Resetting self-tolerance in autoimmune diabetes by pro-resolving mediators derived from apoptotic cell efferocytosis – DIAPOP

Type 1 diabetes (T1D) is a chronic autoimmune disease mostly affecting children and young adults and resulting from the selective destruction of insulin-secreting pancreatic ß-cells by autoreactive T lymphocytes. Current treatment consists in administration of exogenous insulin, which is however imperfect, thus leading to frequent long-term degenerative diseases. We and others have shown that T1D development correlates with an overall defective immune regulation characterized by a decline in the suppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) and an increased resistance of pathogenic T cells to Treg and the modulatory cytokine TGFß. Discovering innovative ways to reset efficient immune regulation allowing durable control of ß-cell-directed autoreactive responses remains a major goal in T1D.
We have demonstrated the feasibility of controlling inflammation through the injection of apoptotic cells in several models of inflammatory and immune-mediated diseases. Apoptotic cell-based therapies use a well-known physiological mechanism called efferocytosis, i.e. the removal of apoptotic cells by macrophages, which participates in the natural resolution of inflammation through the production of pro-resolving mediators. We have recently demonstrated in several experimental models that the injection of supernatant recovered from macrophages and apoptotic cell culture (SuperMApo®, patent WO2014106666, now under clinical development through the biotech MED’INN’ Pharma) favored a long-lasting resolution of ongoing inflammation and allowed tissue healing. SuperMApo contains numerous factors such as lipids and cytokines including TGFß, which contributes to its pro-resolving effect. Based on these promising data, we postulate that administration of pro-resolving mediators may display therapeutic efficacy for resolving the anti-ß-cell inflammatory responses characteristic of T1D and provide a clinically relevant innovative alternative to current treatment.
To test this hypothesis, we will perform in-depth explorative analyses in the non-obese diabetic (NOD) mouse model to inform human studies that will be conducted in parallel. We will first assess the capacity of NOD macrophages to produce pro-resolving mediators after apoptotic cell efferocytosis. In addition to TGFß assay, we will perform a lipidomic analysis to identify the specialized pro-resolving lipid mediators (SPMs) at play in SuperMApo. The impact of specific SPMs on antigen-presenting cells (APCs) and on effector or regulatory T cells will be investigated as well. Second, we will evaluate the therapeutic efficacy of pro-resolving mediators in T1D. NOD mice will be treated with SuperMApo at different time points of disease progression i.e. from weaning to diabetes onset. Diabetes occurrence or remission will be followed and induction of efficient regulatory mechanisms (induction of tolerogenic APCs, Tregs) will be assessed by in vitro and in vivo mechanistic studies. Additionally, serum SPM profiling of NOD mice will be investigated to apprehend its usage as a potential biomarker of diabetes progression and response to SuperMApo treatment. Third, we will produce human SuperMApo from T1D patients and compare it to SuperMApo issued from healthy subjects in terms of TGFß and SPM content and impact on APC and T cell functions. In parallel, serum SPM signature of T1D patients will be determined to identify qualitative and/or quantitative differences that may, together with mouse studies, provide novel biomarkers of T1D. This project will benefit from the complementary expertise of Sylvaine You (T1D, immunotherapy, NOD mice), Sylvain Perruche (apoptotic cell-based therapy, resolution, SuperMApo®) and Charles N. Serhan (lipidomics, SPMs).