RESEARCH SUMMARY

Approximately 5-10% of the population in the developed world is affected by at least one of >80 autoimmune disorders; these chronic, debilitating diseases have an enormous social and economic impact. To analyse the mechanisms that operate in autoimmune diseases and identify new drug targets and therapeutic strategies, we study intracellular signaling pathways that induce autoimmunity or inflammation when hyperactivated, as well as the mechanisms that maintain peripheral tolerance in the immune system.

Our lab studies several aspects of the initiation and progression of autoimmune disease in murine models:

1) the role of p110 PI3K in T cell activation and autoimmunity,

2) the role of p110 PI3K in secondary lymphoid organs and in the onset/ progression of immune responses and autoimmunity,

3) how p85 PI3K contributes to CD28 costimulation in the activation of effector and regulatory T cells, and how its absence affects rheumatoid arthritis onset and development, and

4) crosstalk between negative regulators of T cell activation that enforce T cell quiescence and PI3K isoforms, and how crosstalk affects autoimmunity.

NKG2D in autoimmunity and tumour immunotherapy

NKG2D is an activating receptor expressed by natural killer (NK) cells and T cells; it is implicated in immune responses to infections and tumours and in autoimmunity. NKG2D ligands are not expressed by most normal cells but are up-regulated on numerous tumor cell . In addition, their inappropriate expression in certain tissues can trigger or exacerbate autoimmune disease. In fact, implicating NKG2D and its ligands in the pathogenesis of several autoimmune diseases.

Our projects study the role of NKG2D in autoimmunity and tumour immunotherapy:

1) NKG2D associates with the adaptor protein DAP10, which binds and activates the PI3K p85 subunit. We are analyzing the specific contribution of each PI3K isoform to cell activation via NKG2D.

2) To study the contribution of NKG2D to the initiation/progression of autoimmune processes, we analyse NKG2D ligand expression in several mouse models of autoimmune disease, and study the correlation between ligand expression and disease onset/severity.

Nanomedicine as a therapeutic approach for treating cancer and autoimmune disease

Radiotherapy- and chemotherapy-based cancer treatments affect both tumours and healthy tissue, leading to a search for more specific ways to fight tumours. Tumour immunotherapy is a promising treatment strategy, as it could enhance the immune system’s natural capacity to control tumour development. Studies suggest IFN-γ as effective in tumour elimination, although it is difficult to deliver an appropriate cytokine dose to the tumour without causing toxicity to surrounding tissues. Directed targeting to the tumour could improve the efficiency of its delivery, increasing local dosage without augmenting the systemic concentration.

Nanotechnology provides a means to target drugs using superparamagnetic iron oxide nanoparticles as drug delivery systems in conjunction with a magnetic field, applied externally or implanted internally. In mouse models of cancer, we tested uniform dimercaptosuccinic acid (DMSA)-coated monodisperse magnetic nanoparticles (MNP) as a delivery system for IFN-γ. IFN-γ-adsorbed DMSA-coated MNP were targeted to the tumour site by applying an external magnetic field. We found nanoparticle accumulation and cytokine delivery at the tumour site, which led to increased T cell and macrophage infiltration and promoted an antiangiogenic effect, resulting in a notable reduction in tumour size.

Our findings show that these nanoparticles can be an efficient in vivo drug delivery system for tumour immunotherapy. We are also developing and validating a nanoparticle-based system for controlled, localized release of small interfering RNA (siRNA), microRNA, antagomirs and aptamers for specific gene silencing and cell targeting. for treatment of cancer and autoimmunity.