The field of immunology has advanced tremendously over the last 40 years, with seminal findings that have guided the development of powerful new therapies. However, the ability to induce safe and long-lasting antigen-specific tolerance has remained elusive. A therapy that could prevent the immune system from aberrantly destroying self-tissues, without impairing its capacity to eliminate dangerous pathogens, would be transformative for the treatment of autoimmune diseases. In addition, such a therapy could also greatly advance the field of organ transplantation by inducing antigen-specific tolerance to prevent graft rejection.
In this thesis, the overarching goal was to develop a biomaterial delivery system that could recruit and program antigen presenting cells, specifically dendritic cells (DCs), in a non-inflammatory environment, allowing them to orchestrate downstream immune responses that are both antigen-specific and tolerogenic. Gold nanoparticles (AuNPs) were used to deliver a DC recruitment factor, GM-CSF, from an injectable alginate based hydrogel. Both the release of GM-CSF and the physical porous structure of the gel were tuned to achieve effective recruitment of a highly enriched population of DCs. The ability of this system to generate downstream antigen-specific responses in T cells was demonstrated in a mouse model of type 1 diabetes (T1D). Additionally, the DCs recruited in this system were characterized and found to exhibit features that would make them competent to induce tolerance. Finally, a new method was developed for localized delivery and cell-triggered release of a peptide antigen from the material. Over time, antigen-specific T cells expressing FoxP3, a marker of regulatory T cells, which are key mediators of immune tolerance, accumulated in the gels. Together, these findings demonstrate that it is possible to recruit and program DCs in a non-inflammatory context, and that these DCs can induce downstream antigen-specific responses. These promising results suggest that this system may be able to promote tolerance in the setting of autoimmune disease.
This thesis advances the field of immunomodulatory biomaterials by introducing new methodologies for precisely recruiting and manipulating DCs in a non-inflammatory context. This work may provide the basis for further development of a highly effective and therapeutic antigen-specific tolerogenic vaccine.
|Advisor:||Mooney, David J.|
|Commitee:||Joshi, Neel S., Wucherpfennig, Kai W.|
|Department:||Engineering and Applied Sciences|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 75/10(E), Dissertation Abstracts International|
|Subjects:||Biomedical engineering, Immunology|
|Keywords:||Antigen-specific, Biomaterials, Dendritic cells, Immunotherapy, Tolerance, Treg|
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