A clinical research consortium sponsored by NIAID
Phippard D, Long SA, Rieck M, Sanda S, Bollyky J, Goland R, Bianchine P, Ehlers M, Greenbaum C, Buckner J
Benaroya Research Institute, Seattle, WA, Naomi Berrie Diabetes Center, New York, NY, National Institutes of Health, Bethesda, MD, Immune Tolerance Network, Bethesda, MD
ABSTRACT
Combination of rapamycin and IL-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice through selective inhibition of effector responses and promotion of CD4+CD25+ Treg. We have previously shown that CD4 T cells of T1D subjects have impaired IL-2 responsiveness as compared to controls. To determine the impact of IL-2 in vivo in T1D, we performed immuno-phenotyping as part of a rapamycin plus IL-2 Phase I clinical trial. T1D subjects (n=9) received IL-2 for one month and rapamycin for three months. Phenotyping was performed using multi-color surface, intracellular and phospho-flow cytometry on PBMC collected prior to, during and after therapy. A 2-fold increase in Treg and NK cells occured in patients after IL-2 dosing, returning to baseline levels at week 8. At baseline, IL-2 responsiveness in CD4 of these T1D subjects, as measured by pSTAT5, was lower than average responses observed in controls for 5 of the 7 subjects tested. In all subjects, response to IL-2 increased within the first month of treatment in CD25+ Tregs, but also in NK and CD25- T cells (p<0.05). Interestingly, in all three cell types, this response was sustained even a year following therapy as compared to pre-treatment values in 5 out of 6 patients tested. These data suggest that rapamycin plus IL-2 combination therapy, as given in this Phase 1 study, does not promote Treg in isolation, but also promotes the expansion of both T effectors and NK cells along with increasing responsiveness to IL-2 in the Treg, T effectors and NK populations.
