done on humans were successful in inducing Treg production^4,5. The adult study showed that low concentration of expanded Tregs maintained C-peptide levels while high concentration showed decline of C-peptide levels⁴. The children study showed higher incidence of clinical remission and C-peptide levels than the untreated cohort⁵. The antigen specific treatments done on NOD mice were successful in inducing islet specific Treg production^6,7. One study suppressed late preclinical T1D and the other prevented spontaneous development of T1D^6,7. Conclusions: Within the human models, the use of non-antigen specific Tregs has more potential managing T1D in children. However, the successful use of ex vivo expanded Tregs allow for future Treg correction and/or manipulation to open up more possibilities for better management of T1D⁴. Within the NOD mice models, the use of antigen specific Tregs poses great potential in suppressing T1D in the long run or preventing T1D development altogether^6,7. Collectively, these studies indicate that induction of Tregs is effective against T1D^4-7. Therefore, Treg use against T1D should be further explored, such as use of different surface markers and effectiveness amongst different cohorts (age, gender, disease progression, etc.).

1. Katsarou, A., GudbjÃrnsdottir, S., Rawshani, A., Dabelea, D., Bonifacio, E., Anderson, B. J., Jacobsen, L. M., Schatz, D. A., Lernmark, Ã. (2017). Type 1 diabetes mellitus. Nature Reviews Disease Primers, 3, 17016-17016.
2. Bayry, J., Gautier, J. (2016). Regulatory T Cell Immunotherapy for Type 1 Diabetes: A Step Closer to Success?. Cell metabolism, 23(2), 231-233.
3. Alroqi FJ, Chatila TA. T Regulatory Cell Biology in Health and Disease. Current allergy and asthma reports. 2016;16(4):27. doi:10.1007/s11882-016-0606-9.
4. Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Science translational medicine. 2015;7(315):315ra189. doi:10.1126/scitranslmed.aad4134.
5. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, et al. Administration of CD4 +CD25highCD127 – regulatory T cells preserves beta]-cell function in type 1 diabetes in children. Diabetes Care. 2012;35(9):1817-20.
6. Johnson, M. C., Garland, A. L., Nicolson, S. C., Li, C., Samulski, R. J., Wang, B., & Tisch, R. (2013). β-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice. Diabetes, 62(11), 3775-3784. doi:10.2337/db13-0669.
7. Manirarora, J. N., Wei, C. (2015). Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice. The journal of immunology, 195(11), 5203-5214. doi: 4049/jimmunol.1402540.