Dendritic cells (DC) play a central role in defining immunologic self and peripheral tolerance. Activation or enhancement of peripheral tolerance by administration of tolerizing DC is proposed as strategy for the treatment of immune-mediated pathologies including chronic autoimmune diseases, including type 1 diabetes (T1D). Our published work, and recently those of others clearly demonstrate injection of tolerizing DC is highly effective means of preventing T1D in NOD mice. Several issues, however, need to be addressed before this approach can be safely and effectively translated into humans with or at risk for T1D. Therefore, during the R21 pre-clinical developmental phase we will; 1.) Define essential features of tolerogenic NOD DC, 2.) Determine whether tolerance induction by DC requires specific autoantigen presentation 3.) Characterize mechanisms by which NOD DC enforce peripheral tolerance, and 4.) Define genetically regulated DC maturation defects, controlled by the Iddl 0/18 diabetes susceptibility locus that partially suppress tolerogenic DC development and contribute to T1D pathogenesis. As it is our goal to translate DC-based tolerizing therapy to human T1D, we are encouraged by studies suggesting injection of DC into healthy subjects is safe and promotes regulatory T cells. Therefore, will build upon the murine studies from the R21 phase and initiate phase lb studies in patients with T1D. During the extended development phase (R33) we will; 1.) Determine the safety of injection of immature monocyte derived DC (iMoDC) into humans subjects with T 1D, 2.) Determine whether single followed by multiple injections of iMoDC pulsed with a T 1D target antigen, insulin B9-23 chain is safe, and 3.) Determine if injection of iMoDC modifies peripheral blood T cell and autoantibody responses to diabetes-related target autoantigens. The proposed studies in T1D patients will establish scientific basis and clinical experience necessary for moving DC-based therapies forward into phase 2 studies. The research team includes; M. Clare-Salzler, M.D. (PI), a diabetologist and immunologist, will direct clinical and murine studies in DC biology, genetics and mechanisms of protection, M. Atkinson, Ph.D. (Co-Investigator), will characterize T cell responses and autoantibodies, L. Moldawer, Ph.D., will provide analysis of inflammatory cytokines and DC biology, L. Morel, Ph.D., will develop and analyze new NOD congenic sublines for Idd10/18 that dysregulates NOD DC development, H. Baker, Ph.D., will characterize gene expression profiles in tolerogenic DC and congenic NOD.IddlO/]8 by high density microarray, and D. Schatz, M.D. and L. Kennedy, M.D., diabetologists, who along with Clare-Salzler will assess adverse events, diabetes management, and toxicity and safety in the R33 study.
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