OverviewThe Immunobiology Laboratory investigates treatments that permanently eliminate the underlying disease in autoimmunity, with a focus on type 1 diabetes. Under the direction of Denise Faustman MD PhD, the laboratory has pursued the reversal of established autoimmunity as the prerequisite to successful treatment of type 1 diabetes and other autoimmune diseases.
Basic ResearchOur research found that in non-obese diabetic (NOD) mice and in diabetic humans, autoreactive (bad) T cells have a defect (disruption of the NFkB signaling pathway) that makes them sensitive to death in the presence of elevated levels of tumor necrosis factor (TNF).
In a major breakthrough published in Clinical ResearchA human clinical trial initiated in January 2008 is now being conducted based on this approach to reversing type 1 diabetes. The trial will evaluate whether treatment with BCG vaccination can eliminate the abnormal T cells in subjects with Type 1 diabetes. Most type 1 diabetic trials with immune interventions are nearly exclusively conducted in only new onset diabetics. This trial is unique in the testing is being conducted in type 1 diabetics with established diabetes. The trials are also unique in testing diabetes reversal using an inexpensive generic drug.
Denise Faustman, MD PhD, is currently Director of the Immunobiology Laboratory at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. She has spent over a decade researching the nature of the molecular defect in T-cells that results in the development of autoimmunity. This work led her to discover a novel way to treat diabetic mice, accomplishing in 2001 for the permanent reversal of established diabetes. Currently, Dr. Faustman’s laboratory is working on strategies for applying this method to treat human type 1 diabetes and to explore the applicability of this process in other autoimmune diseases, including Crohn’s disease, lupus, scleroderma, Sjogren’s syndrome, rheumatoid arthritis, and multiple sclerosis..
Dr. Faustman’s earlier research accomplishments include the first introduction of the concept of modifying the antigens on donor tissues to prevent their rejection, a scientific accomplishment that is now in human clinical trials for diverse human diseases treatable with cellular transplants. After completing her internship, residency, and fellowships in Internal Medicine and Endocrinology at Mass General, Dr. Faustman became an independent investigator at Mass General and Harvard Medical School in 1987. She is a member of the American Association for the Advancement of Science (AAAS) and frequently serves in an advisory capacity to the Institute of Medicine of the National Academies in Washington, DC.
Basic Science Programs The Immunobiology Laboratory investigates mechanisms used by the immune system to allow the survival of autoimmune T cells with the normal T cells. The laboratory is also working to identify drugs that kill the autoimmune T cells but not normal T cells. The laboratory is also working to characterize the proteins in splenic stem cells from the mouse and the human that may contribute to pancreas regeneration, a consequence of targeted T cell removal.
Autoimmunity Programs Dr. Faustman's 15 year research program on autoimmunity has utilized comparisons of proteins and cells between affected and unaffected identical human twins or disease disparate mice with autoimmune diabetes. This has led to the discovery of antigen presenting cells, defects in MHC class I presentation of self-peptides, altered NFkB activation/regulation and hampered resistance to cytokine induced apoptosis, also known as T cell death. These protein processing defects are specific to the diseased cell of the diabetic. These traits have successfully been used as therapies to permanently reverse disease in spontaneously diabetic mice. The long-term follow-up of these mice reveals restored normoglycemia is due to the regeneration of the pancreas.
Type 1 Diabetes Clinical Translational ProjectAlong with David Nathan, MD PhD, Dr. Faustman and colleagues are undertaking a program of research aimed at developing a curative therapy for human type 1 diabetes. This project consists of three major parts:
Studies in the NOD MouseStudies in the NOD mouse are being conducted to refine and optimize therapies to eliminate type 1 diabetes in humans. Dr Faustman's studies were the first to show permanent reversal of type 1 diabetes in end stage diabetic mice.
Bioassay Development and AutomationThis new bioassay (also known as a blood test) will be used to evaluate how well a potential diabetes therapy works in eliminating the "bad" T cells in type 1 diabetes. It will also be used to establish the best dose and timing of the BCG trials in humans.
BCG Human Clinical Trial will determine whether treatment with bacillus Calmette-Guerin (BCG) vaccination can eliminate the abnormal white blood cells in patients with type 1 diabetes. This trial is FDA approved.
More information about the BCG human trial:
Generic Drug Screening Program for Autoimmune DiseaseUsing the BCG human trial as a model for the re-evaluation of therapies for specific diseases, the Immunobiology Laboratory is employing a parallel strategy to host a screening program to find appropriate generic drugs that can be recycled for new clinical indications in autoimmune diseases including lupus, Crohn's disease, rheumatoid arthritis, scleroderma, multiple sclerosis, and Sjögren's syndrome.
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