Teresa P. DiLorenzo, Ph.D. – Albert Einstein College of Medicine
Type 1 diabetes occurs when the T cells of the immune system kill the pancreatic beta cells and insulin can no longer be made. Suppressing all of the T cells of the body could prevent, or even reverse, type 1 diabetes. However, suppression of all of the T cells would lead to serious side effects such as an increased susceptibility to infections and cancer. The DiLorenzo laboratory seeks to suppress only those T cells that are responsible for destroying the beta cells. These T cells bind beta cell peptides that activate the T cells and cause them to destroy the beta cells. This work hopes to harness dendritic cells to help in the silencing of the disease-causing T cells. Under certain conditions, dendritic cells can present peptides to T cells in a way that silences or eliminates them, thus rendering them harmless. A beta cell protein can be delivered to dendritic cells by coupling it to an antibody that binds to DEC-205, which is a protein present on the surface of dendritic cells. DEC-205 helps dendritic cells to take up the protein and present peptides to T cells. In this project, the beta cell protein proinsulin will be delivered to dendritic cells, because proinsulin is an important target of the disease-causing T cells. By delivering proinsulin to dendritic cells, the lab hopes to eliminate the disease-causing T cells that recognize this protein. They also hope to facilitate the development of T cells that can suppress the remaining pathogenic T cells. They will use a new disease model that they have developed which will allow them to better predict the effects of proinsulin-linked anti-human DEC-205 treatment in humans.
Denise Faustman, M.D., Ph.D. – Massachusetts General Hospital
Dr. Faustman is leading the human clinical trial program at Massachusetts General Hospital testing Bacillus Calmette-Guérin (BCG), an inexpensive generic drug, as a treatment for advanced type 1 diabetes. In a Phase I study, BCG was administered to adults who had been living with type 1 diabetes for an average of 15 years. This treatment not only helped eliminate the defective T cells that mistakenly attack and destroy the insulin-producing cells of the pancreas, it also temporarily restored the ability of the pancreas to produce small amounts of insulin. A Phase II trial is currently in process, again in individuals living with type 1 diabetes. The goal of these trials is to put advanced type 1 diabetes into remission by halting the immune attack on the pancreas and clinically improving blood sugar control. These are the first global trials using targeted immune interventions based on inducing host TNF to correct the immune defects and also performing these trials in people with disease, not only new onset subjects. The trials hope to allow individuals with type 1 diabetes to enjoy better blood sugar control and fewer diabetic complications.
Maike Sander, M.D. – University of California, San Diego
Dr. Sander’s laboratory is focused on understanding the molecular mechanisms that underlie the formation and function of the diverse cell types of the pancreas, most notably the insulin-producing beta cells, which are affected in diabetes. Her laboratory aims to identify strategies for beta cell regeneration and replacement in order to develop novel treatments for diabetes. A central focus of Dr. Sander’s research is the discovery of pathways and molecules that stimulate beta cell growth. Since residual beta cells persist in patients with type 1 diabetes, drugs that stimulate expansion of residual beta cells could have significant clinical impact. The project supported by the Foundation seeks to investigate a novel signaling pathway that Dr. Sander’s laboratory found to stimulate beta cell proliferation.
Ivana Stojanovic, Ph.D. – Institute of Biological Research “Sinisa Stankovic”
Dr. Stojanovic and her group explore novel approaches for generation of highly efficient and stable insulin-specific T regulatory cells that can be used for suppressing type 1 diabetes. The basic idea of this project is to utilize insulin-specific effector T cells (from NOD mice) that promote beta cell destruction and convert them in vitro into insulin-specific T regulatory cells using different manipulations. These manipulations include interference with specific signaling pathways crucial for effector phenotype of T cells, conversion of the metabolic state of the cells toward T regulatory phenotype, epigenetic modifications that promote activation of key genes for T regulatory cell phenotype, or combinations of the mentioned approaches. Finally, the efficiency of converted insulin-specific cells with T regulatory phenotype will be tested in the prophylactic or therapeutic time-frame in NOD mice. Hopefully, the results of this study will lead to shaping the fast and easy protocol for generation of highly-efficient and stable antigen-specific T regulatory cells for the treatment of type 1 diabetes or autoimmunity in general.
Roland Tisch, Ph.D. – University of North Carolina at Chapel Hill
The Tisch group has been studying nondepleting (ND) antibodies as an alternative approach to selectively block the activity of autoreactive T cells. The group has reported that a short course of ND anti-CD4 and -CD8 antibodies rapidly reverses diabetes in recent onset diabetic NOD mice, and prevents recurrent diabetes indefinitely while normal immunity is unperturbed. Work supported by the Foundation focuses on obtaining proof-of-principle that ND antibodies specific for human CD4 and CD8, recently established by the group, selectively suppress tissue destructive human T cells. To study these novel ND antibodies, humanized mice are being used. Experiments will define the effects of the ND anti-CD4 and CD8 antibodies on pathogenic human CD4+ and CD8+ T cells. The potency of these ND antibodies to protect human islet grafts transplanted into humanized mice will also be tested. If successful, the ND humanized anti-CD4 and -CD8 antibodies will be applicable for preventing diabetes in at risk individuals, rescue residual beta cells in new and longstanding type 1 diabetic patients, and enhance islet transplantation or other beta cell replacement strategies.