Raimondi, Giorgio , PhD
Modulation of T cell reactivity by inflammatory cytokines and promotion of pancreatic islets transplant tolerance
General Research Subject: Type 1 Diabetes
Type of Grant: Junior Faculty
Project Start Date: January 1, 2010
Project End Date: December 31, 2013
Type 1 diabetes is a chronic metabolic disorder that results from autoimmune-mediated destruction of insulin-secreting beta-cells in the islet of Langerhans of the pancreas. With the advent of the 'Edmonton protocol,' pancreatic islet transplantation has resurged as a possible therapeutic approach. However, long-term function of the transplanted islets is difficult to accomplish. Additionally, the side effects of prolonged immunosuppression (required by the protocol) compromise the patient's quality of life. There is thus an urgent need to develop safe and successful alternative therapies.
The main focus of the current proposal is to understand how inflammation, induced by the transplantation of pancreatic islets, negatively affects inherent immune regulatory mechanisms and contributes to transplant rejection. Using mouse models and multi-disciplinary approaches, the PI will test the therapeutic potential of specific recipient cells, the regulatory T cells [Treg] (so called as they possess immunosuppressive capacities), to re-train the patient's immune system to accept the graft. The PI will also investigate the molecular mechanisms involved in the modulation of immune reactivity by inflammation, that the PI hypothesizes can be blocked to improve the protective function of Treg.
The final goal of this study is to develop a therapeutic protocol, based on the use of the patient's own cells in combination with treatments that enhances immuno-modulation, to promote acceptance of transplanted pancreatic islets that will not depend on life-long immunosuppression.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project focuses on delineating a strategy to instruct the patient immune system to accept the presence of transplanted insulin-producing pancreatic islets that might derive from unrelated donors; an area commonly referred to as 'beta cell replacement'.
In particular, this approach is targeted to the treatment and cure of diabetes. It aims at providing the diabetic patient with a new tissue that will produce the vital amount of insulin, but will not be destroyed/rejected over time. If successful, this project will define the conditions for deviating from the current need of life-long immunosuppression required to protect a transplanted organ (and commonly associated to significant side effects).
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project is based on our most recent understanding of the principles that govern the immune system. It is designed to define the conditions that will allow to re-train the patient immune system (by using her or his own cells) and allow the long-term survival of transplanted pancreatic islets. The proposed therapeutic protocol belongs to the category of personalized medicine, an approach that is recognized to be the most advantageous for every single patient although not easy to be implemented on a large scale. However, the investigated therapy will rely on a standardized procedure and this will allow a broad application that could be clinically implemented.
If successful, this project will define a therapy that will free the diabetic patient from daily injections of insulin without the need of life-long immunosuppression (required by currently used protocols). This will represent a giant leap in the improvement of a patient life-style.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I believe that true scientific accomplishments rely on the successful application of the knowledge gained through dedicated investigations (and perseverance).
Through the past years, an impressive amount of knowledge has been accrued and has helped clarifying some of the principles that govern the behavior of the immune system. I believe that this knowledge can now benefit the design of successful therapeutic protocols for the promotion of transplant tolerance. This benefit can certainly extend to diabetic patients, for which the transplantation of pancreatic islet represent a valid, but still unmet, solution. Finding the conditions to establish tolerance and free the diabetic patient from the specter of having to substitute life-long insulin administration with life-long immunosuppression (required by current transplant protocols) will maintain a central role in my research efforts.
In what direction do you see the future of diabetes research going?
I personally believe the future of diabetes research is associated to a tight integration of stem-cell based research and immunological research. The former will provide the tools to generate perfectly functional insulin-producing tissues. The latter will define the necessary protocols to induce long-lasting tolerance to said products.
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