Interleukin-2 based therapy for the treatment of Type I Diabetes
Public Deposited- Last Modified
- March 21, 2019
- Creator
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Johnson, Mark Christopher
- Affiliation: School of Medicine, Department of Microbiology and Immunology
- Abstract
- Type I diabetes (T1D) is an autoimmune disease characterized by the destruction of the insulin producing beta cells. Although multiple cell types contribute, the main mediators of beta cell destruction are pathogenic Th1 effectors (Teff). Preferential differentiation and expansion of pathogenic Teff is partly attributed to dysregulation of FoxP3+ regulatory T cells (FoxP3+ Treg). Consequently, current strategies for treating T1D have focused on re-establishing the balance between Teff and FoxP3+ Treg. The aims of the studies described are to: i) analyze the temporal effect of IL-2 on FoxP3+ Treg and disease incidence, ii) to test whether beta cell-specific IL-2 secretion prevents T1D by expanding islet resident FoxP3+ Treg, and iii) to investigate the synergistic ability of T cell immunotherapies to induce remission in non obese diabetic (NOD) mice. Our first study demonstrates that NOD mice congenic for a C57BL/6-derived disease-resistant Il2 allele (NOD.idd3) have a reduced incidence of T1D compared to NOD mice. Diabetes protection in NOD.idd3 mice was attributed to elevated systemic IL-2 levels over time that maintained more suppressive FoxP3+CD62L+ Treg in the islets and draining pancreatic lymph nodes (PLN). Therefore, our findings underscore the relationship between systemic IL-2 expression, FoxP3+ Treg function in vivo and disease incidence. Our second study investigated the ability of islet-localized IL-2 to prevent diabetes in NOD mice. We found that vaccination with a recombinant adeno-associated viral vector (rAAV) expressing IL-2 under control of the mouse insulin promoter (AAV8mIP-IL2) prevented diabetes. Protection correlated with increased number and function of islet FoxP3+ Treg. Importantly, the effects of AAV8mIP-IL2 vaccination were islet specific. This shows that IL-2 expression driven by AAV8mIP-IL2 protected NOD mice, highlighting the potential of targeted immunotherapeutic treatment. Our third study examined the ability of AAV8mIP-IL2 to work synergistically with other immunotherapies to induce remission. Co-administration of AAV8mIP-IL2 to diabetic NOD mice receiving nondepleting antibodies specific for the T cell co-receptors, CD4 and CD8, induced long-term remission. Notably, IL-2 levels in long-term remission NOD mice were elevated and maintained throughout treatment. Collectively, this shows that islet-localized IL-2 driven by rAAV vectors provides a viable immunotherapeutic approach for treating human patients.
- Date of publication
- May 2013
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Tisch, Roland
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill
- Graduation year
- 2013
- Language
- Publisher
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