Objective
This project will develop an innovative workflow to screen T1D candidate drugs in in-vitro autoimmune T-cell killing assays comprising three autoimmune model systems that share common disease pathways: T1D (using iPSC-derived beta cells), thyroiditis (using thyrocyte lines), and vitiligo (using melanocyte lines). Molecules that perform well in each arm of this multiorgan screen will be more likely to succeed in clinical translation and could potentially be applied across multiple autoimmune diseases.
Background Rationale
Type 1 diabetes (T1D) has many close similarities and is associated with other autoimmune diseases like Hashimoto’s thyroiditis and vitiligo. Conditions for developing these diseases are shared: T cells become inappropriately programmed to attack tissue-specific proteins (autoantigens) critical to the function of the target cells. In T1D, T cells attack preproinsulin (PPI) in beta cells; in Hashimoto’s thyroiditis they attack thyroglobulin (TG) in thyrocytes; and in vitiligo, they attack tyrosinase (TG) in melanocytes. These autoantigens (PPI, TG, and TYR) also share key features that give hints about how the diseases develop: they are all highly expressed, and produced in conjunction with a signal peptide byproduct that is discarded at a very high rate. Fragments of these signal peptides are presented to the immune system at very high levels, making them frequent mediators of the autoimmune response.
Description of Project
Type 1 diabetes (T1D) displays many close similarities and is often associated with other autoimmune diseases like Hashimoto’s thyroiditis and vitiligo. Conditions for developing these diseases are shared: T cells become inappropriately programmed to attack tissue-specific proteins (autoantigens) critical to the function of the target cells. In T1D, T cells attack preproinsulin (PPI) in beta cells; in Hashimoto’s thyroiditis they attack thyroglobulin (TG) in thyrocytes; and in vitiligo, they attack tyrosinase (TG) in melanocytes. These autoantigens (PPI, TG, and TYR) also share key features that give hints about how the diseases develop: they are all highly expressed, and produced in conjunction with a signal peptide byproduct that is discarded at a very high rate. Fragments of these signal peptides are presented to the immune system at very high levels, making them frequent mediators of the autoimmune response.
In this project, we aim to leverage the overlap between thyroiditis, vitiligo, and T1D to accelerate the development of beta-cell-protective/immunomodulatory therapies. We will develop a preclinical drug screening workflow that evaluates drug candidates in terms of their ability to inhibit the autoimmune process and boost survival in beta cells under siege by PPI-targeting T cells, in thyrocytes being attacked by TG-targeting T cells, and in melanocytes facing TYR-targeting T cells. This workflow will improve T1D drug screening by creating better short-lists of robust candidates that work against the most important shared features of autoimmune pathogenesis and may have clinical relevance for multiple autoimmune diseases beyond T1D.
This approach requires highly specialized immune tools that we have mastered to engineer. First, we need human cell lines that accurately recapitulate target cell features in the setting of disease development: they should express high levels of the autoantigen of interest, present that autoantigen at very high levels specifically under inflammatory conditions, and have the right HLA genotype to match and be recognized by the attacking T cells. We have engineered beta cell, thyrocyte, and melanocyte lines suitable for this purpose. Second, we are developing human T cells that are specific for fragments of the signal peptide of those autoantigens being presented on the HLA proteins expressed by the target cells. With these specialized immune tools – the engineered cell lines and T cells – we are able to assess the autoimmune process on both the “attacking” T-cell side and the “defending” target cell side. This allows us to screen drug candidates for their ability to inhibit the cytotoxic T cell killing that causes the autoimmune disease.
Anticipated Outcome
In this project, we aim to leverage the overlap between thyroiditis, vitiligo, and T1D to accelerate the development of beta-cell-protective/immunomodulatory therapies. We will develop a preclinical drug screening workflow that evaluates drug candidates in terms of their ability to inhibit the autoimmune process and boost survival in beta cells under siege by PPI-targeting T cells, in thyrocytes being attacked by TG-targeting T cells, and in melanocytes facing TYR-targeting T cells. Genes implicated in the protective effects will be analyze to identify possible shared modes of action.
This workflow will improve T1D drug screening by creating better short-lists of robust candidates that work against the most important shared features of autoimmune pathogenesis and may have clinical relevance for multiple autoimmune diseases beyond T1D.
Relevance to T1D
This novel approach will lay the foundation for accelerated discovery of novel treatments for T1D. Molecules that perform well in each arm of this multiorgan screen will be more robust candidates to prioritize for further clinical development. The potential applicability of these treatments to other autoimmune diseases will further enhance their translational potential.