Abstract
BackgroundType 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet β cells. The complexities of overcoming autoimmunity in T1D have contributed to the challenges the research community faces when devising successful treatments with conventional immune therapies. Overcoming autoimmune T cell memory represents one of the key hurdles. MethodsIn this open-label, phase 1/phase 2 study, Caucasian T1D patients (N=15) received two treatments with the Stem Cell Educator (SCE) therapy, an approach that uses human multipotent cord blood-derived multipotent stem cells (CB-SCs). SCE therapy involves a closed-loop system that briefly treats the patient's lymphocytes with CB-SCs in vitro and returns the “educated” lymphocytes (but not the CB-SCs) into the patient's blood circulation. This study is registered with ClinicalTrials.gov, NCT01350219. FindingsClinical data demonstrated that SCE therapy was well tolerated in all subjects. The percentage of naïve CD4+ T cells was significantly increased at 26weeks and maintained through the final follow-up at 56weeks. The percentage of CD4+ central memory T cells (TCM) was markedly and constantly increased at 18weeks. Both CD4+ effector memory T cells (TEM) and CD8+ TEM cells were considerably decreased at 18weeks and 26weeks respectively. Additional clinical data demonstrated the modulation of C–C chemokine receptor 7 (CCR7) expressions on naïve T, TCM, and TEM cells. Following two treatments with SCE therapy, islet β-cell function was improved and maintained in individuals with residual β-cell function, but not in those without residual β-cell function. InterpretationCurrent clinical data demonstrated the safety and efficacy of SCE therapy in immune modulation. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects. FundingObra Social “La Caixa”, Instituto de Salud Carlos III, Red de Investigación Renal, European Union FEDER Funds, Principado de Asturias, FICYT, and Hackensack University Medical Center Foundation.
Highlights
Type 1 diabetes (T1D) is a major global health issue, and its incidence is increasing
Due to the likelihood that significant numbers of pathogenic autoimmune cells may have remained in lymph nodes and other tissues, failing to enter into the bloodstream during the procedure, and may have escaped the exposure to cord blood-derived multipotent stem cells (CB-SCs), we added a second treatment three months following the initial session in these T1D subjects (n = 15, Table 1)
Overcoming autoimmune memory is essential for eliminating autoimmunity in T1D and other autoimmune diseases
Summary
Type 1 diabetes (T1D) is a major global health issue, and its incidence is increasing. Several recent clinical trials (Bach, 2011; Wherrett et al, 2011) highlight the challenges in conquering T1D, but their failures provide some valuable lessons about the limitations of conventional immune therapy and the future direction of the quest. They point to the need for an approach that produces comprehensive immune modulation at both the local pancreatic and systematic levels rather than targeting the pancreatic effects of one or a few components of the immune system. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects
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