Regulatory T cell therapy for type 1 diabetes: May the force be with you

Abstract

a b s t r a c tType 1 diabetes mellitus (T1DM) results from autoimmune destruction of insulin producing beta cells. Regulatory T cells (Tregs) have been shown to be defective in this setting. Immuno-therapies targeting T cells, and resetting the balance between T effectors and Tregs, have had some initial success in preserving beta cell function. With a goal to use Tregs themselves as a novel therapeutic, we developed a technique to isolate and expand Tregs from patients with T1DM. These ex vivo expanded CD4 þ CD127 lo/À CD25 þ cells exhibit improved function and retain their T cell receptor diversity. These cells have subsequently been used in phase I clinical trials in patients with recent onset T1DM. The infusions were well tolerated, with no safety concerns. The studies are too small to assess efficacy definitively, although some individuals exhibit stable beta cell function over intervals as long as 2 years. These efforts set the stage for a larger phase II effort in new onset T1DM, and combination studies with other drugs, as well as efforts in other autoimmune diseases.

After Moving of Regulatory T-Cell Therapy to the Clinic: Will We Need a New Tregs Source?

“…These results support the development of a phase II trial to test efficacy of the Treg therapy in new onset T1DM, 15 as well as studying the efficacy in other autoimmune diseases.…”

Expansion of Human Tregs from Cryopreserved Umbilical Cord Blood for GMP-Compliant Autologous Adoptive Cell Transfer Therapy

“…That said, unlike peripheral blood collection, the singular opportunity to store autologous CB creates a situation in which efforts to utilize fractions of stored CBUs, facilitated by multi-compartment storage bags, are needed to allow for longitudinal treatment regimens. Given the high safety profile observed with whole CB infusion 30 as well as peripheral blood Treg ACT therapy,5, 23 we expect autologous CB Treg ACT therapy to be well tolerated. Moreover, expanded CB Tregs may offer an allogeneic cell source when autologous cell therapy is demonstrated to be safe.…”

“…There is growing interest in the use of adoptive cell transfer (ACT) therapies involving regulatory T cells (Tregs) as a means to control host responses, given their essential role in limiting both innate and adaptive immune activation 3 . A key component of the therapeutic activity of Tregs resides in their capacity to exert their function(s) as “living drugs.”4, 5 Specifically, Tregs function to maintain dominant peripheral tolerance by consuming growth factors of pathogenic T cells and exerting their tissue-directed suppressive activities through an array of anti-inflammatory biochemical pathways, expression of co-inhibitory receptors, and production of immunoregulatory cytokines 6 . These seemingly redundant mechanisms allow Tregs to track to various tissues to suppress host inflammation in a tissue- and context-dependent manner.…”

Getting Back to Normal

“…Autologous T cells are being programmed to target specific antigens expressed by previously lethal leukemias, achieving unprecedented apparent cures. 1 Conversely, regulatory T cells are being tested in type 1 diabetes mellitus in an attempt to re-establish immune tolerance in this condition, 2,3 with some earlier examples of resultant insulin independence. 4 In the cardiovascular (CV) arena, the use of a variety of cell types to treat heart failure 5,6 and ischemic heart disease 7 is being widely tested.…”