Laure Cundiff

Introduction.  Type 1 diabetes (T1D) is an autoimmune disease characterized by T-cell destruction of host pancreatic insulin-producing beta cells, resulting in chronic hyperglycemia and long-term vascular complications.^1,2  HLA-DQ-restricted CD4 T-cells are found in the pancreatic islets of these patients, causing IFN-γ mediated destruction of insulin producing cells.^4,5,6  Further, it has been noted that T1D islets are also characterized by a lack of Foxp3 T-regulatory cells, allowing for proliferation of self-reactive T-cells that escaped thymus detection.^3,6  Current treatment involves exogenous administration of insulin or systemic immunosuppression, which both come with adverse side effects and reduced lifespan.^1,2  With current understanding of the aberrant T-cell response in T1D, researchers are exploring development of peptide immunotherapy (PIT), in which a mimetope of insulin with modified binding affinity could be delivered as a “vaccine” in at-risk individuals (as determined by HLA and autoantibody screening), causing an immunoprotective T-regulatory response rather than self-reactive T-cell proliferation.^1,5,9  Methods.  Insulin-reactive T-cells found in islets of T1D individuals were found to be highly reactive to HLA-DQ8-restricted segments of the insulin B-chain comprising common residues.^6,7,8  Researchers developed insulin mimetopes (Ins.mim1, Ins.mim4, CD19-A3, pCI/ppinsΔA_12-21) of these self-reactive segments, lacking the immunogenic sequence and therefore with reduced binding affinity.^6,7,8  These mimetopes were then delivered to HLA-DQ humanized mice or to PD-1 deficient mice and T-regulatory response was measured using presence of T-reg signature genes (Foxp3) and cytokine levels.^6,7,8  Results.  These transgenic mice showed increased frequencies of Foxp3 CD25+ T-regulatory cells post-vaccination, when compared to the high levels of CD4+ self-reactive T-cells and low levels of Foxp3 T-reg cells found in T1D individuals.⁶  Further, these induced T-regs were mixed with insulin-reactive T cells from T1D patients ex vivo, and self-reactive effector T cell proliferation was suppressed.⁶  These studies also indicate that decreased levels of IFN-γ and increased levels of IL-10 and TGF-β characterize the protective T-regulatory response.^7,8  Conclusions.  Studies have found that by delivering insulin mimetopes with attenuated TCR binding at subimmunogenic levels to humanized mice, the immune system may be modulated to promote a T-regulatory protective response and inhibit an insulin-reactive one.^6,7,8,9  Current questions now include what the most effective mimetope and most effective dosing schedule may be.⁷  Such insulin vaccination in individuals determined to be at-risk of developing T1D may provide the specific immunosuppressive therapy option that allows for prevention of hyperglycemia and its associated complications, while also avoiding the adverse effects that come with current insulin therapy and systemic immunosuppression.

1. Smith EL, Peakman M. Peptide immunotherapy for type 1 diabetes-clinical advances. Front Immunol. 2018;9:392. doi: 10.3389/fimmu.2018.00392 [doi].
2. Alhadj Ali M, Liu YF, Arif S, et al. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Sci Transl Med. 2017;9(402):10.1126/scitranslmed.aaf7779. doi: eaaf7779 [pii].
3. Burrack AL, Martinov T, Fife BT. T cell-mediated beta cell destruction: Autoimmunity and alloimmunity in the context of type 1 diabetes.Front Endocrinol (Lausanne). 2017;8:343. doi: 10.3389/fendo.2017.00343 [doi].
4. Pathiraja V, Kuehlich JP, Campbell PD, et al. Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes.Diabetes. 2015;64(1):172-182. doi: 10.2337/db14-0858 [doi].
5. Yu L, Dong F, Miao D, Fouts AR, Wenzlau JM, Steck AK. Proinsulin/insulin autoantibodies measured with electrochemiluminescent assay are the earliest indicator of prediabetic islet autoimmunity.Diabetes Care. 2013;36(8):2266-2270. doi: 10.2337/dc12-2245 [doi].
6. Serr I, Furst RW, Achenbach P, et al. Type 1 diabetes vaccine candidates promote human Foxp3(+)treg induction in humanized mice.Nat Commun. 2016;7:10991. doi: 10.1038/ncomms10991 [doi].
7. Gibson VB, Nikolic T, Pearce VQ, Demengeot J, Roep BO, Peakman M. Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model. Clin Exp Immunol. 2015;182(3):251-260. doi: 10.1111/cei.12687 [doi].
8. Stifter K, Schuster C, Schlosser M, Boehm BO, Schirmbeck R. Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination. Sci Rep. 2016;6:29419. doi: 10.1038/srep29419 [doi]
9. 9. Caton AJ, Kropf E, Simons DM, Aitken M, Weissler KA, Jordan MS. Strength of TCR signal from self-peptide modulates autoreactive thymocyte deletion and Foxp3(+) treg-cell formation. Eur J Immunol. 2014;44(3):785-793. doi: 10.1002/eji.201343767 [doi].