Harnessing natural autoimmune regulation for the treatment of type 1 diabetes
Date
2011
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Abstract
In Type 1 Diabetes (TlD), multiple genetic and environmental factors contribute to the loss of tolerance towards pancreatic ?? cells, resulting in a CD4+ and CDS+ T cellĀdependent autoimmune process that leads to complete destruction of insulin-producing ?? cells. The non-obese diabetic (NOD) mouse model manifests several of these aspects of the disease and has thus been instrumental in studying the immunobiology of TlD. Using this model, we set out to analyze the natural immunoregulatory pathways that underlie TlD resistance in mice that are otherwise predisposed to develop disease. We approached this problem from two different angles- by studying tolerance pathways in NOD mice rendered diabetes-resistant by the expression of protective MHC class II molecules, I-Ab and I-E, and by investigating the mechanism of action of an antigen-specific immunotherapy in blunting TlD. Our findings from studying I-Ab_ and I-E-transgenic mice led us to propose that protective MHC class II molecules afford dominant resistance to TlD through their interaction with MHC-promiscuous, diabetogenic TCRs, endowing them with the opportunity to differentiate into regulatory T cells and acquire enhanced suppressive function, or undergo central tolerance in the thymus. In addition, we demonstrated that dendritic cell expression of the protective MHC class II molecules is critical and sufficient to achieve TlD-inhibitory effects. On the other hand, through dissecting the mechanisms of action of a novel antiĀTlD vaccine, consisting of?? cell-associated antigenic peptide-MHC-coated nanoparticles (pMHC-NP), we unveiled a subset of antigen-specific, memory-like, CDS+ regulatory T cells that arise as a negative feedback circuit in response to chronic autoimmunity. Through amplifying this negative feedback circuit, pMHC-NP effectively prevented and reversed TlD without compromising the body's general immune response. We propose that similar negative feedback mechanisms are at work in other autoimmune settings, where pMHC-NPs may be equally applicable for the treatment of disease. In summary, we described two naturally existing regulatory pathways used by Nature to tackle autoimmunity - one that is designed to eliminate or convert autoreactive T cells, and one that manifests itself after the onset of autoimmunity as an auto-regulatory feedback loop. In both cases, the very features of the autoimmune process or its participants are exploited in an attempt to restore the immune system to its healthy state.
Description
Bibliography: p. 253-301.
A few pages are in colour.
Includes copy of Certification of Animal Protocol Approval forms. Original with original copy of Partial Copyright Licence.
A few pages are in colour.
Includes copy of Certification of Animal Protocol Approval forms. Original with original copy of Partial Copyright Licence.
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Citation
Tsai, S. (2011). Harnessing natural autoimmune regulation for the treatment of type 1 diabetes (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/3949