The present studies demonstrate the safety and therapeutic efficacy of Stem Cell Educator therapy in T1D patients. The device, essentially a stack of specially-designed Petri dishes with adherent CB-SCs, functions as part of a closed-loop system that circulates a patient's blood through a blood cell separator, briefly co-cultures the patient's lymphocytes with CB-SCs in vitro
, and returns the educated lymphocytes to the patient's circulation. Through secreted and cell-surface signaling molecules, the CB-SCs educate the lymphocytes passing through the device [9
]. The cells returned to the patients are autologous lymphocytes that have been treated (or educated) by CB-SCs. The Stem Cell Educator therapy requires only two venipunctures, carries a lower risk of infection than a typical blood transfusion, and does not introduce stem cells or reagents into patients. In addition, CB-SCs have very low immunogenicity, eliminating the need for human leukocyte antigen (HLA) matching prior to treatment [9
]. Thus, this innovative approach may provide CB-SC-mediated immune modulation therapy for multiple autoimmune diseases while mitigating the safety and ethical concerns associated with other approaches [4
]. The relative simplicity of the approach may also provide cost and time savings relative to other approaches.
Results from this trial confirm prior studies indicating that the adherence of CB-SCs could be exploited to develop therapies that do not introduce the CB-SCs into the patient [9
]. Furthermore, the trial confirms our expectation that co-culturing patient lymphocytes with CB-SCs alters the patient's immune response and leads to clinically relevant improvement in the autoimmune process. Previous studies that have demonstrated improved metabolic control in T1D have usually been limited to new- or recent-onset participants with residual β cell function [36
], but this study demonstrates that Stem Cell Educator therapy is effective both in T1D with and without residual β cell function. Although we were not able to directly evaluate the status of islets or β cells through histological examination in this study, previous studies have demonstrated that patients with long-standing, severe T1D have lost all islets due to infiltration of autoimmune cells [39
]. Thus, the successive improvement we observed in C-peptide levels (both fasting and OGTT) following Stem Cell Educator therapy suggests improvement in the number and/or function of islet β cells. The improvement of islet β cell function in T1D patients with residual islet β cells is impressive, but the recovery of islet β cell function in T1D patients without evident β cell function prior to treatment indicates Stem Cell Educator therapy addresses the underlying challenge of autoimmunity and controls the immune response sufficiently to allow regeneration of the native β cell population. Thus, this trial provides powerful evidence that exposing a patient's lymphocytes to CB-SCs can achieve the two essential outcomes required to cure T1D: reversal of autoimmunity and regeneration of islet β cells. However, longer post-treatment observations with larger samples are needed.
Importantly, the trial provides additional support for the mechanisms of CB-SC-mediated immune modulation and demonstrates that these mechanisms are apparent and lasting in patients. Specifically, the trial provides evidence that CB-SCs in the device educate effector T cells and/or Tregs, resulting in lasting changes in the expression of costimulating molecules, increasing the population of Tregs, and restoring Th1/Th2/Th3 cytokine balance, each of which is expected to improve control of autoimmunity of T1D [14
]. Therapy also increases production of TGF-β1 in plasma of T1D subjects, one of the best-characterized cytokines contributing to the induction of peripheral immune tolerance [23
]. Results from a NOD mouse study [14
] demonstrated that increased plasma TGF-β1 may contribute to the formation of a 'TGF-β1 ring' around pancreatic islets that protects β cells against infiltrating lymphocytes, providing a safe environment for promotion of β cell regeneration [14
]. Due to the limitation of obtaining pancreatic tissues from human subjects, evidence from our trial indicates that β cell regeneration occurs even in patients who do not appear to have β cells prior to treatment. CB-SCs from the device are not likely to be the source of this regeneration because they are not transferred to the patient during therapy. As demonstrated in other studies, the regenerated cells may be derived from multiple endogenous resources such duct cells, α cells [11
], and peripheral blood-derived insulin-producing cells [42
]. Further studies may provide additional insight into the role of TGF-β1 in β cell regeneration and the source of regenerated cells in T1D patients without functional β cell populations.