Objective
The general objective of our proposal is to demonstrate the role of secretory leukocyte protease inhibitor (SLPI) in the pathophysiology of T1D.
We aim to show that:
1) Expression of SLPI in the pancreatic islets is dysregulated during the development of T1D.
2) SLPI treatment prevents the initiation of the diabetogenic response by the pancreatic neutrophils.
3) SLPI inducers are efficient therapeutic tools to prevent or cure T1D.
Background Rationale
Secretory leukocyte protease inhibitor (SLPI) is known to be expressed by pancreatic endocrine cells since more than 20 years, however its role in the physiopathology of T1D is totally unknown. SLPI is known since many years as a potent anti-inflammatory molecule and particularly the function of neutrophils. Since we and others have revealed the critical role for neutrophils in the initiation of T1D both in mouse model and patients, it appears highly relevant to explore whether SLPI could regulate the development of the disease.
Description of Project
Although many therapies targeting the adaptive immune system have been tested in patients to overcome their insulin dependence, medical research has encountered a very limited success to halt the onset or to reverse type 1 diabetes. There is an urgent need to develop innovative therapies that prevent T1D targeting the initiation of the autoimmune cascade. The discovery of very-early biomarkers, and potentially others, offers the opportunity to prevent the development of T1D by targeting the early events that initiate the diabetogenic cascade. Some years ago, we revealed the role of neutrophils in the initiation of autoimmune diabetes. raising the possibility that neutrophils may be a relevant candidate for therapeutic interventions. A physiological regulator of neutrophil activity is the secretory leukocyte protease inhibitor (SLPI), an antimicrobial peptide constitutively secreted by most mucosal epithelial cells. SLPI is as an important anti-inflammatory molecule preventing harmful excessive response from neutrophils. Noteworthy we discovered that SLPI is expressed in human and mouse pancreatic islets prompting us to investigate whether SLPI could regulate the development of T1D and, at middle term, whether SLPI inducers could be used as attractive therapeutic tools against T1D.
Anticipated Outcome
We anticipate to demonstrate:
M1: Defective pancreatic SLPI expression is associated with critical steps of development of diabetes.
M2: The gut microbiota is a regulator of pancreatic SLPI expression.
M3: SLPI regulates pancreatic beta-cell function.
M4: Pancreatic neutrophil is as a therapeutic target of SLPI.
M5: Other pancreatic immune cell types are therapeutic targets of SLPI.
M6: SLPI treatment is protective and/or curative against diabetes.
M7: SLPI inducers are efficient therapeutic tools against diabetes.
Relevance to T1D
While the role of secretory leukocyte protease inhibitor (SLPI) in the pathophysiology of T1D is an unexplored landscape, the immunomodulatory role of SLPI is well described and its immune targets identified. Importantly, these immune targets, such as neutrophils, are critical players in the development of autoimmune diabetes in mouse model and human. Consequently, our project could lead at middle term to novel therapeutic approach to prevent or cure the disease. Our project will benefit of a complementary partnership between expert laboratories providing the optimal conditions for the achievement of our project and a rapid translation of our results to the benefit of T1D patients.