Background: Regulatory T cells (Tregs) have been shown to be master regulators of autoimmunity and, as such, Treg cell-based immunotherapeutics have gained increasing interest. We have previously shown that adoptive Treg cell therapy can block autoimmune destruction of beta-islet cells in mouse type 1 diabetes (T1D) model. In addition, we performed a Phase I clinical trial, infusing in vitro expanded autologous Treg cells into patients with recent onset T1D and demonstrated the good safety profile of the therapy with durable insulin production in about 50% of patients treated. Recently, a number of studies have shown that Interleukin-2 (IL-2) is a potent Treg growth factor that promotes Treg expansion after in vivo treatment in a variety of human diseases. It has been suggested that low doses of IL-2 treatment in vivo, selectively expands Tregs without altering effector T cell or NK populations.

Objective: To assess safety of combined Tregs and low dose IL-2 treatment in T1D patients.

Methods: A phase I protocol was initiated to treat recently diagnosed T1D patients with a single infusion of ex-vivo expanded autologous polyclonal Tregs followed by two 5-days courses of low dose IL-2. Patients were monitored for safety and diabetes-related metabolic profiles. PBMCs were analyzed at different time points by flow cytometry, CyToF and 10X genomic single cell RNAseq to monitor immune cell activation.

Results: The overall safety profile was excellent but all 9 patients treated with the combined therapy failed to maintain c-peptide production at pre-treatment levels. Although expansion of endogenous Tregs was shown, a subset of granzyme B (GZMB) producing CD8+ T and NK subsets also expanded after IL-2 administration. Further analysis revealed clonal proliferation in the CD8+ GZMB+ T cell compartment in several patients.

Conclusion: These data suggest that the usage of low dose IL-2 together with polyclonal Tregs infusion may induce deleterious GZMB producing immune cells that will aggravate the progression of T1D.


S. Dong: None. C.T. Mowery: None. K.C. Herold: Consultant; Self; Provention Bio, Roche Pharma. S.E. Gitelman: Advisory Panel; Self; Avortes, Intermountain Therapeutics, Lilly Diabetes, Tolerion, Inc. Research Support; Self; Caladrius Biosciences, Inc., Janssen Research & Development. Other Relationship; Self; Novo Nordisk Inc. J.H. Esensten: None. W. Liu: None. A.P. Lares: None. A.S. Leinbach: Stock/Shareholder; Self; Johnson & Johnson. M.R. Lee: None. V.Q. Nguyen: None. A.L. Putnam: None. J. Ye: None. Q. Tang: Consultant; Self; Third Rock Venture. Research Support; Self; Immune Tolerance Network, JDRF, Juno Therapeutics/Celgene. J. Bluestone: Board Member; Self; Pfizer. Consultant; Self; Celsius, Kadmon Holdings, Inc., Quentis, Vir. Research Support; Self; Merck & Co., Inc. Stock/Shareholder; Self; Rheos, Solid. Other Relationship; Self; Macrogenics.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at