Objective
The final objective of the proposal is to define, by a state-of-the-art genetical engineer technology, if regulatory DC can be used to modulate pathogenic responses and promote regulatory cells in T1D.
Background Rationale
The incidence of type 1 diabetes (T1D) has increased markedly over the last 3-4 decades. T1D results from a failure to maintain immune tolerance to islet antigens. Therapies targeting polyclonal pathogenic T cells or enhancing the number of regulatory T cells have been shown to alter disease course and preserve beta cell mass only short-term, providing evidence that targeting either pathogenic or regulatory cells is not sufficient to cure T1D, thus specific immunoregulatory strategy is needed to control diabetogenic responses and restore tolerance in T1D. An attractive strategy to concomitantly inhibit pathogenic cells and promote regulatory cells to restore tolerance in T1D is the adoptive transfer of a specific subset of cells (tolerogenic DC). In the past years we focused our research interest on IL-10-producing tolerogenic DC, showing that these cells are critical involved in promoting tolerance via regulatory cells. More recently, we established a method to engineer DC to over-express IL-10, resulting cells effectively modulate T cell responses and promote regulatory cells in healthy subjects. We now propose to validate our strategy in T1D patients. If successful, our study will help to the identification of new therapeutic approaches to cure T1D.
Description of Project
Type 1 diabetes (T1D) is a chronic autoimmune disease resulting in progressive destruction of beta cells. Insulin replacement therapy is life-saving but does not cure T1D pts. Alternative therapies, based on the injection of specific beta-cell-derived antigens (immunotherapy), have been shown to alter the disease course only short-term. Therefore, a successful strategy to prevent disease development in at risk subjects or to cure T1D patients still represents an unmet need. With this proposal we plan to define the potential role of a specific cell subsets (tolerogenic DC) to modulate pathogenic cell responses and promote regulatory cells in vitro using cells isolated from T1D pts. To this end, we bring together recognized expertise in tolerogenic DC and IL-10-mediated tolerance and in T1D together with direct access to several T1D patients at different disease stage.
Anticipated Outcome
Out of our state-of-the art approach we expect to identify innovate cell-based approach for the cure of T1D.
Relevance to T1D
A successful strategy to prevent disease development in at risk subjects or to cure diabetic patients still represents an unmet need. Thus far, several approaches have been applied to subjects at risk or to T1D patients with limited success, since they only delay disease onset. If successful, the proposed strategy will open new perspectives for the development of safe personalized therapies for subjects at risk of T1D, or diabetic pts at early onset.