Tissue-specific cytokine-based immunotherapy to treat type 1 diabetes Public Deposited

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  • March 20, 2019
Creator
  • Manzoor, Fatima
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Type 1 diabetes (T1D) is characterized by the T cell-mediated destruction of the insulin-producing β cells. Progressive loss of β cell mass results in the inability to control blood glucose levels, leading to hyperglycemia. Although other immune cells such as B cells, dendritic cells (DC), and macrophages also contribute to β cell destruction, the anti-islet autoimmune response is driven primarily by pathogenic effector T cells (Teff). Maintaining a balance between Teff and suppressive Foxp3-expressing regulatory T cells (Foxp3+Treg) is important in preserving self-tolerance in the periphery. In T1D, the inflammatory response in the islets is skewed towards proliferation and survival of pathogenic Teff, due in part to defects within Foxp3+Treg. To reestablish tolerance and suppress the autoimmune response, the Foxp3+Treg pool needs to be augmented, both qualitatively and quantitatively. Our first study describes the role of IL-35 in suppressing autoreactive Teff in pre-diabetic NOD mice. Ectopically expressing IL-35 using an adeno-associated virus (AAV) vector protected NOD female mice at a late preclinical T1D stage from diabetes onset. This protection from diabetes was characterized by a reduction in overall islet conventional T cell numbers and proliferative status, as well as a reduction in islet-resident DC and IFNγ-producing CD4+ Teff. Although protection from disease was not due to an increase in islet Foxp3+Treg, ectopic IL-35 induced a qualitatively distinct pool of Foxp3+Treg marked by high expression of cytotoxic-lymphocyte antigen-4 (CTLA-4), a molecule necessary for contact-mediated suppression. Importantly, we found that using a pancreas-tropic capsid serotype of AAV restricted the potent suppressive function of IL-35 to Teff in the islets; making it a promising immunotherapy tool to treat T cell mediated immune disorders, including T1D. The aim of our second study was to establish an approach to enhance human FOXP3+Treg in a tissue-specific manner. Reports demonstrate that FOXP3+Treg derived from T1D patients exhibit various defects, and sensitivity of T1D-derived Teff to FOXP3+Treg-mediated suppression is reduced. Accordingly, we determined whether ectopic human IL-2 expression using AAV gene transfer expands FOXP3+Treg in humanized mice engrafted with T1D and non-T1D-derived T cells. NOD.RagnullIL2rγnull (NRG) mice injected with PBMC derived from T1D and non-diabetic (ND) donors were readily reconstituted with human CD4+ and CD8+ T cells, and β cell-specific human IL-2 increased pancreatic FOXP3+Treg in both T1D and non-T1D-derived humanized mice.
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  • In Copyright
Advisor
  • Maile, Robert
  • Su, Maureen
  • Tisch, Roland
  • Matsushima, Glenn
  • Su, Lishan
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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