Therapeutic Interventions to Modulate the Anti-Islet Response in Autoimmune Diabetes
- Author(s): Penaranda, Cristina
- Advisor(s): Bluestone, Jeffrey A
- et al.
Autoimmunity is caused by a loss of tolerance and results in an imbalance in immune homeostasis, particularly regulatory versus effector activities against self-antigens. Therapeutic approaches for the treatment of autoimmune diseases need to attack key components of the immune response to restore this balance. In this body of work I have worked toward this end using three distinct approaches to in the context of type 1 diabetes using the non-obese diabetic mouse model. First, I used a global approach to shift the balance of regulatory to effector T cells. I show that non-Fc receptor binding anti-CD3 monoclonal antibody treatment, which has been previously shown to reserve diabetes, alters the ratio of effector to regulatory T cells (Tregs) due to preferential depletion of activated effector T cells. In addition, treatment with anti-CD3 mAbs leads to increased expression of Helios in Tregs, suggesting stabilization of Tregs may account to the extended efficacy of this antibody. Second, I used FTY720 to "lock" lymphocytes in the lymph node and pancreas thereby isolating these locations. I show that continuous treatment with FTY720 prevents diabetes development but treatment withdrawal leads to rapid onset of disease. Furthermore, morphological changes that occur during the development of the disease in control and treated mice show that tertiary lymphoid organ development and their subsequent destruction correlate with disease progression suggesting that islet destruction maybe be due to loss of TLO integrity. Finally, I used a targeted approach to directly alter memory T cells. I show that treatment of NOD mice with anti-IL-7Rα monoclonal antibodies prevents and cures diabetes and induces expression of the inhibitory receptor PD-1 on memory T cells. Moreover, inhibiting the interaction of PD-1 with its ligand PD-L1 restores disease in cured mice. The data suggest that IL-7 contributes to the pathogenesis of autoimmune diabetes by keeping memory T cells in a functionally competent, tolerance-resistant state, and uncover a novel link between IL-7 and the PD-1/PD-L1 tolerance pathway. Together the data reveal biological the mechanisms at the basis of therapeutic interventions aimed at preventing or reversing diabetes through manipulating the immunological pathways underling the pathogenesis of the disease. The insights will improve our ability to translate these interventions to the treatment of patients with type 1 diabetes.