Antigen specific regulatory B cells: a new therapy for type 1 diabetes
General Research Subject: Type 1 Diabetes
Focus: Complications\Nephropathy, Immunology, Transplantation
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
The goal of our proposal is to establish novel and feasible cures for Type 1 Diabetes (T1D) and its complications. The treatments proposed will be tested in murine model of diabetes and diabetic complications. (i) Antigen specific regulatory B cells: a new therapy for T1D. A population of B lymphocytes, called regulatory B cells (Bregs), can suppress autoimmune response. The aim of the proposal is to understand the origins, characteristics, functions and Ag-specificity of naturally occurring Bregs. Naturally occurring Ag-specific Bregs will be then expanded, generated de novo and finally B-cells precursors will be reprogrammed into Bregs, paving the immunobiological basis for a Breg-based cell therapy in T1D. (ii) IL-21: an anti-tolerogenic cytokine in islet transplantation. Pancreatic islet transplantation in T1D normalizes glycemic control and halts diabetes complications. Unfortunately long-term graft survival is poor mainly because of immune activation. IL-21 is a key molecule in resistance to tolerance, genetically reprogramming and inactivating regulatory cells. The mechanisms behind IL-21 action will be defined and IL-21 will be targeted as a proof-of-principle for future anti-IL-21-based therapy in clinical islet transplantation. (iii) B7.1 on podocytes: a new therapeutic target for diabetic nephropathy. Diabetic nephropathy (DN) is a serious complication that leads to renal failure, dialysis, increased mortality. The first major event in DN is death of podocytes, crucial renal cells. Podocytes death is preceded by B7.1 over-expression. In this project a new drug, CTLA4-Ig, will be used to target B7.1 expressed by podocytes, providing the rationale for developing CTLA4-Ig-based therapeutic approaches for DN.
Mentor: Fiorina, Paolo, M.D., Ph.D. Postdoctoral Fellow: Bassi, Roberto
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Historically, approaches aiming to cure T1 D have made a negligible number of patients insulinindependenT. Our hypothesis is that a population of B lymphocytes may arise under certain conditions, thus abrogating the onset of autoimmune diabetes. In this grant, we are proposing the development of a novel therapeutic strategy for T1 D that has never been offered before: the establishment of an antigen-specific Breg-based cell therapy for T1 D.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our project if successful will be seen as a new cure for type 1 diabetes. If we can expand and newly generate in vitro antigen specific regulatory B cells (means anti inflammatory) we can then infuse them in patients with new onset diabetes and cure the patients.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Beginning in my early years of medical school, I have been fascinated by diabetes and its complications, and how a successful transplantation (e.g. pancreas or islet) can prevent the well-known ravages of diabetes. In 2004, I joined the Transplantation Research Center at Children's Hospita1JBrigham and Women's HospitallHarvard Medical School, directed by Dr. Mohamed Sayegh, to address the basis of the immunobiology of diabetes. My research fellowship at the Brigham allowed me to expand my research interests and to improve my expertise in the field of immunobiology. After becoming a faculty member at Harvard Medical School in 2006 and Assistant Professor at Harvard Medical School in 2009, I envision finding new immune-based strategies to cure diabetes and prevent islet allograft rejection. The skills and expertise gained during the period of this grant will foster my career path in the field of immunology. In particular, this grant will be a cornerstone for my research endeavors, providing the financial support necessary to continue with my research activities, and ultimately will help me to develop my dream: to find a feasible and safe cure for type 1 diabetes.
In what direction do you see the future of diabetes research going?
I can see more effort in developing translational science and less in publishing fancy research made for scientist more than for patients.
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